Diagnosis and Treatment

of Patients with early and advanced Breast Cancer

Herausgegeben von der Kommission Mamma
(vertreten durch: Wolfgang Janni)
der Arbeitsgemeinschaft Gynäkologische Onkologie e. V.
in der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe e. V.
sowie in der Deutschen Krebsgesellschaft e. V.

Table of Contents
Levels of Evidence and Grades of Recommendation
Abbreviations
Members of the AGO Breast Commission
Conflict of Interest
How to Use these Slides Zuckschwerdt Verlag GmbH
München
Editor & Copyright

2020 vs 1
Table of Contents Diagnosis and Treatment of Patients
Levels of Evidence and Grades of Recommendation
Abbreviations
with early and advanced Breast Cancer
Members of the AGO Breast Committee
Conflict of Interest
Guidelines of the AGO Breast Committee
How to Use these Slides
Editor & Copyright

1) Options for Primary Prevention: Modifiable Lifestyle Factors

2) Breast Cancer Risk and Prevention
3) Early Detection and Diagnosis
4) Pathology
5) Prognostic and Predictive Factors
6) Lesions of Uncertain Malignant Potential (B3) – ADH, LIN, FEA, Papilloma, Radial Scar
7) Ductal Carcinoma in situ (DCIS)
8) Breast Cancer Surgery Oncological Aspects
9) Oncoplastic and Reconstructive Surgery
10) Adjuvant Endocrine Therapy in Pre- and Postmenopausal Patients
11) Adjuvant Cytotoxic and Targeted Therapy
12) Neoadjuvant (Primary) Systemic Therapy
13) Adjuvant Radiotherapy
14) Supportive Care and Management of Side Effects
15) Breast Cancer: Specific Situations
16) Breast Cancer Follow-Up
17) Loco-Regional Recurrence
18) Endocrine Therapy of Metastatic Breast Cancer
19) Chemotherapy with or without Targeted Drugs in Metastatic Breast Cancer
20) Osteooncology and Bone Health
21) Specific Sites of Metastases
22) CNS Metastases in Breast Cancer Zuckschwerdt Verlag GmbH
23) Complementary Therapy Survivorship München
24) Gynecological Issues in Breast Cancer Patients
25) Health Literacy and Communication

2020 vs 1
 Oxford Levels of Evidence (LOE)
LOE Therapy/Prevention, Aetiology/Harm Prognosis
© AGO e. V.
in der DGGG e.V.
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1a Systematic review (with homogeneity) of randomised Systematic review (with homogeneity) of inception cohort studies;
in der DKG e.V. controlled trials clinical decision rule validated in different populations

Guidelines Breast 1b Individual randomised controlled trials (with narrow Individual inception cohort study with > 80% follow-up; clinical
Version 2020.1 Confidence Interval) decision rule validated in a single population

1c All or none All or none case-series

2a Systematic review (with homogeneity) of cohort studies Systematic review (with homogeneity) of either retrospective cohort
studies or untreated control groups in randomised controlled trials

2b Individual cohort study (including low quality randomised Retrospective cohort study or follow-up of untreated control patients
controlled trials; e.g., <80% follow-up) in a randomised controlled trials; Derivation of clinical decision rule or
validated on split-sample only

2c "Outcomes" Research; Ecological studies "Outcomes" Research

3a Systematic review (with homogeneity) of case-control

studies
3b Individual Case-Control Study
www.ago-online.de
4 Case-series (and poor quality cohort and case-control Case-series (and poor quality prognostic cohort studies)
studies)

5 Expert opinion without explicit critical appraisal, or based on Expert opinion without explicit critical appraisal, or based on
physiology, bench research or "first principles" physiology, bench research or "first principles"
 Oxford Grades of Recommendation (GR)
© AGO e. V.
in der DGGG e.V.
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A consistent level 1 studies
in der DKG e.V.

Guidelines Breast
Version 2020.1

B consistent level 2 or 3 studies or extrapolations from

level 1 studies

C level 4 studies or extrapolations from level 2 or 3

studies

D level 5 evidence or troublingly inconsistent or

www.ago-online.de
inconclusive studies of any level
 AGO Grades of Recommendation
© AGO e. V.
in der DGGG e.V.
++ This investigation or therapeutic intervention is highly beneficial for patients,
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in der DKG e.V.
can be recommended without restriction, and should be performed.
Guidelines Breast + This investigation or therapeutic intervention is of limited benefit for patients
Version 2020.1
and can be performed.
+/- This investigation or therapeutic intervention has not shown benefit for
patients and may be performed only in individual cases. According to current
knowledge a general recommendation cannot be given.
- This investigation or therapeutic intervention can be of disadvantage for
patients and might not be performed.
-- This investigation or therapeutic intervention is of clear disadvantage for
patients and should be avoided or omitted in any case.

www.ago-online.de
 Abbreviations – I
© AGO e. V. 10+ LN ≥ 10 tumor infiltrated axillary lymph nodes
in der DGGG e.V.
sowie A Doxorubicin
in der DKG e.V. ABCSG-8 Austrian Breast- and Colorectal Cancer Study Group
AC Doxorubicin / cyclophosphamide
Guidelines Breast
ACR American College of Radiology
Version 2020.1
AD Doxorubicin / docetaxel
ADH Atypical ductal hyperplasia
adj. A Adjuvant doxorubicin
AGO Arbeitsgemeinschaft Gynäkologische Onkologie e.V.
AH Atypical hyperplasia
AI, AIs Aromatase inhibitor(s)
ALH Atypical lobular hyperplasia
Alip Liposomal doxorubicin
ALND Axillary lymph node dissection
AML Acute myeloid leukemia
ANC Absolute neutrophil count
AP Doxorubicin / paclitaxel
ARNO Arimidex® versus Nolvadex® (trial on adjuvant therapy)
ASCO American Society of Clinical Oncology
ATAC Arimidex®, Tamoxifen Alone or in Combination Trial
autolog LADO Autologous latissimus dorsi muscle flap
AxDiss Axillary dissection
www.ago-online.de
BC, bc Breast cancer
Bc-spec Breast cancer specific
BCS Breast conserving surgery
BCSF Breast cancer-free survival
 Abbreviations – II
© AGO e. V. BCT Breast conserving therapy
in der DGGG e.V. BIG 1-98 Breast International Group
sowie bilat. Bilateral
in der DKG e.V. Bip TRAM Bi-pedicled TRAM
BMD Bone mineral density
Guidelines Breast BMI Body mass index
Version 2020.1 BR Breast reconstruction
BRCA Breast cancer
BS-BM Basic score for brain metastases (Viani GA et al. BMC Cancer. 2007;7:53)

C Cyclophosphamide
CA Cancer
CAF Cyclophosphamide / doxorubicin / 5-fluorouracil
Castr. Castration
CB Clinical benefit
CBC Contralateral breast cancer
CBE Clinical breast examination
Cc CCNU (chemotherapy)
CC Capsular contracture
CEA Carcinoembryonic antigen
CEF Cyclophosphamide / epirubicin / 5-fluorouracil
CEF 120 F “Canadian FEC” (“Levine”): Cyclophosphamide/ epirubicin 120 / 5-fluorouracil
CF Cyclophosphamide / 5-fluorouracil
www.ago-online.de CGF Cyclophosphamide / gemcitabine / 5-fluorouracil
CGF Cyclophosphamide / gemcitabine / 5-fluorouracil
CHF Congestive heart failure
CHT Chemotherapy
 Abbreviations – III
Circ. Circulating
© AGO e. V.
Cis / Capec Cisplatin / capecitabine
in der DGGG e.V. CisG Cisplatin / gemcitabine
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CISH Chromogenic in situ hybridization
in der DKG e.V.
Cl Confidence interval
Guidelines Breast CMF Cyclophosphamide / methotrexate / 5-fluorouracil
Version 2020.1 CMFP CMF + prednisolon
CNS Central nervous system
CREC Cardiac Review Evaluation Committee
CT Computed (assisted) tomography
CTR Control (group)
CTX Chemotherapy
cum. Dose Cumulative dose
CUP Cancer of unknown primary
CYP2D6 Cytochrome peroxidase P 450 2D6

D Docetaxel
D&C Dilatation and curettage
D / Carbo Docetaxel / carboplatin
DAC Docetaxel / doxorubicin / cyclophosphamide
DARB Darbepoetin
DC Docetaxel / cyclophosphamide
DCIS Ductal carcinoma in situ
www.ago-online.de dd Dose-dense
DepoCyt® Liposomal cytarabine, liposomal ara-C
DFI Disease-free interval
DFS Disease-free survival
DI Dose intensity
 Abbreviations – IV
DIEP-flap Deep inferior epigastric perforator flap
© AGO e. V. Doc + Cap Docetaxel + capecitabine
in der DGGG e.V. DOX, Doxo Doxorubicin
sowie
in der DKG e.V. E2, E2 Estradiol
EBCTCG Early Breast Cancer Trialists’ Collaborative Group
Guidelines Breast EC Epirubicin / cyclophosphamide
Version 2020.1 ECD Extracellular-domain
ECOG Eastern Cooperative Oncology Group
ELISA Enzyme-linked immunosorbent assay
ENT Ear-nose-throat (otorhinolaryngologic)
EORTC European Organization for Research and Treatment of Cancer
Epi Epirubicin
EPO Erythropoetin
ER Estrogen receptor
ErbB2 v-Erb-B2-erythroblastic leukemia viral oncogene homolog 2 = neuro-glioblastoma-derived oncogene
homolog (avian) = human epidermal growth factor receptor = c-erbB2 = HER-2/neu = HER-2
ESF Erythropoesis-stimulating factor
ETC Epirubicin / paclitaxel / cyclophosphamide (dose-dense chemotherapy)
EWGBSP European Working Group for Breast Screening Pathology

F 5-Fluorouracil
F/U, f.-up Follow-up
FA 60 C “US-FAC”: 5-Fluorouracil / doxorubicin 60 / cyclophosphamide
www.ago-online.de
FACT-F Functional Assessment of Cancer Therapy (fatigue scale)
FASG French Adjuvant Study Group
FDG-PET / CT (18)F2-fluoro-D-2-desoxyglucose – Positron emission tomography / in combination with computed tomography
FEA Flat epithelial atypia
 Abbreviations – V
FEC 5-Fluorouracil / epirubicin / cyclophosphamide
© AGO e. V. FEC100 “French FEC”, (“Bonneterre”): 5-fluorouracil / epirubicin 100 / cyclophosphamide
in der DGGG e.V. FISH Fluorescence in situ hybridization
sowie FNA / FNB / FNP Fine needle aspiration biopsy
in der DKG e.V. FSH Follicle stimulating hormone
f-TRAM Free TRAM-Flap
Guidelines Breast
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G Gemcitabine
GABG German Adjuvant Breast Cancer Group
GCP Good clinical practice
G-CSF Granulocyte-colony stimulating factors
GEICAM Grupo Español de Investigation en Cancer de Mamma (Spanish Breast Cancer Research Group)
GnRHa Gonadotropin releasing hormone analogue / agonist
GnRHa + AI Gonadotropin releasing hormone analogue + aromatase inhibitor
GOS Goserelin (Zoladex®)
Gy Gray

Hand-Foot-Sy. Hand-foot-syndrome
Hb Haemoglobine
HDCT High dose chemotherapy
HER-2 Human epidermal growth factor receptor
high-dose / AST High-dose chemotherapy with autologous stem cell transplantation
HIP Health insurance plan
www.ago-online.de
HR (Steroid) hormone receptor
HRT Hormone replacement therapy
 Abbreviations – VI
© AGO e. V. I/S-GAP-GRACILIS-Flap Inferior / superior gluteal artery perforator-flap and gracilis-flap
IBC Inflammatory breast cancer
in der DGGG e.V.
sowie IBCSG International Breast Cancer Study Group
in der DKG e.V. ICE Ibandronat Capecitabine Elderly
IES International Exemestane Study
Guidelines Breast IGAP-Flap Inferior gluteal artery perforator-flap
Version 2020.1 IHC Immunohistochemistry
Inh. Inhibitor
INT 0101 Intergroup study 0101
IR Implant reconstruction
ITA Italian Tamoxifen Anastrozole Trial

JCO Journal of Clinical Oncology

Ki-67 Kiel-antigen 67 (proliferation marker)

KPS Karnofsky performance score

LABC Locally advanced breast cancer

LADO, LDF Latissimus dorsi muscle flap
LCIS Lobular carcinoma in situ
LDH Lactat dehydrogenase
LHRH Luteinizing hormone releasing hormone
LIN Lobular intraepithelial neoplasia
www.ago-online.de LITT Laser-induced thermotherapy
LN Lobular neoplasia
Lnn. Axillary lymph nodes
LoE / GR Level of evidence / grade of recommendation (Oxford Centre for Evidence-based medicine)
 Abbreviations – VII
© AGO e. V.
Locoreg Loco-regional
LRR Loco-regional recurrence
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LVEF Left ventricular ejection fractions
in der DKG e.V.
MBC Metastatic breast cancer
Guidelines Breast MDS Myelodysplastic syndrome
Version 2020.1 Med Median
Menop. Menopause
MG / MS Mammography / breast sonography
MIB Minimal invasive breast biopsy
Mitox Mitoxantrone
Mo / mo Months
mod. Modified
MPA/MA Medroxyprogesterone acetate / megestrole acetate
MRI Magnetic resonance imaging
MRM Modified radical mastectomy
MTX Methotrexate
MUGA Multiple-gated acquisition scan
Mx Mastectomy, mammography

n.s., ns Not significant

N+ Node-positive
www.ago-online.de Nab-Paclitaxel Nanoparticle-albumin-bound-paclitaxel
NAC Nipple-areola-complex
NBS National Breast Screening Study (Canada)
NCI-CTC2 National Cancer Institute – Common Toxicitiy Criteria
 Abbreviations – VIII
NEAT / SCTBG National Epirubicin Adjuvant Trial / Scottish Cancer Trials Breast Group
© AGO e. V. Neg. Negative
in der DGGG e.V. NMR MRI
sowie NSABP National Surgery Adjuvant Breast and Bowel Project
in der DKG e.V. NSABP B14 NSABP Breast trial 14
NSABP B17 NSABP Breast trial 17
Guidelines Breast
Version 2020.1 NSABP B20 NSABP Breast trial 20
NSABP B-33 NSABP Breast trial 33
NSABP P1-trial NSABP Prevention trial 1
NX Vinorelbine / capecitabine
NYHA New York Heart Association

OAS Ovarian ablation or suppression

OFS Ovarian function suppression
ONJ Osteonecrosis of the jaw
OP Operation
OR Odds-ratio
ORR Overall response rate
OS Overall survival
OSNA One-step nucleic acid amplification
Oxford Oxford Centre for Evidence-based medicine levels of evidence and grades of recommendations

www.ago-online.de P+L Paclitaxel + lapatinib

P weekly, Pw Paclitaxel weekly
p.o., PO Per os
Pac + Cap Paclitaxel + capecitabine
PAI-1 Plasminogen-activator inhibitor type I
 Abbreviations – IX
PAP PAP-Smear (Papanicolaou), cytologic test of the uterine cervix
© AGO e. V.
PBI Partial breast irradiation
in der DGGG e.V. PEG-Liposomal Doxo Pegylated liposomal doxorubicin
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PET Positron emission tomography
in der DKG e.V.
PFS Progression free survival
Guidelines Breast PgR Progesterone receptor
Version 2020.1 PMMA Polymethylmethacrylate
PMRT Postmastectomy radiotherapy
Pos. Cells Positive cells
prosp.-rand. Phase III Prospective and randomized phase III
PS Performance score
PST Primary systemic therapy
Pts. Patients

R0 No microscopic tumor residual

RAD Radiotherapy
rand. Pat. Patients randomized
RCT Radiochemotherapy
Rec pos Receptor positive
reg. CT + OP Regional chemotherapy and operation
Rel. Risk Relative risk
Reop Re-operation
www.ago-online.de resp. Respectively
RFA Radiofrequency ablation
RFS Recurrence-free survival
RPA Recursive partitioning analysis
RR Relative risk
 Abbreviations – X
RT Radiotherapy
© AGO e. V. RT-PCR Reverse transcriptase – polymerase chain reaction
in der DGGG e.V.
sowie S3 Highest level of evidence based guidelines according the Delphi-technique
in der DKG e.V. SABCS San Antonio Breast Cancer Symosium
Scottish CTPG and ICRF Breast
Guidelines Breast
Version 2020.1 Unit Scottish Cancer Trials Breast Group and Imperial Cancer Research Foundation
SD Standard deviation
SERD Selective estrogen receptor down-regulator
SERM Selective estrogen receptor modulator
SF Shortening fraction
SGAP-flap Superior gluteal artery perforator-flap
signals/nucl. Signals per nucleus
SIRT Selective internal radiation therapy
SN Sentinel lymph node
SNB- Sentinel lymph node negative (not tumor infiltrated)
SNE, SLNE Sentinel lymph node excision
Solitary Meta. Solitary metastasis
Sonogr. Sonography
SPF S-phase fraction
SSM Skin-sparing mastectomy
supra-/infraclav Supraclavicular, infraclavicular
SWE Sweden
www.ago-online.de
T Taxane
TAM Tamoxifen
TAM + C Tamoxifen and chemotherapy
TBP Treatment beyond progression
TCH Docetaxel / carboplatin and trastuzumab
 Abbreviations – XI
TEAM Tamoxifen exemestane multicenter trial
© AGO e. V. Ther. Therapy
in der DGGG e.V. TIA Treatment-induced amenorrhea
sowie TLI Thymidine labelling index
in der DKG e.V. Tox. Toxicity
TRAM Transverse rectus abdominis muscle
Guidelines Breast TT DR Time to distant recurrence
Version 2020.1 TTR Time to recurrence
UK/ANZ United Kingdom / Australia and New Zealand
uPA Urokinase-type plasminogen activator
Upper GI Upper gastro-intestinal
US Ultrasound

VAB Vacuum-assisted breast biopsy

VAT Video-assisted thoracoscopy
VATS Video-assisted thoracical surgery
Vc Vincristine
VNPI Van Nuys Prognostic Index
Vomit. Vomiting

WBI Whole breast irradiation

WHO World Health Organization
Wks Weeks
www.ago-online.de XRT Radiotherapy

Yrs. Years

ZEBRA Zoladex® Early Breast Cancer Research Association

 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
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in der DKG e.V.

Guidelines Breast
Version 2020.1
Members of the
AGO Breast Committee

www.ago-online.de
 Members of the
Breast Committee 1
© AGO e. V.
in der DGGG e.V.
 Prof. Dr. Ute-Susann Albert, Würzburg  Prof. Dr. Bernd Gerber, Rostock
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in der DKG e.V.  Dr. Ingo Bauerfeind, Landshut  Prof. Dr. Volker Hanf, Fürth
Guidelines Breast
Version 2020.1  PD Dr. Joachim Bischoff, Dessau  Prof. Dr. Nadia Harbeck, München
 Prof. Dr. Jens Uwe Blohmer, Berlin  Prof. Dr. Jens Huober, Ulm
 Prof. Dr. Wilfried Budach, Düsseldorf  Prof. Dr. Christian Jackisch,
Offenbach
 Prof. Dr. Peter Dall, Lüneburg
 Prof. Dr. Wolfgang Janni, Ulm
 Prof. Dr. Ingo J. Diel, Mannheim
 Prof. Dr. Cornelia Kolberg-Liedtke, Berlin
 Prof. Dr. Nina Ditsch, Augsburg
 Prof. Dr. Hans H. Kreipe, Hannover (DGP)
 PD Dr. Eva Fallenberg, Augsburg
 Dr. David Krug, Kiel
 Prof. Dr. Peter Fasching, Erlangen
www.ago-online.de
 Prof. Dr. Thorsten Kühn, Esslingen
 Prof. Dr. Tanja Fehm, Düsseldorf
 Prof. Dr. Sherko Kümmel, Essen
 Prof. Dr. Michael Friedrich, Krefeld
 Members of the
Breast Committee 2
© AGO e. V.
 Prof. Dr. Sibylle Loibl, Neu-Isenburg /  Prof. Dr. Marcus Schmidt, Mainz
in der DGGG e.V. Frankfurt
sowie  Prof. Dr. Andreas Schneeweiss, Heidelberg (AIO)
in der DKG e.V.  Prof. Dr. Hans-Joachim Lück, Hannover
Guidelines Breast
 Prof. Dr. Florian Schütz, Heidelberg
Version 2020.1  Prof. Dr. Diana Lüftner, Berlin
 Prof. Dr. H. Peter Sinn, Heidelberg (Pathologie)
 Prof. Dr. Michael Lux, Paderborn
 Prof. Dr. Christine Solbach, Frankfurt
 Prof. Dr. Nicolai Maass, Kiel
 Prof. Dr. Erich F. Solomayer, Homburg
 Prof. Dr. Volker Möbus, Frankfurt
 Prof. Dr. Elmar Stickeler, Aachen
 Prof. Dr. Volkmar Müller, Hamburg
 Rrof. Dr. Marc Thill, Frankfurt
 Prof. Dr. Christoph Mundhenke,
Bayreuth  Prof. Dr. Christoph Thomssen, Halle

 Prof. Dr. Ulrike Nitz, Mönchengladbach  Prof. Dr. Michael Untch, Berlin
www.ago-online.de

 PD Dr. Kerstin Rhiem, Köln  Prof. Dr. Isabell Witzel, Hamburg

 Prof. Dr. Achim Rody, Lübeck  Prof. Dr. Achim Wöckel, Würzburg
 Previous Members of
the Breast Committee
© AGO e. V.  Prof. Dr. Werner Audretsch, Düsseldorf  Prof. Dr. Gunter von Minckwitz,
in der DGGG e.V.
sowie  Dr. Michael Böhme, Magdeburg Neu-Isenburg / Düsseldorf
in der DKG e.V.
 Dr. Klaus E. Brunnert,  Prof. Dr. Markus Müller-Schimpfle,
Guidelines Breast
Version 2020.1 Osnabrück Frankfurt

 Prof. Dr. Dr. Serban D. Costa, Magdeburg  PD Dr. Carsten Oberhoff, Essen

 PD Dr. Nikos Fersis, Duisburg  Dr. Mahdi Rezai, Düsseldorf

 PD Dr. Kay Friedrichs, Hamburg  Prof. Dr. Gerhard Schaller, München

 Prof. Dr. Uwe-Jochen Göhring, Bonn  Prof. Dr. Anton Scharl, Amberg

 Dr. Georg Heinrich, Fürstenwalde  Prof. Dr. Rita Schmutzler, Köln

 Prof. Dr. Walter Jonat, Kiel (DKH)  Prof. Dr. Ingrid Schreer, Hamburg

 Dr. H. Junkermann, Bremen  Prof. Dr. H. Seegenschmiedt, Essen

www.ago-online.de  Prof. Dr. Manfred Kaufmann, Frankfurt  Prof. Dr. W. Simon, Stuttgart

 Dr. Björn Lisboa, Hamburg  Prof. Dr. Rainer Souchon, Berlin

 Prof. Dr. Frederik Wenz, Freiburg
 Potential Conflict of Interest (COI)
© AGO e. V.
 The members of the editing committee of these guidelines are specialists in diagnosis,
in der DGGG e.V. treatment, and research in breast cancer. Most of the members therefore have
sowie
in der DKG e.V. cooperations with industry. Thus, potential conflict of interest cannot be excluded.
Guidelines Breast
Version 2020.1
 In order to minimize potential bias within the statements we followed the pre-defined
rules:
 These guidelines are strictly based on available evidence from the scientific
literature.
 The chapters of each edition were prepared by annually alternating teams of
authors.
 Each statement and the correspondent AGO-recommendations were thoroughly
discussed within the entire group and accepted by majority decisions.
 Each member of the editing committee is required to submit a written declaration of
his/her conflicts of interests to an elected internal COI committee on an annual
www.ago-online.de
basis.
 Members who do not submit a COI declaration may not participate in the guideline
preparation.
 Potential Conflicts of Interest (COI)
2019–2020
© AGO e. V. All members of the AGO Breast Committee have submitted their COI report for the past year.
in der DGGG e.V. Members of the AGO Breast Committee indicated that they have received support (e.g.
sowie
in der DKG e.V. research funding, lecture or consulting honoraria etc.) from the following commercial entities:
Guidelines Breast
Version 2020.1 Abbvie, ABC, ABCSG, AFT, Agendia, Amgen, AOK, Astra Zeneca, Aurikamed, Bayer, Berliner
Krebsgesellschaft, BIG, BMBF, BMS, bsh medical communications, Carl Zeiss Meditec, Celgene, Cepheid Inc.,
Chugai, ClinSol Research, Clovis, Connectmedia, Daiichi-Sankyo, Deutsche Krebsgesellschaft, Deutsche
Krebshilfe, Dialogservice GmbH, Dietmar-Hopp-Stiftung, Dt. Ges. f. Senologie, ECR, Eickeler
Kongressmanagement, Eisai, EORTC, Erbe, ESOR, Ethicon, European School of Oncology, EUSOBI, FBA,
GBA-Innovation-Fond, GBG, GE Healthcare Breast Academy, Gedeon Richter, Genentech, Genomic Health,
GSK, Gyn-Onko-Update, HMO Ag Health Management, Hologic, if Kogressmanagement, I-MED Institute,
Immunomedics, IQWIG, Janssen-Cilag, Karl Storz, KCR, LÄKH, Lilly, LIV Pharma, L'Oreal, MCI, Medac,
Medconcept, Medexo, medpublico, Medtronic, Merck, MSD, Myelo Therapeutics, Mylan, Nanostring, Nektar
Pharmaceuticals, Novartis, NSABP, Odonate, Onkowissen.de, Pantarhei Onkology, Patent K67 Quantifier an
Institution, Pfizer, pfm medical, Phaonscientific, Pierre Fabre, prime, Promedicis, Puma Technology, Riemser,
Roche, Saarländische Krebsgesellschaft, SAKK, Samsung, Sandoz Hexal, Sanofi, Schattauer Verlag,
Schoeppl Kongressmanagement, Seattle Genetics, Siemens Healthineers Breast Care Day, Sirtex, Somatex,
SonoScape, SurgVision, Tesaro Bio, Teva, Theraclion, Theramex, Universitätsspital Zürich, Vifor Pharma,
www.ago-online.de WSG, Zuckschwerdt Verlag

The Committee did not consider any of the reported support to represent a conflict of interest that would
preclude participation in AGO Breast Committee discussions or voting.
 How to Use these Slides
 The AGO Breast Committee encourages everyone to use these slides for his or her own
© AGO e. V.
in der DGGG e.V.
information, improvement of patient care, medical education, presentations, and publications.
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in der DKG e.V.
 For presentations, the slides should only be used in their original
version and layout, e.g. by using a PDF-copy of each slide. The
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Version 2020.1
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 The following citation needs to be used: "AGO Breast Committee. Diagnosis and Treatment of
Patients with Primary and Metastatic Breast Cancer. Recommendations 2020. www.ago-online.de"
 Prior to any print media or electronic publication (except for oral pre-
sentations), the corresponding tables or figures have to be submitted to the chairman of the AGO
Breast Committee in order to obtain written permission (currently at
direktion.frauenklinik@uniklinik-ulm.de).
 Further commercial distribution of the whole set of slides is only possible via W. Zuckschwerdt
Verlag (for contact: post@zuckschwerdtverlag.de).
 A summary of the slides is availabe as publication in the journal „Breast Care“
AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2019
www.ago-online.de Ditsch N., Untch M., Thill M., Müller V., Janni W., Albert U.-S. on behalf of the AGO Breast Committee Breast Care
2019;14: 224–245 (DOI:10.1159/000501000)
AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast
Cancer: Update 2019 Thill M., Jackisch C., Janni W., Müller V., Albert U.-S. on behalf of the AGO Breast Committee
Breast Care 2019;14: 247–255 (DOI:10.1159/000500999)
 Editor & Copyright
© AGO e. V. Kommission „Mamma“ der
in der DGGG e.V.
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in der DKG e.V.
Arbeitsgemeinschaft für gynäkologische
Guidelines Breast
Version 2020.1
Onkologie
(AGO)
www.ago-online.de
Address for correspondence: Univ.-Prof. Dr. med. Wolfgang Janni
Frauenklinik, Dpt. Obst&Gyn
Universitätsklinikum Ulm
Prittwitzstr. 43
D-89075 Ulm
Tel. +49 731 500 58 500
www.ago-online.de Fax +49 731 500 58 502
direktion.frauenklinik@uniklinik-ulm.de
Editorial Assistance: Dr. Kristina Ernst
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
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in der DKG e.V.

Guidelines Breast
Version 2020.1
Options for Primary Prevention:
Modifiable Lifestyle Factors
 Prevention
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  Versions 2011–2019:
Guidelines Breast
Version 2020.1
Dall / Diel / Gerber / Hanf / Maass / Mundhenke / Solbach / Solomayer
/ Thomssen / von Minckwitz

 Version 2020:
Dall / Mundhenke

www.ago-online.de
 Risk Factors for Breast Cancer 1
© AGO e. V.
in der DGGG e.V.  Older age  Lifetime number of
sowie
in der DKG e.V.  Genetics menstrual cycles
 Early menarche, late menopause

Guidelines Breast
Version 2020.1 Family history of cancer
 Maternal pregnancy factors (e.g.
 Personal history of breast pre-eclampsia) (risk reduction), and
lesions low physical activity during
 Non-proliferative lesions
pregnancy (risk increase)
 Proliferative lesions w/o atypia
 High risk lesions (ADH, LIN) Social risk factors
 Breast cancer (DCIS, Inv. BC)  Lower number of births or
 Breast density no pregnancy
www.ago-online.de  Chest irradiation  Advanced age at first full
 Type II Diabetes mellitus term delivery
 Risk Factors for Breast Cancer 2
© AGO e. V.
in der DGGG e.V.
 Short duration or absence  Light exposure at night (night shifts)
sowie
in der DKG e.V. of breast feeding contradictory
Guidelines Breast
Version 2020.1
 BMI < 18.5 and > 25 and  Low physical activity
especially > 40 (obesity)  Endocrine disruptors in fetal and
 Food content early childhood development
 Steroid hormone therapy (e.g. DES, bisphenol-A, DDT)
 Recent oral contraceptive use  Effect of carcinogenic substances /
 Hormone therapy working materials
(estrogen/gestagen combination) in
postmenopausal women
 Exposition to ionizing radiation
 Alcohol intake
www.ago-online.de
 nicotine
 Deodorant-use and risk
Breast Cancer and Deodorants/Antiperspirants: a Systematic Review.
Allam MF1: Cent Eur J Public Health. 2016 Sep;24(3):245-247. doi: 10.21101/cejph.a4475.
© AGO e. V.
in der DGGG e.V.
sowie So far there is no evidence of a correlation between aluminum containing
in der DKG e.V.
deodorants and breast cancer risk
Guidelines Breast
Version 2020.1

 All observational studies that evaluated the association between breast

cancer risk and deodorants/antiperspirants use were reviewed. We have only
identified two case-control studies, carried out between 2002 and 2006.
 There was no risk of antiperspirants use in the pooled risk (odds ratio 0.40, 95%
confidence interval 0.35-0.46).

 Our comprehensive search has identified an insufficient number of studies to

conduct a quantitative review and obtain reliable results. Further prospective
studies are strongly needed.
www.ago-online.de
 High Proportion of Postmenopausal Breast
Cancer Attributable to Lifestyle Factors
© AGO e. V. population attributable fractions (PAFs) of modifiable risk factors
in der DGGG e.V.
sowie
in der DKG e.V. Risk factors: obesity, physical inactivity, alcohol, low-fiber intake, smoking
Guidelines Breast
Version 2020.1
Results: retrospective cohort study (Netherlands Cancer Registry)
2000: subpopulations of obese women, inactive women, alcohol drinkers, smokers etc.
2010: breast cancer incidence as compared to background incidence in these subgroups

‎25.7% of postmenopausal breast cancer cases in the Netherlands

in 2010 were attributable‎to lifestyle factors
8.8% attributed to‎obesity Update 2019: Tamimi et al, 2016
6.6% attributed to‎alcohol USA: more than a third of
postmenopausal breast cancers are
www.ago-online.de 5.5% attributed to‎physical inactivity
preventable through changes in
3.2.% attributed to‎low fiber intake modifiable risk factors
4.6% attributed to‎smoking
van Germert et al., Int J Cancer 2015; 152: 155-162
 Prevention by
Pregnancy Related Factors
© AGO e. V.
Oxford
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.
 Any full term pregnancy 2b B
Guidelines Breast
Version 2020.1  Number of pregnancies 2b B
 First full term pregnancy before age of 30 years 2b B
 Breast feeding
(protective if total breast feeding time exceeds 3a B
1.5–2 years)
 Assisted reproduction (no influence) 2b B
 Lower birth weight of the first born (3000-3500 vs. > 4500g
2b B
RR=1,53)
www.ago-online.de  Lower length of pregnancy first born 2b B
(26-31. WOP vs. 40-41. WOP; HR=2,38, p=0,03)
 Polycystic Ovarian Syndrome PCO (no influence on BC) 3b C
 Medical Prevention
© AGO e. V.
in der DGGG e.V.
sowie
Kehm RD et al. Regular use of aspirin and other non-steroidal
in der DKG e.V.
anti-inflammatory drugs and breast cancer risk for women at familial or
Guidelines Breast
Version 2020.1 Genetic risk: a cohort study, Breast Cancer Res. 2019 Apr. 18;21(1):52

Prospective multinational cohort study, n=5606, healthy women questionaire,

regular intake of ASS, NSAID, COX2-inhibitors

Regular ASS-intake: HR 0.61, CI 0.33-1.14, breast cancer incidence

Regular COX2-inhibitors : HR 0.39, CI 0.15-0.97, breast cancer incidence other
NSAIDs: n.s.
www.ago-online.de
[independent of BRCA-status]
 Prevention by Changing Lifestyle Factors:
Body Mass Index / Diet
© AGO e. V.
in der DGGG e.V.
sowie
Oxford
in der DKG e.V.

Guidelines Breast LoE GR AGO

Version 2020.1
 Maintaining normal weight
2a B ++
(BMI at 18.5 – 25 kg/m²)*
 Premenopausal 3a B ++
 Postmenopausal 2a B ++
 Prevention/screening and treatment of
diabetes mellitus type II 2b B ++
(reduction of breast cancer incidence and mortality)
www.ago-online.de
* Amount of body fat can be increased in people with normal BMI and correlates with breast cancer risk
 The risk of breast, ovarian and endometrial cancer in obese women
submitted to bariatric surgery: A meta-analysis
SABCS 2019, B Ishihara, D Farah, M Fonseca and A Nazário.
© AGO e. V.
in der DGGG e.V.  Meta-analysis, of a total of 150,528 patients in the bariatric surgery arm
sowie
in der DKG e.V. and 1,461,938 women in the control arm.
Guidelines Breast
Version 2020.1
 The risk of breast cancer was reduced by 61% [RR: 0.39 (95%CI [0.24 to
0.64]; I2= 90%; 6 studies).
 The risk of ovarian cancer was reduced by 53% [RR: 0.47 (95%CI [0.27 to
0.81]; I2= 0%; 3 studies).
 The risk of endometrial cancer was reduced by 67% [RR: 0.33 (95%CI [0.21
to 0.51]; I2= 88%; 7 studies).

www.ago-online.de
 Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women
With Normal Body Mass Index: A Secondary Analysis of a Randomized Clinical
Trial and Observational Study.
Iyengar NM et al.: JAMA Oncol. 2019 Feb 1;5(2):155-163
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1  WHI substudy
 Among the 3460 women included in the analysis (mean [SD] age, 63.6 [7.6]
years), multivariable-adjusted hazard ratios for the risk of invasive breast
cancer were 1.89 (95% CI, 1.21-2.95) for the highest quartile of whole-body
fat and 1.88 (95% CI, 1.18-2.98) for the highest quartile of trunk fat mass.
 The corresponding adjusted hazard ratios for ER-positive breast cancer
were 2.21 (95% CI, 1.23-3.67) and 1.98 (95% CI, 1.18-3.31), respectively.

www.ago-online.de
 BMI and epigenetics link between
obesity and breast cancer?
© AGO e. V.
in der DGGG e.V.
sowie Changing the ESR1-promoter activity by methylation of CpG-islands
in der DKG e.V.

Guidelines Breast
Version 2020.1 n = 120 breast tissue samples of cancer free patients

ESR1-promoter methylation

BMI > 30 > BMI 25–29 > BMI 25 kg/m² (p < 0.001 resp.)

postmenopausal > premenopausal (p = 0.046)

www.ago-online.de
[multivariate analysis]
Daraei A., Genet Test Mol Biomarkers 2017, 21:464-470
 BMI and epigenetics link between
obesity and breast cancer?
© AGO e. V.
in der DGGG e.V.
sowie
 The epigenetic code (methyl marks) determines how the
in der DKG e.V.
genome functions, dictating which genes are turned on and
Guidelines Breast
Version 2020.1 which genes are turned off

 Development is the critical period when this programming

occurs, directing cell and organ development

www.ago-online.de

Walker, CL, SABCS 2011

 Prevention by Changing
Lifestyle Factors: Diet
* As recommended by German Society of Nutrition (DGE) Oxford
© AGO e. V. ** Recommended as a part of healthy nutrition
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.
 Preference of a balanced diet* 2b B +
Guidelines Breast
Version 2020.1  Mediterranean Diet 2a B +
 Dietary components
 Olive oil (extra virgin olive oil), as part of mediterranean diet 2b B +
 Fat reduced food 2a B +
 Reduced consumption of red meat 2b C +
 Supplementation of vitamins, minerals, trace elements 2a B -
 Vitamin D substitution for prevention (MaCa HR1,02) 1b B +
 Vegetables / fruits ** 2a B +/-
 Phytoestrogens / soy 2a B +/-
 Fiber containing food 2a B +
www.ago-online.de
 Vegetarian/vegan diet (no significant risk reduction) 2b C +/-
 Coffee reduces the BC risk (esp. receptor neg.) 2a B +/-
 nuts/peanuts (> 10g/d) (peanut butter without effect) 2b B +
 Coffee Consumption and Risk of Breast Cancer: An Up- To-Date Meta-
Analysis
Xiu Juan Li: PlosOne, January 2013 | Volume 8 | Issue 1 | e52681

© AGO e. V.
in der DGGG e.V.
49497 breast cancer cases
sowie
in der DKG e.V. 26 studies (16 cohort and 10 case–control studies)
Guidelines Breast
Version 2020.1
The pooled RR showed a borderline significant influence of highest coffee
consumption (RR = 0.96; 95% CI 0.93–1.00), low-to moderate coffee
consumption (RR = 0.99; 95% CI 0.95–1.04), or an increment of 2 cups/ day
of coffee consumption (RR = 0.98; 95% CI 0.97–1.00) on the risk of breast
cancer.

In stratified analysis, a significant inverse association was observed in ER-

negative subgroup. However, no significant association was noted in the
www.ago-online.de others.
 Vitamin D Supplements and Prevention of Cancer and Cardiovascular
Disease
N Engl J Med. 2019 Jan 3;380(1):33-44. doi: 10.1056/NEJMoa1809944. Epub 2018
Nov 10.
© AGO e. V.
in der DGGG e.V.
randomized, placebo-controlled trial, with a two-by-two factorial design,
sowie
in der DKG e.V. of vitamin D3(cholecalciferol) at a dose of 2000 IU per day and marine n-3
Guidelines Breast (also called omega-3) fatty acids at a dose of 1 g per day
Version 2020.1

Primary end points were invasive cancer of any type and major
cardiovascular events

25,871 participants

median follow-up of 5.3 years

www.ago-online.de 124 breast cancers (Vit D group) vs. 122 (placebo group) Hazard Ratio: 1,02
 Epidemiological Evidences on Dietary Flavonoids and Breast Cancer Risk:
A Narrative Review
Sak, K.: Asian Pac J Cancer Prev. 2017 Sep 27;18(9):2309-2328.

© AGO e. V. Conclusions and further perspectives

in der DGGG e.V.
sowie …probably the most apparent relationship prevails for consumption of
in der DKG e.V.
isoflavones, whereas beneficial effects seem to be expressed only at high
Guidelines Breast
Version 2020.1 intake levels typical to Asian women ….compared to Western countries where
the intake of soy products is remarkably low.

protective activities of isoflavones might appear only in females consuming

soy foods since their early age as childhood and adolescence can be crucial
periods of exposure

At present: “recommendations for consumption of high-dose isoflavones …

www.ago-online.de
to reduce the individual susceptibility towards breast carcinogenesis are still
premature and can also be not completely without .. risks.”
 Prevention by Modifying
Lifestyle Risk Factors: Alcohol
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast
Version 2020.1
 Reduction of alcohol intace reduces risk of breast
2a B +
cancer (ideal <10g/d, class II evidence)

Particularly for
 ER+/PgR+ tumors 2a B

 Invasive lobular tumors 2a B

www.ago-online.de
 Nature, Nurture and cancer risks: Genetic and nutritional contributions to
cancer
Theodoratou, E.: Annu Rev Nutr. 2017 August 21; 37: 293–320.
doi:10.1146/annurev-nutr-071715-051004
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

No association was classified as convincing (class I). The association between

alcohol intake and ER+ breast cancer was classified as highly suggestive (Class II)
based on a meta- analysis of 20 prospective studies (≥ 30g/d of alcohol
consumption versus non-drinkers
RR (95% CI): 1.35 (1.23, 1.48, p-value=5.2 x 10-10, I2 = 26%,
Psmall effect bias = 0.184, P excess significance bias = 4 x 10-8)

www.ago-online.de
 Prevention by Modifying
Lifestyle Risk Factors: Smoking
© AGO e. V.
Oxford
in der DGGG e.V.
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast
Version 2020.1

 Never smoking reduces risk of breast cancer

2a B ++
∼ 15–24% reduction of lifetime risk)

 Young women smoking have a 60% increased risk of BC,

when smoking > 10 years before the first childbirth
(vs. never smokers)

www.ago-online.de
 Smoking and risk of breast cancer in the Generations Study cohort
Jones, M.E.:Breast Cancer Res. 2017 Nov 22;19(1):118. doi: 10.1186/s13058-017-0908-4.

© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
102,927 women recruited 2003–2013
Guidelines Breast
Version 2020.1
average of 7.7 years of follow-up

The HR (reference group was never smokers) was

1.14 (95% CI 1.03–1.25; P = 0.010) for ever smokers,
1.24 (95% CI 1.08–1.43; P = 0.002) for starting smoking at ages < 17 years
1.23 (1.07–1.41; P = 0.004) for starting smoking 1–4 years after menarche

Women with a family history of breast cancer (ever vs never smokers HR 1.35;
www.ago-online.de 95% CI 1.12–1.62; P = 0.002) had a significantly larger HR … than women without
(ever smoker vs never smoker HR 1.07; 95% CI 0.96–1.20; P = 0.22).
 Prevention by Modifying
Lifestyle Risk Factors: Physical Activity
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Version 2020.1
 Physical exercise 2a(-) B ++
(Metabolic equivalents to 3–5 hrs
moderate pace walking per week)

These effects also apply to BRCA1/2 mutation carriers and for women
www.ago-online.de
with an increased family risk.
 Recreational Physical Activity Is Associated with Reduced Breast Cancer Risk in Adult
Women at High Risk for Breast Cancer: A Cohort Study of Women Selected for Familial and
Genetic Risk.
Kehm RD et al.: Cancer Res. 2020 Jan 1;80(1):116-125. doi: 10.1158/0008-5472.CAN-19-1847. Epub 2019 Oct 2.

© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
 Prospective cohort study
Version 2020.1
 N=15550, women with fam. Hx of breast cancer
 multiplicative interactions of physical activity with predicted absolute
breast cancer familial risk based on pedigree data and with BRCA1 and
BRCA2 mutation status
 Higher physical activity => 20% reduction of breast cancer incidence
 (HR0.80, CI 0.68-0.93), independent of BRCA-status or pedigree risk

www.ago-online.de
 Prevention by Modifying Lifestyle Risk Factors:
Hormone Therapy in Postmenopausal Women
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast
Version 2020.1
 Avoiding hormonal therapy in
postmenopausal women
 Avoiding estrogen / progestin combinations 1b A +
 Avoiding estrogens only
(no increased, possibly reduced breast cancer risk, but 1b A +/-
increased risk for endometrial cancer, if not hysterectomized)

www.ago-online.de
 Epigenome-wide association study for lifetime estrogen exposure
identifies an epigenetic signature associated with breast cancer risk.
Johansson A et al.: Clin Epigenetics. 2019 Apr 30;11(1):66.
© AGO e. V.
in der DGGG e.V.
sowie
epidemiological data from EPIC-Italy (n = 31,864)
in der DKG e.V.
Study: estimated lifetime estrogen exposure
Guidelines Breast
Version 2020.1

Method: epigenome-wide association study, blood DNA samples, N=216 ,

and 440 healthy controls

Results: an estimated 5% increase in breast cancer risk per 1-year longer ELEE
(OR = 1.05, 95% CI 1.04-1.07, P = 3 × 10-12) in EPIC-Italy.
694 CpG sites were associated with ELEE (FDR Q < 0.05)

www.ago-online.de
 Prevention of Hormones
in Postmenopausal Patients
© AGO e. V. N MC-RR (95%CI) Further information
in der DGGG e.V.
sowie WHI ∼ 27 000 1.3 1.3 (1.1-1,6) coronary events
1.4 (1,1-1,9) insults
in der DKG e.V. WHI: JAMA 2002, (1,0-1,6)
2.1 (1,4-3,3) pulmonary embolism
JAMA 2017
Guidelines Breast 2.1 (1,5-2,9) deep vein thrombosis
Version 2020.1
med. age 67 J
HERS I 2763 1.2 no secondary prevention
Hulley S: JAMA 2002 RCT, med. 4.1 J (0.95-1.5)
side effects as comp. to WHI + cholcystectomy
II 2321
open-label, 2.7J
EPC > E
Million 1.084 110 1.66 mode of applic. not relevant
∼ 50% HRT (1.6-1.8)
Women 4.1 J. follow-up
duration > 5 yrs.
Beral V: Lancet 2003 Tibolon RR 1.45 (1.2-1.7)

E-Mono
EPIC 1.153 747 1.4 (1.2-1.6)
person-years EPC > E
Int J Cancer 2010
1.8 (1.4-2.2)
side effects as compared to WHI +
Metaanalyse 16 Studies 1.21-1.40
www.ago-online.de Nelson HD: JAMA 2002

Chlebowski et al., Climacteric 2015, 18:336-8

Chlebowski et al., J Natl Compr Canc Netw 2015, 13:917-24
Manson JE et al., JAMA 2017; 318: 927-938
 Prevention of Hormones (EGC)
in Postmenopausal Patients
© AGO e. V.
in der DGGG e.V. N MC-RR (95% CI) Further statements
sowie
in der DKG e.V. CLEAR-study (NSW) 1236 BC 2.09 current user
(1,57-2.78)
Guidelines Breast cases
Version 2020.1
1.03 past user
(0.82-1.28)
Case-Control-Study,
retrospect. 2.62 E/P combination
Australia (1.56-4.38)

1.80 E only
(1.21-2.68)

www.ago-online.de

Salagame et al., Int J Cancer. 2016;138(8):1905-14

 Prevention by Modifying
Lifestyle Risk Factors: Oral Contraception (OC)
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE
Guidelines Breast
Version 2020.1  OC does not increase the risk of mortality
1a
from breast cancer
 Risk of breast cancer slightly increased,
1a(-)
risk of ovarian, endometrial cancer is decreased

www.ago-online.de
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Breast Cancer Risk
and Prevention
 Breast Cancer Risk and Prevention
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  Versions 2003–2019:
Guidelines Breast
Version 2020.1 Schmutzler mit Albert / Bischoff / Blohmer / Ditsch / Fasching / Fehm /
Kiechle / Maass / Müller-Schimpfle / Mundhenke / Rhiem / Rody /
Schmidt / Schmutzler / Stickeler / Thomssen /

 Version 2020:
Fasching / Rhiem

www.ago-online.de
 Principles of Prevention
© AGO e. V.
in der DGGG e.V.
sowie
 Women at increased risk for breast cancer are not considered
in der DKG e.V. patients but healthy women or counselees
Guidelines Breast
Version 2020.1

 A comprehensive informed consent taking into consideration

all potential side effects and risks is warranted prior to offering
preventive measures

 Highest priority: „First, do no harm!“

www.ago-online.de
(Primum nil nocere)
 Who Should be Tested for BRCA1/2 Mutations
and Possibly Further Risk Genes? (Part 1 of 2)
© AGO e. V.
in der DGGG e.V.
Oxford LoE: 2b GR: B AGO: ++
sowie
in der DKG e.V.
Families with (each from one family branch)*
Guidelines Breast
Version 2020.1  at least three women with breast cancer independent of age or
 at least two women with breast cancer, one < 50 yrs. or
 at least one woman affected by breast and one by ovarian cancer or
 at least one woman affected by breast and ovarian cancer or
 at least two women affected by ovarian cancer or
 at least one woman affected by bilateral breast cancer, first < 50 yrs. or

www.ago-online.de * Inclusion criteria of the German Consortium of Hereditary Breast and Ovarian Cancer (GCHBOC)
based on a BRCA1/2 mutation prevalence ≥ 10% tested in 21,401 families. All mutation carriers should be
registered in scientific databases, to validate the inclusion and exclusion criteria (including population-based
studies).
 Who Should be Tested for BRCA1/2 Mutations
and Possibly Further Risk Genes? (Part 2 of 2)
© AGO e. V.
Oxford LoE: 2b GR: B AGO: ++
in der DGGG e.V.
sowie
in der DKG e.V. Families with (each from one family branch)*
Guidelines Breast
Version 2020.1  at least one woman affected by breast cancer < 35 yrs. or
 at least one man affected by breast cancer and one additional relative
affected by breast or ovarian cancer
 Other recommended criteria:
 own disease of triple negative breast cancer ≤ 60 yrs. of age
 own disease of ovarian cancer
 if therapeutically relevant (e.g. PARPi)

www.ago-online.de * Inclusion criteria of the German Consortium of Hereditary Breast and Ovarian Cancer (GCHBOC)
based on a BRCA1/2 mutation prevalence ≥ 10% tested in 21,401 families. All mutation carriers should be
registered in scientific databases, to validate the inclusion and exclusion criteria (including population-based
studies).
 Checklist according to Public Health
Insurance Policies (German GKV#)*
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

www.ago-online.de

* online tool provided by the Ärztekammer Westfalen-Lippe in cooperation with the GC-HBOC based on the inclusion
criteria of the GC-HBOC (Kast et al., J Med Genet 2016;53:465-71)
https://www.aekwl.de/fileadmin/qualitaetssicherung/Zertifizierungsstelle/2018-07-17-CL-Genetik.pdfc
 State of research: Relevance of genetic and
non-genetic risk factors
© AGO e. V. Single genes
in der DGGG e.V.
sowie high high risk genes (e.g. BRCA1, BRCA2, PALB2)
in der DKG e.V.
disease risk

Guidelines Breast
Version 2020.1
moderately penetrant risk genes
(e.g. CHEK2, BARD1, ATM, RAD51C, RAD51D) reduced
penetrance

low risk variants / modifiers

(>300) multifactorial
non-
genetic genetic

BRCA1/2
low

Very
rare allele frequency (genetic variants) common Mod. penetrant risk genes

www.ago-online.de
Other genes/genet. risk factors

Low risk variants/modifiers

 Breast Cancer Risk Genes with
moderate to high Lifetime Risk
© AGO
For following genes, risk calculations are available with varying degree of
e. V.
in der DGGG e.V. evidence. The clinical benefit must be proven by the effectiveness of preventive
sowie
in der DKG e.V. measures. ORs from studies with selected populations cannot be transferred to
Guidelines Breast other populations.
Version 2020.1
Oxford
Clinical benefit of genetic test LoE GR AGO
 BRCA1(#), BRCA2* 1b A ++°
 PALB2(#) , CDH1, TP53** 3a B +/-°
 ATM, CHEK2, BARD1(#) , RAD51C, RAD51D*** 3a B +/-°
* BRCA1/2 are genes with a high lifetime risk. Furthermore genes with a medium and a low lifetime risk have
been described.
** High ORs allow for the assumption that these are high risk genes. Prospective and age-related penetrances
www.ago-online.de
are not yet available.
***These genes are classified as genes with a moderate lifetime risk based on currently available data.
(#) These genes are associated with an increased risk of triple-negative breast cancer.
°Participation in prospective registries or studies is highly recommended.
 Current Clinical Impact of Further Risk Genes
© AGO e. V.
 Further moderate and low-risk gene variants are most likely transmitted by an oligo- or
in der DGGG e.V. polygenic trait.
sowie
in der DKG e.V.
 The penetrance of such genes depends on the own and family cancer history.
Guidelines Breast
 Single low-risk variants confer only small risk elevations and also seem to be associated with
Version 2020.1 specific tumor subtypes. Potential multiplicative effects that may be relevant for risk
stratification and provision of clinical prevention strategies remain to be elucidated.
Therefore, the analysis of multiple gene regions may be of clinical relevance in the future.
 Therefore, genetic testing of moderate and low-risk genes and variants should only be
performed within large prospective cohort studies like the German Consortium for
Hereditary Breast and Ovarian Cancer (GC-HBOC).
Oxford
LoE GR AGO
 Clinical genetic testing of moderate-risk genes,
3a B +/-
e.g. gene panels
www.ago-online.de  Clinical genetic testing for low-risk variants 3b D --
 Referral to centers of the GC-HBOC or cooperating centers 5 D +
 Non BRCA-associated Hereditary Cancer
Syndromes with Increased Risk for Breast Cancer
© AGO e. V. Syndrome Gene Risk for malignancy
in der DGGG e.V.
sowie
in der DKG e.V.
Li Fraumeni TP53 Breast, endometrium, colorectal, small intestine, stomach, hepato biliary,
skin, osteosarcoma, soft tissue sarcoma, urogenital, CNS, ACC, leukemia,
Guidelines Breast lymphoma, lung
Version 2020.1
Cowden PTEN breast, endometrium, thyroid, colorectal, kidney, melanoma

Hereditary diffuse gastric cancer CDH1 Hereditary diffuse gastric cancer, lobular invasive breast cancer
syndrome
Peutz-Jeghers Syndrome STK11/ LKB1 Colorectal, small intestine, stomach, pancreas, testicle, endometrium

Lynch MLH1, MSH2, MSH6, Endometrium, ovary, colorectal, small intestine, stomach, hepato biliary,
PMS2, EPCAM pancreas, kidney, urogenital, CNS

Ataxia telangiectasia ATM breast cancer, leukemia, stomach, melanoma, sarcoma

(AT-Syndrome)
Franconi Anämie BRCA2, BRIP1, RAD51C, AML, MDS, SCC, medulloblastoma, nephroblastoma, breast, pancreas, ovary
www.ago-online.de PALB2
 Current version of the TruRisk® BC/OC* Gene Panel
by the German Consortium (GC-HBOC)
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

Selection of genes: 11 BC/OC ‘core genes’ (Data on risk increase)

7 other syndrome-associated genes (Lynch, Cowden, Peutz-Jeghers) with suspected
BC/OC association
www.ago-online.de 16 BC/OC candidate genes from scientific projects (validation in the GC-HBOC)
Strategy: Validation in prospective cohort, continuous expansion and improvement

*BC=breast cancer, oc=ovarian cancer

 Distinct Genetically Subtypes
Defines Distinct Tumor Entities
© AGO e. V.
in der DGGG e.V.
Distinct genetic subtypes of breast cancer may show distinct clinical features.
sowie
in der DKG e.V.
Prior to the offer risk reducing clinical procedures the following facts and data
Guidelines Breast should be adressed:
Version 2020.1

 Age related disease penetrance?

 Typical histopathological features?
 Sensitivity to current screening modalities?
 Better survival of early detected tumors?
 Natural disease course?
 Response to anti-tumor therapy?
www.ago-online.de Genotype-phenotype-correlations must be known before performing
preventive clinical measures
 VUS: Problems and Questions
© AGO e. V.
in der DGGG e.V.
 „A Variant of Unknown Significance (VUS IARC class 3) is a genetic variant
sowie
in der DKG e.V.
with unknown clinical relevance.“ (Plon et al. Hum Mutat 2008)
Guidelines Breast
Version 2020.1
 Most VUS are extremely rare (≤3 variants in >80% of families)
 Classification of sequence variants should be performed according to the
IARC classification system
 Frequency of VUS (IARC class 3) increases with numbers of tested genes
 Clinical interpretation and decision making depending on the IARC
classification system is not standardized yet
 In silico prediction tools (PolyPhen2, SIFT) are not adequate or sufficient
for clinical decision making
www.ago-online.de  Additional analyses are required, e.g. in vitro splicing assay, functional
assay, segregation analysis, co-occurence analysis, large case / control
studies
 Variant classification proposed by IARC
(Plon et al., Human Mutation, 2008)
© AGO e. V.
in der DGGG e.V.
Proposed Classification System for Sequence
sowie
in der DKG e.V.
Variants Identified by Genetic Testing
Guidelines Breast
Version 2020.1
Probabilty of being
Class Discription pathogenic
5 Definitly pathogenic > 0,99
4 Likely pathogenic 0,95 – 0,99
3 Uncertain 0,05 – 0,949
2 Likely not pathogenic or of little clinical 0,001 – 0,049
significance
1 Not pathogenic or no of clinical < 0,001
www.ago-online.de
significance
Only class 4 and 5 variants are considered clinically relevant.
 Classification of IARC Class 3 Variants
© AGO e. V.
in der DGGG e.V. Requires additional information and analyses, e.g.
sowie
in der DKG e.V.  Co-occurence data from large data banks
Guidelines Breast
Version 2020.1  Segregation analysis
 Functional analysis etc.
 Data should be pooled in large study groups (e.g. ENIGMA)

*Most class 3 variants can be downgraded to clinically irrelevant classes 1 or 2 by these analyses.
Few are upgraded to the clinically relevant classes 4 or 5. Any re-evaluation of the IARC class
should be communicated to the tested persons (see for example the concept of supervision in
centres of the German Consortium/GC-HBOC).
www.ago-online.de
 Requirements for the Introduction of New
Diagnostic or Predictive Genetic Testing*
© AGO e. V.
in der DGGG e.V.  The risk collective is clearly defined by risk criteria.
sowie
in der DKG e.V.  The positive predictive value of risk critiera with respect to the
Guidelines Breast
Version 2020.1 identification of the genetic risk factor is known.
 The cut-off values for genetic testing evolved through a transparent
consensus process.
 The genetic test is valide and reliable.
 A spectrum bias is excluded or defined.
 A clinical prevention strategy exists that leads to early detection or
prevention and mortality reduction of the genetically defined subset of
the disease.
www.ago-online.de
* Acc. to the position paper on risk-adjusted early detection of cancer of the German National Cancer Plan
developed under the Federal Ministry of Health, e.g. "Präventive Gendiagnostik - Hoffnung und Fluch der
Genanalyse", Heft 26 des Deutschen Ärzteblattes vom 29.06.2012; Dtsch. Ärztebl. 2012; 109(26): A-1371 / B-
1183 / C-1163)
 Non-Directive Counseling regarding
Preventive Measures
© AGO
Oxford
e. V.
in der DGGG e.V. LoE GR AGO
sowie  According to the Genetic Diagnostic Law
in der DKG e.V. 5 D ++
Guidelines Breast
 According to the Medical Devices Act,
Version 2020.1
e.g. risk assessment requires professional training and expertise
 Application of software for risk calculation requires professional training
and experience
 Communicate absolute risks within a manageable timeframe
 Communicate risk and benefit of a multimodal intensive surveillance
program
 Communicate risk and benefit of preventive clinical methods
 Communicate competing risks, e.g. risk of disease progression in relation to
www.ago-online.de risk of a secondary primary in case women already affected by primary
breast cancer
 Allow appropriate time for consideration
 Multimodal Intensive Surveillance Program*
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast  Program für BRCA-Carriers
 For the detection of early stage cancers
Version 2020.1
2b B ++
 Clinical breast exam > = 25 Jahre Semi-annually
 Sonographie > = 25 Jahre Semi-annually
 Mammogram > = 40 Jahre Bi-annually
 Breast MRI > = 25 Jahre Annually
 For improvement of metastasis-free interval 2b B +
 Survivors after tumors in childhood and radiotherapy
2a B ++
of thoracic wall (e.g. M. Hodgkin)
www.ago-online.de

* The multimodal intensified early detection program should be carried out within the framework of transparent
quality assurance and appropriate evaluation.
 High risk screening including MRI
© AGO e. V.  A cohort of 4,573 high-risk, previously unaffected women (954 BRCA1 carriers, 598
in der DGGG e.V.
sowie BRCA2 carriers, 3,021 BRCA1/2 non-carriers) participated.
in der DKG e.V.

Guidelines Breast
 Screening outcomes for 14,142 screening rounds with MRI between 2006 and 2015
Version 2020.1 were analyzed and stratified by risk group, type of screening round, and age.
 A total of 221 primary breast cancers (185 invasive, 36 in situ) was detected.
 84.5% (174/206, 15 unknown) were stage 0 or I.
 Program sensitivity was 89.6% (95%CI 84.9-93.0) with no significant differences in
sensitivity between risk groups or by age.
 Of all cancers, only 1,4 % were symptomatic interval cancers.
 The rate of MRI-only- detected cancers was 15/71 in BRCA 1 carriers (21%), 17/47 in
BRCA 2 carriers (36%), and 29/80 high risk BRCA 1,2 non carriers (36%).
www.ago-online.de  The rate of MG-only detected cancers was 7/198 cases, the rate of US-only cancers
2/198 cases (BRCA 1 carriers in the 6 month interval of first round).
Bick U, Engel C, Krug B, et al. High-risk breast cancer surveillance with MRI: 10-year experience from the German consortium for hereditary breast and
ovarian cancer. Breast Cancer Res Treat. 2019;175(1):217–228. doi:10.1007/s10549-019-05152-9
 High risk screening including MRI
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

www.ago-online.de

Bick U, Engel C, Krug B, et al. High-risk breast cancer surveillance with MRI: 10-year experience from the German consortium for hereditary breast and
ovarian cancer. Breast Cancer Res Treat. 2019;175(1):217–228. doi:10.1007/s10549-019-05152-9
 Surveillance Program for Female Carriers of Pathogenic BRCA
Mutations after Primary Breast Cancer acc. to GC-HBOC *
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
 Multimodal intensive lifelong surveillance program
Version 2020.1
 For detection of early stage breast cancers 2a B ++
 Clinical breast exam > = 25 Jahre Semi-annually
 Sonographie > = 25 Jahre Semi-annually
 Mammogram > = 40 Jahre Biannually
 Breast MRI (until ACR1) > = 25 Jahre Annually
 For mortality reduction (10-year survival) 3a C +/-*

www.ago-online.de
* Follow-up care should be carried out as part of transparent quality assurance and appropriate evaluation.
 Breast Cancer Risk Genes with
moderate to high Lifetime Risk
© AGO e. V.
BRCA1 mutation carriers have a risk of breast cancer corresponding to the
in der DGGG e.V. general population (about 1%) and an up to 1.8 to 3.75 times higher risk for
sowie
in der DKG e.V. prostatic cancer </= 65y.
Guidelines Breast BRCA 2 mutation carriers have an up to 5–7% lifetime risk for breast cancer and
Version 2020.1
an up to 2.5 to 8.6 times higher risk for prostatic cancer </= 65y.
Oxford
LoE GR AGO
Currently, no specific surveillance is recommended
 For breast cancer:
5 D +
self examination and watchful waiting
 For prostate cancer:
Compare recommendations on prostate carcinoma
(https://www.prostatakrebs-bps.de/images/DGU- 3b C +
Stellungnahme_PSA_Pressemappe_2019.pdf)
www.ago-online.de

* Follow-up care /surveillance should be carried out as part of transparent quality assurance and
appropriate evaluation.
 Modified Surveillance Program for
BRCA-neg. Women at Moderate to High Risk
or Survivors of Hodgkin Disease
© AGO e. V.
in der DGGG e.V. Rationale:
sowie
in der DKG e.V.  Increased risk of breast cancer after chest irradiation because
Guidelines Breast
Version 2020.1
of Hodgkin lymphoma in childhood (9–18 years)
 Increased risk of breast or ovarian cancer in women from BRCA1/2
negative families at risk that is, however, lower than in women from
BRCA1/2 positive families
 Referral to centres of the GC-HBOC or cooperating centres for the
evaluation of structured surveillance and follow-up

www.ago-online.de
 Surgical Prevention
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast  A secondary risk-reducing unilateral or bilateral
Version 2020.1
mastectomy is not indicated without the presence of
2a B +*
clearly defined genetic risk factors because it does
not lead to a reduction in mortality.

www.ago-online.de

* study participation recommended

 Surgical Prevention for Healthy
Female BRCA1/2 Mutation Carriers
© AGO
Oxford
e. V.
in der DGGG e.V. LoE GR AGO
sowie
in der DKG e.V.  Risk-reducing bilateral salpingo-oophorectomy
2a B
Guidelines Breast
Version 2020.1
(RR-BSO)**
 Reduces OvCa incidence and mortality ++*
 Reduces overall mortality ++*
 Risk-reducing bilateral mastectomy (RR-BM) 2a B +*
 Reduces BC incidence
 Reduces BC mortality in BRCA1 mutation carriers***
2b B +*

www.ago-online.de * study participation recommended

** The RRSO is recommended from about 35 years for BRCA1 and from about 40 years for BRCA2 mutation
carriers, taking into account the age of ovarian cancer diagnosis in the family and the family planning status.
*** No reduction in mortality could be shown for BRCA2 mutation carriers. RRM counselling should be individualised.
 Risk-reducing Interventions for BRCA1/2 Female
Mutation Carriers Affected by Breast Cancer
Oxford
© AGO e. V.
in der DGGG e.V. LoE GR AGO
 Risk-reducing bilateral salpingo-oophorectomy
sowie
in der DKG e.V.
2b B +*
Guidelines Breast
Version 2020.1
(RR-BSO)
 Reduces OvCa incidence and mortality
 Reduces overall mortality
(contradictory results for reduction of cl BC incidence)
 Prophylactic contralateral mastectomy (RR-CM) 2b B +*
 Reduces BC incidence and mortality
 Tamoxifen (reduces contralateral BC incidence) 2b B +/-*
 Indication for RR-M should consider age at onset of
2a B ++*
first breast cancer in affected gene
www.ago-online.de
 RR-M after ovarian cancer 4 C +/-**

* study participation recommended

** Depends on tumor stage (FIGO I/II ), recurrence free interval (≥ 5y), age
 Improved Overall Survival After Contralateral Risk-
reducing Mastectomy in BRCA1/2 Mutation Carriers
© AGO e. V.
in der DGGG e.V. Improved overall survival after contralateral risk-reducing mastectomy in
sowie
in der DKG e.V. BRCA1/2 mutation carriers with a history of unilateral breast cancer: a
Guidelines Breast
Version 2020.1
prospective analysis.

Heemskerk-Gerritsen BA1, Rookus MA, Aalfs CM, Ausems MG, Collée JM,
Jansen L, Kets CM, Keymeulen KB, Koppert LB, Meijers-Heijboer HE, Mooij
TM, Tollenaar RA, Vasen HF; HEBON, Hooning MJ, Seynaeve C.
Int J Cancer. 2015 Feb 1;136(3):668-77. doi: 10.1002/ijc.29032. Epub 2014
Jul 8.

See table 3: Efficacy of contralateral risk-reducing mestectomy on overall

www.ago-online.de
survival
 Therapy of BRCA1/2-associated
Breast Cancer
© AGO e. V. Oxford
in der DGGG e.V.
sowie Limited prospective cohort studies with LoE GR AGO
in der DKG e.V.

Guidelines Breast
short follow-up time
Version 2020.1
 Breast conserving surgery: adequate local tumor
2a B +
control (~10 years observation)
 Systemic therapy according to sporadic breast
3a B +
cancer
 gBRCA mutation status is predictive for
2b B +
chemotherapy response in TNBC
 Carboplatin (vs. Docetaxel) in metastatic breast
2b B +
cancer
www.ago-online.de  PARP inhibitor in metastatic breast cancer 1b B +
 Medical Prevention for
Women at Increased Risk
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
 Tamoxifen for women >35 years: reduction of
Guidelines Breast
1a A +*
Version 2020.1
invasive BC, DCIS, and LN
 Raloxifen for postmenopausal women: reduction of
1b A +*
invasive BC only
 AI for postmenopausal women 1b A +#

# Significant risk reduction was seen for anastrozole for ovarian and endometrial cancer,
as well as skin, colorectal, hematologic, thyroid and urinary tract cancers. Chemopreventive
www.ago-online.de
regimes should only be offered after individual and comprehensive counseling. The net benefit
strongly depends on risk status, age and pre-existing risk factors for side effects.
* Risk situation as defined in NSABP P1-trial (1.66% in 5 years) or according to #Tyrer-Cuzick model (IBIS-II)
 Risk Reduction for Ipsi- and
Contralateral Breast Cancer
© AGO e. V.
in der DGGG e.V. Rationale: Women with breast cancer have an
sowie
in der DKG e.V. increased risk for a second primary
Guidelines Breast
Version 2020.1
Oxford
LoE GR AGO
 Tamoxifen* 1a A +
 Aromatase inhibitors* 1a A +
 Suppression of ovarian function* + Tamoxifen 1b B +

www.ago-online.de

* Only proven for ER/PgR-positive primary sporadic BC

 Cooperation of Certified Breast Cancer (BC)
Centres (Ctr) with Familial BC Ctr of the GC-HBOC*
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast Check list (inclusion criteria)

Version 2020.1
Counseling for diagnostic genetic testing Genetic testing

Certified Communication, Familial

BC Center Exchange, Advice BC Center

Prophylactic surgery Counseling: Indication for surveillance

Stratified therapy and/or prophylatic surgery

www.ago-online.de

* trans-sectoral contract for integrated care, acc. to code of social law §140a since 2015
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Early Detection and Diagnosis
 Early Detection and Diagnosis
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  Versions 2005–2019:
Guidelines Breast
Version 2020.1
Albert / Blohmer / Fersis / Junkermann /
Maass / Müller-Schimpfle / Scharl / Schreer

 Version 2020
Fallenberg / Maass

www.ago-online.de
 Early Detection Mammography (normal risk)
© AGO e. V. Oxford AGO
in der DGGG e.V.
sowie Age Interval LOE GR
in der DKG e.V.

Guidelines Breast
< 40 na - - --
Version 2020.1
40–49 12–24 1b B +
50–69* 24 1a A ++
70–74 24 1a A ++
> 75** 24 4 C +

www.ago-online.de

* National Mammography-Screening-Program
** health status + life expectancy more than 10 years
 Early Detection in Asymptomatic Women
Digital Breast Tomosynthesis
© AGO e. V.
in der DGGG e.V.
sowie Oxford AGO
in der DKG e.V.

Guidelines Breast
LOE GR
Version 2020.1

Digital Breast Tomosynthesis (DBT alone or

2a B +
in addition to FFDM)*

Replacing FFDM by synthetic MG in addition to DBT** 3b B +

The komplete DBT dataset of images has to be available for judgment/reporting, the synthetic
mammography only is not sufficient.
www.ago-online.de
* Sign. higher sensitivity, heterogeneous specificity, and higher costs [machine, evaluation, archiving]
in comparison to Full-Field Digital Mammography (FFDM)
** Evaluation for Germany in a current prospective trial (TOSYMA)
 Breast Cancer Mortality Reduction
© AGO e. V.
in der DGGG e.V. Meta-Analysis RR 95%CI
sowie
in der DKG e.V. Independent UK Panel, 2012
Guidelines Breast 13-year metaanalysis 0.80 (0.73–0.89)
Version 2020.1
Cochrane Review, 2011
Fixed-effect metaanalysis of 9 RCT-trials 0.81 (0.74–0.87)
As above, but excluding women <50 years 0.77 (0.69–0.86)
Canadian Task Force, 2011
Women aged 50–69 years 0.79 (0.68–0.90)
Duffy et al, 2012
Review of all trials and age groups 0.79 (0.73–0.86)

www.ago-online.de
 Breast Cancer Mortality Reduction
© AGO e. V.
in der DGGG e.V.
Meta-Analysis RR 95%CI
sowie
in der DKG e.V. Case-Control Studies
Guidelines Breast Broeders et al Screening Mx 0.46 (0.4 – 0.54)
Version 2020.1
Corr. for self selection 0.52 (0.42–0.65)
Invited for screening 0.69 (0.57–0.83)
Incidence-based Mortality Studies
Broeders et al Screening Mx 0.62 (0.56–0.69)
Invited to screening 0.75 (0.69–0.81)
Randomized Clinical Trials
Gotsche and Jorgenson Screening Mx 0.81 (0.74–0.87)
ECIBC Screening MX
www.ago-online.de 45–49 0.88 (0.76 - 1.02)
50–69 0.77 (0.66 - 0.90)
70–75 0.77 (0.54 - 1.09)
 Breastcancer: incidence and mortality
 Annual incidence of breast cancer and mortality in the EU (GLOBOCAN
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. 2012)
Guidelines Breast
Version 2020.1 Age Incidence/1000 Mortality/1000
40 to 44 1,2 0,1
45 to 49 1,7 0,2
50 to 69 2,7 0,5
70 to 74 3,0 0,8

www.ago-online.de

From: http://gco.iarc.fr/
 Mammography-Screening
Benefit and Harm
© AGO e. V.
in der DGGG e.V.
Data background: Breast Cancer Surveillance Consortium Registry Data
sowie
in der DKG e.V. per 10.000 Women screened over 10 years
Guidelines Breast
Version 2020.1
Age 40-49 50-59 60-69 70-74
Breast cancer death avoided (CI95%) 3 8 21 (11-32) 13 (0-
(0-9) (2-17) 32)

False-positive (n) 1212 932 808 696

Breast biopsies (n) 164 159 165 175
False-negative (n) 10 11 12 13

www.ago-online.de

Siu Al on behalf of the USPSTF 2016, 164:279–296

 Early Detection Sonography/MRI
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Screening-Breast Sonography allone 5 D --
Version 2020.1
 Automated 3D-Sonography 3a C --
 Breast sonography as an adjunct:
 Dense mammogram
2a B ++
(heterogeneously dense, extremely dense)
 Elevated risk 1b C ++
 Mammographic lesion 2b B ++
 Second-look US (MRI-only detected lesions) 2b C ++
 MRI if screening MG is negative and breast 1b B +
www.ago-online.de
composition: extremely dense* 50–75 LJ
* Definition of extremely dense corresponds to BIRADS-densitiy category D heterogeneously dense categorie
C according to ACR BI-RADS-Atlas 5th ed. 2013
 Early Detection
Clinical Examination
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
As stand alone procedure
Version 2020.1
 Self-examination 1a A -*
 Clinical breast examination (CBE) by health
3b C -*
professionals
 CBE because of mammographic/sonographic lesion 5 D ++
CBE in combination with imaging BCP ++

www.ago-online.de

* May increase breast awareness

 Assessment of Breast Symptoms or Lesions
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
 Clinical examination 3b B ++
Version 2020.1
 Mammography 1b A ++
 Tomosynthesis 2b B +
 Contrast-enhanced mammography (alone or as
3a B +/-
adjunct)
 Sonography 2b B ++
 Elastography (shear-wave) * 2b B +
 Automated 3D-sonography 3b B +/-
 Minimally invasive biopsy 1c A ++
www.ago-online.de  MRI** 1b B +
* Adjunct assessment
**If clinical examination, mammography and sonography incl. needle biopsy do not allow a definite diagnosis
 Pre-therapeutic Assessment
of Breast and Axilla
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Clinical examination 5 D ++
Version 2020.1
 Mammography 2b B ++
 + Tomosynthesis (DBT) 3b B +
 Contrast-enhanced mammography (alone or as
3a B +/-
adjunct)
 Sonography (breast and axilla) 2b B ++
 MRI* 1b B +
 Minimally invasive biopsy** 1b A ++
 Breast-CT 5 D -
* MRI-guided vacuum biopsy is mandatory in case of MRI-detected additional lesions.
www.ago-online.de Individual decision for patients at high familiar risk, with dense breast (density 3-4/diagnostic
assessability C-D), lobular invasive tumors, suspicion of multilocular disease. No reduction in
re-excision rate.
** Histopathology of lesions if relevant for treatment
 MRI: Preoperative Staging
© AGO e. V.
in der DGGG e.V.  9 eligible studies
sowie
in der DKG e.V. (2 randomized trials; 7 comparative cohorts)
Guidelines Breast
Version 2020.1  3112 patients with BC
 MRI versus no-MRI:
 Initial mastectomy 16.4% versus 8.1%
[OR, 2.22 (P < 0.001); adjusted OR, 3.06 (P < 0.001)]
 Re-excision after initial breast conservation 11.6% versus 11.4%
[OR, 1.02 (P = 0.87); adjusted OR, 0.95 (P = 0.71)
 Overall mastectomy 25.5% versus 18.2%
[OR, 1.54 (P < 0.001); adjusted OR, 1.51 (P < 0.001)]

www.ago-online.de

N Houssami et al. Ann Surg 2013; 257

 MRI: Preoperative Staging
in Lobular Invasive Breast Cancer
 766 patients with invasive lobular cancer (ILC)
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  Initial mastectomy: 31.1% versus 24.9%
Guidelines Breast [OR, 1.36 (P = 0.056); adjusted OR, 2.12 (P = 0.008)]
Version 2020.1
 Re-excision after initial breast conservation 10.9% versus 18.0%
[OR, 0.56 (P = 0.031); adjusted OR, 0.56 (P = 0.09)]
 Overall mastectomy 43.0% versus 40.2%
[OR, 1.12 (P = 0.45); adjusted OR, 1.64 (P = 0.034)]

www.ago-online.de

N Houssami et al. Ann Surg 2013; 257

 MRI and DCIS
© AGO e. V. Study No. Cases Overall accuracy Sens. Spec.
in der DGGG e.V.
sowie (%) (%) (%)
in der DKG e.V.

Guidelines Breast Gilles et al 1995 172 70 95 51

Version 2020.1
Westerhof et al 1998 63 56 45 72

Bazzocchi et al 2006 112 80 79 68

Kuhl et al 2007 75 - 88 -
Baur et al. 2013 58 - 79,3

www.ago-online.de

„Negative breast MRI findings should not be considered a sure marker of benignancy.“
 Sensitivities CESM
© AGO e. V. Author n MG CESM MRI US Analyse
in der DGGG e.V. Dromain 2011 110 78 92 Per patient
sowie
in der DKG e.V. Fallenberg 2014 118 77.9 94.7 Per patient
Guidelines Breast Mokhtar 2014 60 93.2 97.7 Per patient
Version 2020.1
Lobbes 2014* 113 96.9 100 Per patient
Perez 2015 ECR 98 78 66 Per lesion
Luczinska 2014 152 91 100
Jochelson 2012 52 81 96 96 Per patient
59 83 93 Per lesion

Fallenberg 2013 80 81 100 97 Per patient

Fallenberg 2016 155 81 94 95 Index
55 72 76 Per Lesion

Lalji 2016* 199 93 96,9 Per patient

10 reader

Tennant 2016 100 84 95

www.ago-online.de
Luczynska 2016 116 90 100 92

* Recall from Screening

CESM is comparable to MRI regarding index, a bit inferior for additional lesions
 Pre-therapeutic Staging
Oxford
© AGO e. V.
in der DGGG e.V. LoE GR AGO
 History and clinical examination
sowie
in der DKG e.V. 5 D ++
Guidelines Breast
Version 2020.1 Additional diagnosis for patients with high metastatic potential and/or
symptoms (in decision making for chemotherapy and/or anti-HER2-therapy):
 CT scan of thorax/abdomen 2a B +
 Bone scan 2b B +
 Chest X-ray 5 C +/-
 Liver ultrasound 5 D +/-
 In case of suspicious lesions further diagnosis (e.g.
2a B +
liver-MRI, CEUS*, biopsy etc.)
www.ago-online.de
 FDG-PET or FDG-PET /CT 3a C +/-
 Whole body MRI 4 C +/-
* Contrast enhanced ultrasound
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
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in der DKG e.V.

Guidelines Breast
Version 2020.1
Pathology

www.ago-online.de
 Pathology
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  Versions 2004–2019:
Guidelines Breast
Version 2020.1
Blohmer / Costa / Fehm / Friedrichs / Huober /
Kreipe / Lück / Maass / Schneeweiss/ Sinn / Thomssen / Schmidt

 Version 2020:
Harbeck / Kreipe

www.ago-online.de
 Preanalytics: Fixation
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Minimize time to fixation (cold ischemia time) 5 D ++
Version 2020.1
 Minimal fixation time of 6 hours for
5 D ++
optimal antigen preservation
 Optimal fixation time 6–72 h for core biopsies 5 D ++
 Optimal fixation time for resection specimens:
5 D ++
12–72 h
 Use of neutral buffered formalin 5 D ++

www.ago-online.de
 Use of Breast Cytology*
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Nipple secretion 5 D +
Version 2020.1
 Tumor 5 D -
 Cyst 5 D +/-
 Lymph node 5 D +/-

www.ago-online.de

* Ultrasound-guided core biopsy recommended

 Workup: Core Needle Biopsies
(US-guided or stereotactic)
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Routine workup in step sections
Guidelines Breast 5 D ++
Version 2020.1
(14G: 1–3 step sections / 11G, 8G: 6–8 step sections)
 Correlation with imaging (density, calcifications),
1b B ++
use of B-classification
 Frozen section diagnosis on core biopsies 5 D --
 Routine evaluation of ER/PgR and HER2 status 3b C ++
 Turn-around time < 24 h (histology) 5 D +

www.ago-online.de
 Workup: Breast-Conserving Specimens
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Slicing perpendicular to the longitudinal axis
Version 2020.1
(or perpendicular to the nipple-peripheral axis 5 D ++
in case of spherical specimens)
 Systematic sampling, at least 1 tissue block
5 D ++
every 1 cm
 Inking of resection margins. Sampling of resection
5 D ++
margins
 Documentation after slicing using specimen
5 D +
radiography, photo documentation or diagram
www.ago-online.de
 Workup: Mastectomy Specimens
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Margins always to be sampled
Version 2020.1  Skin close to tumor
5 D ++
 Deep margin
 Other margins, if close (< 1 cm)
 Attention to soft tissue margins in skin
5 D ++
sparing mastectomy
 Routine sampling of uninvolved quadrants,
5 D ++
skin above tumor, and retroareolar region
 Systematic sampling in prophylactic
5 D ++
mastectomies (patients with BRCA-1/2 mutation)
www.ago-online.de
 Workup: Sentinel Node Biopsy
© AGO
Oxford
e. V.
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.  Full workup using step sections of
5 D ++
Guidelines Breast
Version 2020.1 ≤ 500 µm on paraffin embedded tissue
 Cytokeratin immunohistochemistry
 If suspicious, to detect micrometastases 2b B +
 For micrometastasis detection after NACT 2b B +
 As a routine procedure 5 D +/-
 Frozen section (compromises paraffin histomorphology)
 If clinical consequences 5 D +
 If no clinical consequences from frozen section
5 D -
(e.g. cT1 or cT2 and cN0 and BCT)
 Imprint cytology instead of, or in addition
www.ago-online.de 3b D +/-
to frozen section
 RT-PCR for epithelial genes 4 D -
 OSNA 3b B -
 Workup: Intraoperative pathological evaluation
and frozen sections
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Sentinel node biopsy for invasive cancer
Version 2020.1
(compromises final paraffin histomorphology)
 If clinical consequences 5 D +
 No clinical consequences 5 D -

 Closest margin of resection

 If macroscopically < 1 cm 5 D +
 If macroscopically > 1 cm 5 D -
 Lesions ≥ 1 cm, without core biopsy 5 D +
 Non-palpable lesions or lesions < 1 cm 5 D --
www.ago-online.de  Conservation of fresh tissue (tumor banking) 5 D +
 Reporting: Histologic Tumor Type
© AGO e. V.
in der DGGG e.V.
Oxford
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in der DKG e.V.
LoE GR AGO
Guidelines Breast  Histologic tumor typing according to
Version 2020.1 3a C ++
WHO-Classification, (5th ed., 2019)
 Partial special differentiation:
> 50% NST component
and < 50% special tumor type (minor component)
 Mixed differentiation:
> 50% special tumor type
and < 50% NST component
Example: mucinous breast cancer, mixed type
 Pure types:
www.ago-online.de > 90% special tumor type
Examples: tubular or cribriform Ca.
 Reporting: Grade of Malignancy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Use of Nottingham grading system (Elston & Ellis
Guidelines Breast
Version 2020.1 5 D ++
1991) for all types of invasive breast cancer
 In case of very little tumor tissue, pure nuclear
grading or additional criteria, such as Ki-67 5 D ++
proliferation fraction, may be used
 Grading of DCIS, e.g. according to WHO-
5 D ++
Classification, (5th ed., 2019)
 Reporting of tumor grade in numeric form
5 D ++
(e.g. G3)
www.ago-online.de
 Reporting: Tumor Size
and Total Extent of Tumor
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Reporting of invasive tumor size taking into
Version 2020.1
account macroscopic and histologic findings 5 D ++
and clinical imaging results
 Additional reporting of total extent of invasive
5 D ++
carcinoma in case of satellite nodules or multifocality
 Reporting of size of non-invasive component
(DCIS or LCIS) when DCIS or LCIS component is 5 D ++
extensive (more than 2x invasive Ca)

www.ago-online.de
 Reporting: pTNM
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Use of current UICC classification (8th ed.) 5 D ++
Version 2020.1
pT 1-3: Invasive tumor size (largest focus in
case of multifocality or multicentricity)
pT4: Invasion of dermis alone does not qualify
as pT4. Criteria for pT4a/b/c/d must be met.
pT4d: Negative skin biopsy does not rule out pT4d
(inflammatory carcinoma).
pM: pM1 indicates any non-regional disease,
except 2nd primary contralateral.
www.ago-online.de
Use of MX is not recommended.
 Reporting: Margins of Resection
and R-Classification
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Evaluation of distance to all resection margins
Version 2020.1
macroscopically and close margins histologically 5 D ++
(< 1 cm)
 Reporting of minimal distance to resection margin
5 D ++
and its topography
 R-Classification 5 D ++
R0: No residual tumor
R1: Microscopic invasive or noninvasive
carcinoma involving resection margin
www.ago-online.de
RX: Presence of residual tumor cannot be
assessed (e.g. tumor in multiple specimens)
 Reporting: Lymphovascular Invasion
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast  L1: Lymphovascular invasion
Version 2020.1 5 D ++
L0: No lymphovascular invasion
 IHC for evaluation of lymphovascular invasion 3b C -
 Differentiation of peritumoral and extensive
3b C ++
lymphovascular invasion
 Reporting of venous invasion (V0/V1) optional,
5 D +
prognostic significance not established

www.ago-online.de
 Reporting: Evaluation of
Tumor-Infiltrating Lymphocytes (TIL)
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast  Identification of tumors with predominant
Version 2020.1
lymphocytic infiltrate (> 50%) in tumor stroma 5 D +/-
(according to Salgado et al.*)
Consider only lymphocytic infiltrate in tumor stroma
and not at the invasion front
Do not consider central fibrosis and necrotic areas
Report average of lymphocytic infiltrate as
percentage
www.ago-online.de
* Salgado, R., Denkert, C., Demaria, S., Sirtaine, N., Klauschen, F., Pruneri, G., et al.
(2014). The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer:
recommendations by an International TILs Working Group 2014. Annals of Oncology
 Reporting: Evaluation after
Neoadjuvant Chemotherapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast  Identification of tumor bed, otherwise ypTX 4 D ++

Version 2020.1
 Reporting of tumor size as total extent of tumor bed
area involved by infiltrates of residual vital invasive 4 D ++
carcinoma
 pCR when absence of invasive Ca. and absence of
angioinvasion or LN metastases. 2b D +
Presence of ypTis should be recorded
 Use of IHC to identify tumor residues (lymphnodes) 2b B +/-
 Reporting of ypTN after therapy 5 D ++
www.ago-online.de
 Repeat IHC for ER, PgR, and HER2 4 D +/-
 Intraoperative frozen section (reduced sensitivity) 5 D -
 Special Studies:
ER-Testing by IHC
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Immunohistochemical detection on paraffin
Guidelines Breast 1a A ++
Version 2020.1
embedded (FFPE) tissue
 Reporting percentage of pos. tumor nuclei
1a A ++
(pos. if ≥ 10%, low pos. if ≥ 1%–9%)
 Only Allred Score (0–8) or Remmele Score (0–12) 4 D -
 Re-evaluation on excision specimen if uncertain or
5 D +
triple-negative on core biopsy

www.ago-online.de
 Low ER+ (1–10%)
© AGO e. V. Sanford AS et al. High Incidence of Germline BRCA 314 Pat. 1–9% ER, Anteil
in der DGGG e.V.
sowie
Cancer 2015 Mutation in Patients with ER BRCA mutierter Fälle wie
in der DKG e.V. Low-Positive/PR Low-Positive/HER-2 neu bei ER -
Guidelines Breast Negative Tumors
Version 2020.1
Deyarmin B et al. Effect of ASCO/CAP Guidelines for 26 Pat. 1–9% ER,
Ann Surg Oncol (2013) 20:87–93 Determining ER Status on Molecular Genexpression eher wie
Subtype TN oder HER2 enr

Prabhu YS et al. 2014; J Cancer A Majority of Low (1–10%) ER Positive 21 Pat. 1–9% ER,
5(2): 156–165. Breast Cancers Genexpression wie ER-,
Behave Like Hormone Receptor Negative Überleben < ER+
Tumors

www.ago-online.de Yi et al. Annals Oncol. 2014 Which threshold for ER positivity? a 251 Pat. 1–9% ER
retrospective study based on 9639 Überleben = ER-
patients
 Special Studies:
PgR-Testing by IHC
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Immunohistochemical detection on paraffin
Guidelines Breast 1a A ++
Version 2020.1
embedded (FFPE) tissue
 Reporting percentage of pos. tumor nuclei
1a A ++
(pos. if ≥ 10%)
 Only Allred Score (0–8) or Remmele Score (0–12) 4 D -

www.ago-online.de
 Additional Special Studies:
Molecular Analysis of ER/PgR Status
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Evaluation of hormone receptors using
Guidelines Breast 3b A +/-
Version 2020.1
validated gene expression test kits
 Evaluation of hormone receptor by
5 D -
RNA-quantification
 Use of molecular receptor analysis for subtyping 3b A +/-

www.ago-online.de
 HER2-Analysis by IHC
© AGO e. V.
Oxford
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.
 Reporting of immunohistochemistry (IHC):
Guidelines Breast
Version 2020.1  3+ staining pattern: HER2+ if strong complete
circular membrane staining of > 10% invasive 1a A ++
cells
 2+ staining pattern: If > 10% circular but
moderate/weak membrane staining or ≤ 10%
strong staining, U-shaped staining in 1a A ++
micropapillary carcinoma: ISH required (CISH,
SISH, FISH)
www.ago-online.de
 HER2-Analysis by ISH when IHC 2+
© AGO
Oxford
e. V.
in der DGGG e.V. LoE GR AGO
sowie
in der DKG e.V.

Guidelines Breast  Single-Color In-Situ-Hybridisation (ISH): 3a C ++

Version 2020.1
 HER2+ if signal counts ≥ 6 in at least 20 cohesive cells
 negative if signal counts < 4 signals/nucleus
 2-Color ISH recommended for ≥ 4 and < 6 signals/nucleus
 Two-Color In-Situ-Hybridisation (ISH): 3a D ++
 Group 1: Ratio ≥ 2.0 and signals/nucleus ≥ 4.0 -> HER2+
 Group 2: Ratio ≥ 2.0 and signals/nucleus < 4.0
-> HER2- (no benefit of anti-HER2 therapy)
 Group 3: Ratio < 2.0 and signals/nucleus ≥ 6.0
-> HER2+ (but benefit of anti-HER2 therapy not certain)
www.ago-online.de  Group 4: Ratio < 2.0 and signals/nucleus ≥ 4.0 und < 6
-> HER2- (no benefit of anti-HER2 therapy)
 Group 5: Ratio < 2.0 und signals/nucleus < 4.0 -> HER2-
 HER2 testing by validated dual-probe ISH assay
when IHC = 2+

© AGO e. V. Batch controls and on-slide controls show appropriate hybridization

in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
HER2/CEP17 ratio ≥ 2.0 HER2/CEP17 ratio < 2.0
Version 2020.1

Group 1 Group 2 Group 3 Group 4 Group 5

Average HER2 Average HER2 Average HER2 Average HER2 Average HER2
copy number ≥ 4.0 copy number < 4.0 copy number ≥ 6.0 copy number ≥ 4.0 copy number <4.0
signals/cell signals/cell signals/cell - < 6.0 signals/cell signals/cell

mostly mostly mostly

www.ago-online.de
HER2 HER2 HER2 HER2 HER2
positive negative positive negative negative
 HER2 Testing on Core Biopsies
© AGO e. V.
in der DGGG e.V.
False positive immunohistochemical labeling may occur in core biopsies.
sowie
in der DKG e.V.
Therefore, methods of individual laboratories should be validated by comparison of
Guidelines Breast
core biopsies and resection specimens. Background staining should be evaluated by
Version 2020.1
comparison with normal duct epithelium.
Alternatively, all G1 and G2 cases with HER2 3+ in core biopsies may be analyzed by
ISH or may be re-evaluated in the resection specimen.
False positivity is likely when HER+ was reported in G1 tumors of the following types:
Infiltrating ductal or lobular carcinoma, ER and PgR positive, Tubular (at least 90%
pure), Mucinous (at least 90% pure) Cribriform (at least 90% pure), Adenoid cystic
carcinoma (90% pure).‎
In case of discrepancy between core biopsy and specimen, the HER2 overexpressing
sample should be re-evaluated by a different method. If still discrepancy – anti-HER2-
www.ago-online.de treatment if amplified in one of both samples. Expected rate of HER2-overexpression:
15% HER2 positive
 Additional Special Studies:
Molecular Analysis of HER2 Status
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Therapy decisions should only be based on IHC and
Guidelines Breast 1a A ++
Version 2020.1
ISH
 Evaluation of HER2 using validated gene expression
3b B -
test kits
 Evaluation of HER2-amplification by RNA-sequencing 5 D -
 Use of molecular HER2-testing for subtyping 3b B +/-

www.ago-online.de
 Special Studies:
Evaluation of Ki-67 Score
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Counting of tumor nuclei at the invasion front 5 D ++
Version 2020.1
 Semiquantitative eyeballing or counting of labelled
2 A ++
cells in core needle biopsies
 Consideration of weakly stained tumor nuclei 5 D ++
 Reporting of Ki-67 positive nuclei as percentage 5 D ++
 Establishing of laboratory standards and cut-off
5 D ++
values
 Use of image analysis for objective Ki-67 evaluation 5 D +

www.ago-online.de
 Predictive PD-L1 Assay
Oxford
© AGO e. V.
in der DGGG e.V.
LoE GR AGO
sowie
in der DKG e.V. ▪ Immunhistochemical assay 2b C
Guidelines Breast  Prediction of atezolizumab efficacy in triple-negative
Version 2020.1 metastatic breast cancer
 Suitable for punch biopsies and resected specimens
 Ventana Antibody SP142 with positive control (tonsil)
other PD-L1 antibodies are potentially equivalent (different
cut-offs have to be regarded)
 Cytoplasmic staining of at least 1% of the leucocyte stromal
infiltrate (lymphocytes, macrophages, plasma cells,
granulocytes outside of abscesses)
 No evaluation of tumor staining
▪ Quality assurance
www.ago-online.de
 Obligatory participation in further education and training
programs
5 D ++
 Reference pathology in case of not yet completed
qualification
 Mutational studies in mBC:
„Precision medicine“ for targeted therapies
© AGO e. V. Gene Therapeutic Gene region Source Oxford AGO
in der DGGG e.V. Relevance LOE GR
sowie
in der DKG e.V. BRCA1, BRCA2 PARP Inhibitor all exons Germ line: blood cells 1b A ++
Guidelines Breast
Somatic: tissue 2b B +/-
Version 2020.1
PIK3CA Alpelisib exons 7,9 and 20 Primary tumor, 1b A +
metastases, plasma

HER2-mutation Neratinib, kinase and extracellular Primary tumor, 4 C +/-

(irrespective of HER2- Lapatinib domain; S310, L755, metastases, plasma
status) V777, Y772_A775dup

ESR1 Resistance vs exons 4,7 und 8 metastases, plasma 2b B +/-

aromatase inhibit.

NTRK gene fusion Larotrectinib, Gene fusions and splice Tumor tissue, in 2a B +
www.ago-online.de
Entrectinib variants particular secretory
breast caner
MSI Pembrolizumab Mikrosatellite instability tissue 2a B +
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
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in der DKG e.V.

Guidelines Breast
Version 2020.1
Prognostic and
Predictive Factors
 Prognostic and
Predictive Factors
© AGO e. V.
in der DGGG e.V.
sowie
 Versions 2002–2019:
in der DKG e.V.
Costa / Fasching / Fersis / Friedrichs / Gerber / Göhring / Harbeck / Janni /
Guidelines Breast
Version 2020.1 Kolberg-Liedtke / Loibl / Lück / Mundhenke / Nitz / Rody / Schaller /
Schmidt / Schmutzler / Schneeweiss / Simon / Solomayer / Thill /
Thomssen / Witzel / Wöckel

 Version 2020:
Kreipe / Thomssen

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 Definition
© AGO e. V.
in der DGGG e.V. A Prognostic Factors is associated with the probability of the course of the
sowie
in der DKG e.V. disease (e.g. disease-free or progression-free survival, overall survival). The
Guidelines Breast
Version 2020.1
probability can be influenced by therapy.
A Predictive Factor is associated with the probability of the effect of a given
therapy.

www.ago-online.de
© AGO e. V.
in der DGGG e.V.
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in der DKG e.V.

Guidelines Breast
Version 2020.1

“Low absolute risk implies

low absolute benefit”

www.ago-online.de

Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Lancet 379: 432-444, 2012
 Quality Criteria
© AGO e. V.
in der DGGG e.V.  Biological hypothesis
sowie
in der DKG e.V.  Simple and standardized assessment method, quality assurance (QA) of
Guidelines Breast
Version 2020.1
the test
 Prospectively planned statistical evaluation (primary goal)
 Validation of clinical significance according to
 „Oxford Level of Evidence (LoEOx2001)“ criteria and „Grades of
Recommendation (GR)“
 „Grades of Recommendation (GR)“ as well as modified LoE criteria for the use
in archived specimen (LoE2009) and category of tumor marker study (CTS)
 Clinical relevance for treatment decisions
www.ago-online.de
1 Simon et al, J Natl Cancer Inst 101: 1446-1452, 2009
2 Febbo et al, J Natl Compr Canc Netw 9 Suppl 5: S1-32, 2011
3 McShane, Hayes, J Clin Oncol 30: 4223 – 4232, 2012
 Early Breast Cancer (M0) – eBC
Prognostic Factors I
Oxford
© AGO e. V.
in der DGGG e.V.
Factor LoEOx2001 GR AGO
 Tumor size – pT
sowie
in der DKG e.V. 1a A ++
Guidelines Breast  Axillary lymph node status – pN 1a A ++
Version 2020.1
 Histological tumor type (mucinous, tubular etc.) 2b B ++
 Grade (Elston & Ellis) – G 2a B ++
 Age 2a B ++
 Histologically proven peritumoral lymphatic
vessel and vascular invasion (L1 V1) 1b B ++
 pCR after NACT* in (luminal-B-like, HER2+, TN) 1a A ++
 Increased risk of recurrence in
invasive-lobular BC, cT3/4, N+ 2aa B +/-
 Obesity (BMI > 30 kg/m²) 1b B +
www.ago-online.de  Margins (resection status) – R0/R1 1a A +

* NACT = Neoadjuvant Chemotherapy

 Early Breast Cancer (M0) - eBC
Prognostic Factors II
© AGO e. V. Oxford
in der DGGG e.V.
sowie Factor LoE GR AGO
in der DKG e.V.

Guidelines Breast
 ER / PgR 2a B ++
Version 2020.1
 HER2 (IHC, ISH) 2b B ++
 ER / PgR / HER2/ Ki-67 to assess the
molecular type 2b B ++
 uPA / PAI-1 (Femtelle® ELISA) in N0 1a A +
 Proliferation markers
 Ki-67 before, during, or after treatment 1a B +

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 Reproducibility
© AGO e. V.
in der DGGG e.V.  ER/PR: concordance central vs local is high
sowie
in der DKG e.V. (97%; Plan B, SABCS 2014)
Guidelines Breast
Version 2020.1
 Grading: concordance central vs local is 68%
(PlanB, JCO 2016)
 HER2: frequency of false-positive test results 6%
(ASCO /CAP JCO 2013)
 Impact of routine pathologic review in N0 BC: 20% changes :
grading 40%, LVI 26%, N 15%, margin 12% (JCO 2012)
 pN0 from MIRROR study: pN0 was upstaged in 22%,
in central pathology review (Ann Oncol 2012)
www.ago-online.de
 Inter- and intraobserver variability in measurement of
Ki-67 is high (J Nat. Cancer Institute 2011)
 Early Breast Cancer (M0) - eBC
Prognostic Factors III
Oxford
© AGO e. V. Factor LoE GR AGO
in der DGGG e.V.
sowie  Gene expression profiles (GEP, multigene assays, gene signatures)
in der DKG e.V.
 MammaPrint® (N0-1) 1b A +*
Guidelines Breast
Version 2020.1  Oncotype DX® (N0-1, HR+ HER2-) 1b A +*
 EndoPredict® (N0-1, HR+, HER2 -) 2b B +*
 Prosigna® (N0-1, HR+, HER2 -) 2b B +*
 Breast Cancer IndexSM (N0-1, HR+ HER2-) 2b B +/-*
 CTS Clinical Treatment Score** 2b B +
 Disseminated tumor cells (DTC, in bone marrow) 1a A +/-
 Circulating tumor cells (CTC, in blood, Cell Search®) $ 1b A +/-
 CTC before NACT (regarding OS, DDFS, LRFI) 1b B +/-
 Therapy decisions based on CTC phenotypes 3a C -
www.ago-online.de
 Cell-free DNA (cfDNA, in blood, for DFS, PFS, OS) 2ba B +/-
* Should only be used in selected patients if all other criteria are inconclusive for therapeutic decision making
** estimation of late recurrence; $ Validated clinical data only available for this assay
 Commercially Available Molecular Tests
© AGO 70 gene signature 21 gene Recurrence score 8 gene signature PAM 50 Breast Cancer
e. V.
(MammaPrint®) $ (Oncotype DX®) $ (Endopredict®) $ (Prosigna®) $ IndexSM (BCI) $
in der DGGG e.V.
sowie
Provider Agendia Genomic Health Sividon (Myrirads) NanoString Biotheranostics
in der DKG e.V.
Type of assay 70-gene assay 21-gene recurrence score 11-gene assay 50-gene assay 5 + 2 (MGI+H/I)
Guidelines Breast fresh frozen
Version 2020.1 Type of tissue (technical validation for FFPE FFPE FFPE FFPE
FFPE available)
Direct hybridization
Technique Microarrays for RNA qRT-PCR q-RT-PCR q-RT-PCR
(nCounter®)
Central lab yes yes no no yes
Prognostic
prognostic prognostic
Indication and prognostic pT1-3pNo – pN1
prognostic (pre-) postmenopausal postmenopausal
population N-/+, ER+ ER+ / HER2–
N-/+, < 70 Jahre N-/+, ER+ HER2- N-/+, ER+ HER2-
studied endocrine treated Endocrine treated
endocrine treated endocrine treated
ROR (Low – inter-
Risk classes Low - high RS (Low – intermediate – high) Low - high mediate – high), Low - high
molecular types
Clinical
yes yes yes yes Yes
Validation
FDA clearance as “In Vitro Clinical Laboratory
www.ago-online.de Diagnostic Multivariate Improvement Amendments CE-Mark
Registration Index Assay (IVDMIA)« (CLIA) + College of American CE-Mark FDA 510(k) Service Mark (SM)
CE-Mark Pathologists (CAP)-accredited Clearance
(fresh tissue and FFPE) ref lab
$ Validated clinical data only available for this assay
 Commercially Available Molecular Tests
© AGO e. V. 70 gene signature 21 gene Recurrence score 8 gene signature PAM 50 Breast Cancer
in der DGGG e.V. (MammaPrint®) $ (Oncotype DX®) $ (Endopredict®) $ (Prosigna®) $ IndexSM (BCI)
sowie
in der DKG e.V. Prognosis after 5
yrs (late not separately shown yes yes yes Yes
Guidelines Breast
recurrences)
Version 2020.1E
Predictive impact
(chemotherapy poorly validated yes not shown not shown EAT after 5 yrs
benefit)

Prospective- NSABP B-14 (14%) Ma JCO 2006

ABCSG 6 (19%) MA.12 (59%)
retrospective NSABP B-20 (28%) Jansen JCO 2007
Multicenter ABCSG 8 (36%) MA.5 (66%)
evidence ECOG 9127 Jerevall BRCT 2008
validation GEICAM-9906 (45%) ABCSG 8 (44%)
(% of recruited SWOG 8814 (40%) Bartlett AnnOnc
ATAC (10%) ATAC (16%)
patients) ATAC (30%) 2019
TAILORx (9-year DFS, OS), N0, low-
risk, S<11, intermediate risk RS ≤ 25,
Prospective MINDACT (N0, N1) (5- high risk RS
≥ 26) – – -
evidence year DFS, OS)
PlanB (N0, highrisk/N+) (5-year
DFS, OS)
www.ago-online.de

$ Validated clinical data only available for this assay

 Prospective Randomized Trials
(Oncotype DX [TailorX, PlanB], MammaPrint [MINDACT])
Prognosis in the low-risk group is for both tests favorable
© AGO e. V.
in der DGGG e.V.
(94% 5-Jahres DFS with adjuvant endocrine therapy only)
sowie
in der DKG e.V. TailorX PlanB MINDACT
Guidelines Breast Follow-up period Median 90 mo 5-yr-DFS Median 60 mo
Version 2020.1
Chemotherapy-
6615 of9427 3336 of 6693
Proportion clinically low risk Indication was
(70.2%, adj-onl) inclusion criterion (49.8%, adj-onl)
Proportion of clinically high, genomic low 16.7% 15.3% 23.2% (high clinical
risk patients (clinically suitable for chemotherapy) (RS 0-10) RS (0–11) + low genomic risk)

Test failure rate n.r. 2.9% 26%

(fresh frozen tissue)

Proportion of intermediate risk patients 69.1% 60.4%

n.a.
(applies only to Oncotype DX) (RS 11–25) (RS 12–25)
www.ago-online.de Proportion of high risk patients 14.3% 24.3% 27.0% (high clinical
(applies only to Oncotype DX) (RS ≥ 26) (RS ≥ 26) + high genomic risk)

10-yr-follow up --- --- ---

 Adjuvant endocrine therapy
Predictive factors for DFS
© AGO e. V.
Oxford
in der DGGG e.V.
sowie Therapy Factor LoE GR AGO
in der DKG e.V.

Guidelines Breast  Endocrine therapy  ER/PgR status [%] 1a A ++

Version 2020.1
 IHC staining intensity (ER/PgR) 1a A -
 Extended endocrine  Breast Cancer IndexSM (5y Let (MA.17) 2b B +
therapy (EAT) or 5y Tam (aTTOM), resp., after 5y Tam)
 Tamoxifen  CYP2D6-polymorphism 2b B -
 Ovarian ablation or  Menopausal status 1c A ++
suppression
 Aromatase inhibitors  Menopausal status 1c A ++
vs. tamoxifen  ER / PgR / HER2 as single factor 1c A -
www.ago-online.de  Invasiv-lobular breast cancer 2b B +
 Ki-67 high 2b B +/-
 Obesity (BMI > 30 kg/m²) 2b B +/-
 Adjuvant Chemotherapy and Targeted
Therapy Predictive Factors for DFS
© AGO e. V. Oxford
in der DGGG e.V.
sowie Therapy Factor AGO
in der DKG e.V. LoE GR
Guidelines Breast
Version 2020.1
 Adjuvant uPA / PAI-1 (ELISA, Femtelle®) 1a A +/-
Chemotherapy 70-Gene-signature (Mammaprint®) 1b A +
21-Gene-signature (Oncotype DX RS®) 1b A +
EPclin (Endopredict®) 2b B +
PAM-50 (Prosigna®) 2b B +
 Anti-HER2-Therapy HER2 (IHC, ISH) 1a A ++
www.ago-online.de
 Neoadjuvant Systemic Chemotherapy (NACT)
Predictive Factors for pCR I
© AGO e. V. Oxford
in der DGGG e.V.
Factor pCR* AGO
sowie
in der DKG e.V. Probability
LoE GR
Guidelines Breast
Version 2020.1  Young age  1a A +
 cT1 / cT2 tumors o. N0 o. G3  1a A ++
 Negative ER- and PgR-status  1a A ++
 Triple negative breast cancer (TNBC)  1a A ++
 Positive HER2-status  1a A ++
 Early response, clnically  1b A +
 Invasive-lobular breast cancer  1a A +
www.ago-online.de
 Metaplastic breast cancer  4 C +

* High () or very high () probabililty of pCR, low () or very low () probabililty of pCR
 Neoadjuvant Systemic Chemotherapy (NACT)
Predictive Factors for pCR II
© AGO e. V. pCR* Oxford
in der DGGG e.V. Factor AGO
sowie Probability LoE GR
in der DKG e.V.

Guidelines Breast  Gene expression profiles (gene signatures)

Version 2020.1
(Mammaprint®, Endopredict® Oncotype DX®,  2b B +/-
Prosigna®, Breast Cancer IndexSM)
 Ki-67  2b B +
 Tumor infiltrating lymphocytes**  2a B +
 PIK3CA mutation (for HER2-positive BC)  2a B +/-
 gBRCA-mutation (for the effect of
chemotherapy)  2b B +
 gBRCA-mutation (for the effect of platinum) ↔ 2b B +/-
www.ago-online.de
* High () or very high () probabililty of pCR, low () or very low () probabililty of pCR
** Defined as dense lymphocytic infiltration of inner peritumoral stroma outside of the invasion front (lymphocytes
make up >50% of stroma area)
 Metastatic Breast Cancer (mBC)
Prognostic Factors
© AGO e. V. Oxford
in der DGGG e.V.
AGO
sowie
in der DKG e.V. Factor LoE GR
Guidelines Breast
Version 2020.1
 Circulating tumor cells (CTC in blood, Cell
Search®)
 Prognosis 1a A +
 Early response assessment (3w) 1b B +
 Therapy decision solely based on dynamics
1b A -*
of CTC numbers over time or CTC phenotype
 Cell-free DNA (cfDNA in blood) 2a A +/-

www.ago-online.de

* Study participation recommended

 Treatment of Metastatic Breast Cancer
Predictive Factors for response
Oxford
© AGO e. V.
in der DGGG e.V. Therapy Factor LoE GR AGO
sowie
in der DKG e.V.

Guidelines Breast
 Endocrine therapy ER / PR (prim. tumor, better: metastasis) 1a A ++
Version 2020.1
Response to prior therapy 2b B ++
Autocrine receptor mutation (ESR1) 2b B +
 Chemotherapy Response to prior therapy 1b A ++
 Anti-HER2-therapy HER2 (prim. tumor, better: metastasis) 1a A ++
 Checkpoint-Inhibitors PD-L1 IC positivity# in TNBC
(Atezolizumab) (primary tumor or metastasis) 1b B +

 PARP-Inhibitors gBRCA1/2-mutation 1a A ++
 Bone modifying drugs Bone metastasis 1a A ++
www.ago-online.de
 Any therapy CTC monitoring 1b A +*
* In clinical trials
# ≥ % on immune cells (IC) using SP142 (see chapter „pathology“)
 Mutation diagnostics in mBC:
„Precision medicine“ for targeted therapies
© AGO
Altered genes Therapeutic Gene region Material Oxford AGO
e. V.
in der DGGG e.V. relevance LOE GR
sowie
in der DKG e.V. BRCA1, BRCA2 PARP Inhibitors All exons Germline: Blood cells 1b A ++
Guidelines Breast
Somatic: Tissue 2b B +/-
Version 2020.1
PIK3CA Alpelisib Exons 7,9 and 20 Primary tumor, 1b A +
metastases, plasma

HER2-mutation Neratinib, Kinase- and Primary tumor, 4 C +/-

(independent of HER2- lapatinib extracellular domains; metastases, plasma
status) S310, L755, V777,
Y772_A775dup
ESR1 Resistance Exons 4,7 und 8 Metastases, plasma 2b B +/-
against AI

NTRK gene fusion Larotrectinib, Fusion- and splice Tumor tissue, espec. 2a B +
www.ago-online.de entrectinib variants secretory breast cancer
MSI Pembrolizumab Microsatellite- Tissue 2a B +
instability
 Therapy-relevant mutational analysis for
„actionable“ genomic alterations in BC
© AGO
Oxford
e. V.
in der DGGG e.V. Factor* Outcome LoE GR AGO
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Evidence from studies with other cancer patients („tumor-agnostic testing“)

 Companion Diagnostics for therapies of Efficacy of diverse

4 D +/-**
other tumor entities (z.B. BRAF, FGFR1, …) therapies

 Large Panel Gene Analysis (e.g.

FoundationOne, GPS Cancer, NeoSelect, Efficacy of diverse
3a C +/-**
Molecular Health Guide, local „hand- therapies, prognosis
selected„ panels)
www.ago-online.de

* Assessment method for somatic mutations (tumor tissue, cf-DNA) is not taken into consideration for LOE
** Participation in clinical trials or structured registries recommended
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Lesions of Uncertain
Malignant Potential (B3)

(ADH, LIN, FEA, Papilloma, Radial Scar)

 Lesions of Uncertain Malignant Potential (B3)
(including “Precursor Lesions”)
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. ▪ Versions 2005–2019:
Guidelines Breast
Version 2020.1 Albert / Audretsch / Brunnert / Ditsch / Fersis / Friedrich / Friederichs /
Gerber / Huober / Kreipe / Nitz / Rody / Schreer / Sinn / Thomssen

▪ Version 2020:
Fallenberg / Schmidt / Sinn

www.ago-online.de
 Pathology Reporting for Minimal
Invasive Biopsies
© AGO e. V.
in der DGGG e.V.
sowie
B-Classification*
in der DKG e.V.

Guidelines Breast
Version 2020.1 B1 = Unsatisfactory or normal tissue only
B2 = Benign lesion
B3 = Lesion of uncertain malignant potential
B4 = Suspicion of malignancy
B5 = Malignant
B5a = Non-invasive
B5b = Invasive
B5c = In situ/invasion not assessable
B5d = Non epithelial, metastatic
www.ago-online.de

* National Coordinating Group for Breast Screening Pathology (NHSBSP),

E.C. Working Group on Breast Screening Pathology, S3-Leitlinie Mammakarzinom der DKG
 B3-Lesions
© AGO e. V. 1. Lesions with increased risk of associated DCIS or invasive carcinoma
in der DGGG e.V.
sowie
 Atypical ductal hyperplasia (ADH) or atypical epithelial proliferation of ductal type (classification
in der DKG e.V. possibly as B4, depending on extent of lesion)
Guidelines Breast  Flat epithelial atypia (FEA)
Version 2020.1
 Lobular neoplasia (LIN; LN; now subdivided into ALH and LCIS, no differentiation according to
older nomenclature) classical and non-classical type
 Atypical apocrine adenosis
2. Potentially heterogeneous lesions with risk of incomplete sampling
 Cellular fibroepithelial lesion or phyllodes tumour without evidence of malignancy
 Intraductal papilloma with/without atypia (possibly also B4, depending on the extent of the
lesion)
 Radial scar or complex sclerosing lesion (unless the radial scar only microscopically, not
radiologically detected: B2)
 Hemangioma
www.ago-online.de
3. Rare Lesions
 Adenomyoepithelioma, microglandular adenosis, mucocele-like lesion, nodular fasciitis,
desmoid-type fibromatosis, spindle cell lesion of unknown significance
 Management after
Minimally Invasive Biopsy
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Version 2020.1
 Interdisciplinary conference:
Concordant findings in pathology and imaging?
 yes: proceed according to histologic type 3a C ++
 no: open biopsy 3a C ++
Vacuum-assisted biopsy (after core biopsy) 5 D +

www.ago-online.de
 Atypical ductal Hyperplasia (ADH)
© AGO e. V.
in der DGGG e.V.
 Synonyms: Atypical intraductal epithelial proliferation (AIDEP),
sowie
in der DKG e.V.
atypical epithelial proliferation of ductal type
Guidelines Breast  Definition: Atypical intraductal proliferations with cytological and structural
Version 2020.1
features of well differentiated DCIS, such as rigid bridging or micropapillae, well
demarcated cell borders and occupy less than two separate duct spaces. The
extension of all involved lumens within one ductulo-lobular unit is less than 2 mm.
Atypical ductal proliferations larger than 2 mm or in at least two ductules are
classified as DCIS (low-grade).
 Indicator/Precursor lesion: Ipsi- and contralateral breast cancer risk:
RR 3 - 5 x after 3 - 5 years.
 Particularly high risk for breast cancer when combined with BIRADS IV / V and high
breast volume.
www.ago-online.de
 Strategy after Diagnosis of ADH
in Biopsy Sypecimen
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
ADH in core- / vacuum-assisted biopsy:
Version 2020.1
 Open excisional biopsy 3a C ++
 Open excisional biopsy may be omitted, if:
a) No mass-lesion radiologically, and
b) a small lesion (≤ 2 TDLU*) in vacuum biopsy, and 5a C +/-
c) complete removal of imaging abnormality
ADH at margins in open biopsy specimen:
 No further surgery, if incidental finding
accompanies invasive or intraductal 3a C ++
carcinoma
www.ago-online.de

* Terminal ductal-lobular unit

 Lobular Intraepithelial Neoplasia (LIN)
© AGO e. V.
in der DGGG e.V.  Includes:
sowie
in der DKG e.V.  Atypical lobular hyperplasia
Guidelines Breast
Version 2020.1
 Classical lobular carcinoma in situ (LIN, classical variant)
 Non-Classical lobular carcinoma in situ (LIN, classical variant)
 LIN 1–3 classification is not sufficiently validated prognostically
 Non-Classical LIN (pleomorphic LIN, florid LIN) are classified as
premalignant → B5a
 Indicator/Precursor lesion:
Ipsi- and contralaterally increased breast cancer risk:
7 x after 10 years
www.ago-online.de
 Classical LIN and Variants
of LIN (non-classical LCIS)
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

Classical LIN LIN with comedo type necrosis

www.ago-online.de

Florid LIN Pleomorphic LIN

 LIN with High Risk
© AGO e. V.
in der DGGG e.V.  Non-Classical LCIS:
sowie
in der DKG e.V.  Pleomorphic LCIS: high grade cellular atypia, frequent involvement of
Guidelines Breast ductules, comedo-type necrosis, microcalcifications
Version 2020.1
 Florid LCIS: Involvement of numerous lobuli with distension and near
confluence, extension to ductules and neighboring TDLU
 LCIS with microinvasion*:
 classical LCIS: n = 11
 florid LCIS: n = 4
 pleomorphic LCIS: n = 1

www.ago-online.de

* Ross DS. Am J Surg Pathol 2011 35: 750–6.

 Strategy after Diagnosis of LIN
© AGO
Oxford
e. V.
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.
 LIN in core- / vacuum-assisted biopsy:
Guidelines Breast
Version 2020.1  No further measures if LIN (LCIS, classical variant)
with involvement of ≤ 3 TDLU (terminal ductulo-lobular unit) in 2b C ++
vacuum biopsy and concordant with imaging
 Open excisional biopsy, with pleomorphic LIN,
florid LIN, or LIN with comedo type necrosis
or if not concordant with imaging findings 2b C ++

 LIN at margins of resection specimen (BCT):

 No further surgery 2a C ++
Exceptions:
www.ago-online.de a) Pleomorphic LIN, florid LIN, or LIN with necrosis
a) Imaging abnormality is not removed
 Flat Epithelial Atypia (FEA)
© AGO e. V.
in der DGGG e.V.
 Synonyms: Columnar cell hyperplasia with atypia,
sowie
in der DKG e.V.
columnar cell metaplasia with atypia,
Guidelines Breast
ductal intraepithelial neoplasia grade 1A (DIN 1A)
 Differential diagnosis:
Version 2020.1

 ADH is discriminated by architectural features (micropapillary, cribriform) →

B3
 Clinging carcinoma is discriminated by high grade nuclear atypia (G2/G3)
and classified as ductal carcinoma in situ → B5a
 Marker lesion:
FEA frequently is associated with calcifications and may be associated with low-
grade intraductal carcinoma. Frequent occurrence in combination with high density
of the breast (OR1.3). High risk for associated breast cancer in the presence of
www.ago-online.de
extensive calcifications (also when 75% of calcification remained after biopsy), age >
= 57J, > 1 cm in imaging, > = 4 foci.
 Strategy after Diagnosis of FEA
© AGO e. V.
Oxford
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.
 FEA in core biopsy/vacuum-assisted biopsy:
Guidelines Breast
Version 2020.1  Open excisional biopsy may be omitted under the following
circumstances:
3b C +
a. a small lesion (≤ 2 TDLU* in vacuum biopsy)
and
b. Complete or near complete removal of imaging
abnormality
 Representative open excisional biopsy in radiologically
extensive microcalcifications or discordance to the 5 C +
radiological result
 FEA at margins in resection specimen:
www.ago-online.de
 No further surgery, unless calcifications have not been
completely removed
3b C ++

* Terminal ductal-lobular unit

 Papilloma
© AGO e. V.
in der DGGG e.V.  Includes: Central and peripheral papilloma > 2 mm,
sowie
in der DKG e.V. atypical intraductal papilloma (B3)
Guidelines Breast
Version 2020.1
 To be distinguished from peripheral micropapilloma arising in the TDLU,
size ≤ 2 mm, may be multiple
 To be distinguished from papilloma with DCIS, from intraductal papillary
carcinoma, and from encapsulated papillary carcinoma
 Precursor lesion:
May be associated with in-situ or invasive cancer (up to 6% without atypia
if concordant imaging, up to 30% with atypia), increased ipsilateral risk for
cancer (up to 4.6% and up to 13% in case of atypical papilloma) .
www.ago-online.de
 Strategy after Diagnosis of
Papilloma
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Papilloma without atypia in core needle or
Version 2020.1
vacuum biopsy:
→ no further therapy, if biopsy sufficiently
representative (100 mm2) and concordant with 3a C ++
imaging
 Multiple papillomas
→ open biopsy 3a C ++
 Papilloma with atypia in core needle or
vacuum biopsies:
→ open biopsy 3a C ++
www.ago-online.de
 Papilloma at resection margin:
→ no published data available
 Radially Sclerosing Lesion

 Benign pseudoinfiltrative lesion with central fibroelastic core and

© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. radical configuration.
Guidelines Breast
Version 2020.1  Includes:
 radial scar
 complex sclerosing lesion (> 1 cm)
 Additional risk factor in patients with benign epithelial
hyperplasia (proliferating breast disease)
 Risk for upgrade in open biopsy after diagnosis of a radial
sclerosing lesion, depending on the size of the needle (CNB) or
www.ago-online.de method (VAB) and additional atypia: 1–18%
 Strategy after Diagnosis of Radial Scar,
Complex Sclerosing Lesion (CSL)
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Radial scar / CSL in core- / vacuum-assisted
Version 2020.1
biopsy:
→ Open excisional biopsy may be omitted with a small (<
5mm) lesion or complete removal or near complete 5a C +
removal of imaging abnormality
 Radial scar / CSL at margins in resection specimen:
→ No further surgery 3b C ++

www.ago-online.de
 Management Radial Scar
 “When RS (radial scar) is associated to atypia (such as flat epithelial atypia
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. (FEA), atypical ductal (ADH), or lobular neoplasia (classical LN)),
Guidelines Breast
Version 2020.1
management can the same as recommended in cases of atypia alone.

www.ago-online.de Rageth CJ, O`Flynn EAM, Pinker K et al.: Second International Consensus Conference on lesions
of uncertain malignant potential in the breast (B3 lesions). Review, Breast Cancer Res Treat, 2018,
doi: 10.1007/s10549-018-05071-1
 Follow-up Imaging for Women Age
50–69 Years with B3-Lesions
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast  FEA, non-atypical papilloma

Version 2020.1
 Screening mammography 5 C ++
 LIN
 Mammography (12 months) 3a C ++
 ADH
 Mammography (12 months) 3a C ++
 Women with LIN and ADH should be
3a C ++
informed about their elevated risk of breast cancer

www.ago-online.de
 Medical Prevention for Lesions with Uncertain
Biological Behavior (incl. LIN, ADH)
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast
Version 2020.1
 Tamoxifen for women > 35 years 1a A +/-
 Low-dose Tamoxifen 5mg (3 years) 2b B +/-
 Aromatase inhibitors (Exemestane, Anastrozole)
1b A +/-
for postmenopausal women
 Raloxifen for postmenopausal women: Risk reduction
1b A +/-*
of invasive BC only

Medical prevention should only be offered after individual and

www.ago-online.de
comprehensive counseling; overall benefit depends on classification, age,
and pre-existing conditions that may influence occurrence of side effects.
* Risk situation as defined in NSABP P1-trial (1,66% in 5 years)
 Low-dose Tamoxifen
© AGO e. V.
in der DGGG e.V.  500 women ≤ 75 with intraepithelial neoplasia (ADH, LCIS, DCIS)
sowie
in der DKG e.V.  Tamoxifen 5 mg/d for 3 years vs. placebo
Guidelines Breast
Version 2020.1  Breast cancer events: 14 vs. 28
 invasive: 11 vs. 19
 HR 0,48; 95% CI 0,26-0,92; P = 0,02
 NNT 22
 PROM comparable except for hot flushes

www.ago-online.de

DeCensi et al. J Clin Oncol 37:1629-1637, 2019

 Tamoxifen Chemoprevention—
End of the Road?
© AGO e. V.
in der DGGG e.V. Placebo Verum
sowie
in der DKG e.V.
Participants 18.322 18.355
Guidelines Breast
Version 2020.1

Invasive breast 805 537

cancer
ER-positive 632 350
ER-negative 144 173
Breast cancer- 48 60
related death
www.ago-online.de

Narod. JAMA Oncol 1:1033-4, 2015

 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

Ductal Carcinoma in Situ

(DCIS)

www.ago-online.de
 Duktales Carcinoma in situ
(DCIS)
© AGO e. V.
in der DGGG e.V.
sowie
 Versions 2002–2019:
in der DKG e.V.
Audretsch / Bauerfeind / Blohmer / Brunnert / Budach / Costa/ Fersis /
Guidelines Breast
Version 2020.1 Friedrich / Gerber / Hanf / Junkermann / Kühn / Lux / Maass / Möbus /
Mundhenke / Nitz / Oberhoff / Scharl / Schütz / Solomayer / Souchon / Thill
/ Thomssen / Wenz

 Version 2020:
Friedrich / Gerber

www.ago-online.de
 Pretherapeutic Assessment of
Suspicious Lesions (BIRADS 4-5)
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Mammography 1b B ++
Version 2020.1  Magnification view of microcalcifications 4 C ++
 Increased detection rate of G1/G2 DCIS by full-field
2b B +
digital mammography (versus screen-film)
 Stereotactic core needle / vacuum biopsy (VAB) 2b B ++
 Specimen radiography 2b B ++
 Marker (clip) left at biopsy site for localization if lesion
5 D ++
is completely removed
 Assessment of extension
 MRI 1b B +/-
www.ago-online.de  Clinical examination 5 D ++
 FNA / ductal lavage 5 D -
 Interdisciplinary board presentation 5 D ++
 Original Investigation
Breast Cancer Mortality After a Diagnosis of Ductal
Carcinoma In Situ
Narod A. et al.: JAMA Oncol. 2015 Oct; 1(7): 888-96

© AGO e. V.
in der DGGG e.V.
sowie  108,196 patients from the SEER data base
in der DKG e.V.

Guidelines Breast
 Retrospective analysis
Version 2020.1
 Breast cancer specific mortality 3.3 %
 Increased in young women (< 35 years)
and black ethnicity
 The risk of death increases after ipsilateral
invasive recurrence HR 18 (95%CI, 14,0–23,6)
 Prevention of invasive recurrence by radiotherapy
does not diminish mortality at 10 years
www.ago-online.de
 Original Investigation
Breast Cancer Mortality After a Diagnosis of Ductal
Carcinoma In Situ
Narod A. et al.: JAMA Oncol. 2015 Oct; 1(7): 888-96

© AGO e. V. Treatment Cases, No 10–Year BCS Univariate HR P Value Multivariate3 P Value

in der DGGG e.V. Mortality (95%CI), (95% CI) HR
sowie
in der DKG e.V. % (95%)

Guidelines Breast
Lumpectomy
Version 2020.1
Without 19762 0.9 (0.7 - 1.1) 1 [Reference] 1 [Reference]
radiotherapy
With radiotherapy 42250 0.8 (0.7 – 1.0) 0.86 (0.67 – 1.10) 0.22 0.81 (0.63 – 1.04) 0.10

all 63319 0.8 (0.7 – 1.0) 1 [Reference] 1 [Reference]

Unilateral 19515 1.3 (1.1 – 1.5) 1.45 (1.18 – 1.79) < 0.001 1.20 (0.96 – 1.50) 0.11
mastectomy

www.ago-online.de

3 Adjusted for year of diagnosis, age of diagnosis, ethnicity, income,

ER-status, tumor size and grade
 General Therapeutic Principles
© AGO e. V.
in der DGGG e.V.
Surgical excision (BCS or mastectomy) is the standard
sowie
in der DKG e.V.
treatment for DCIS.
Guidelines Breast
Version 2020.1

Adjuvant treatment (radiotherapy, endocrine treatment)

must be discussed with the patient individually. Adverse
effects should be weighed against risk reduction.

www.ago-online.de
 Surgical Treatment for
Histologically Proven DCIS I
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Excisional biopsy (wire guided) 2b B ++
Version 2020.1
 Bracketing wire localization in large lesions 3a C +
 Specimen radiography 2b B ++
 Intraoperative ultrasound (visible lesion) 3a C +/-
 Immediate re-excision for close margins (specimen
1c B ++
radiography)‫‏‬
 Intraoperative frozen section (in individual cases for
3a D +/-
margin assessment)
 Interdisciplinary board presentation 2b C ++
www.ago-online.de

Open biopsy in suspicious lesions (mammographic microcalcifications, suspicious US,

MRI etc.) without preoperative needle biopsy should be avoided
 Surgical Treatment for
Histologically Proven DCIS II
© AGO e. V. Oxford
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.
 Histologically clear margins (R0) 1a A ++
 Multifocal DCIS: BCS if feasible
Guidelines Breast
Version 2020.1 2b B +
 Re-excision required for close margin (≤ 2 mm in paraffin
2b C +
section)*
 Mastectomy**
 Large lesions confirmed by multiple biopsies; no clear margins
2a B ++
after re-excision
 SLNE
 Mastectomy 3b B +
 BCS 3b B -
 In case of DCIS in the male breast 5 D +/-
www.ago-online.de  ALND 2b B --
* Especially if postoperative radiation therapy is not performed
** Patients who present with a palpable mass have a significantly higher potential for
occult invasion (26%), multicentricity and local recurrence.
 Prognostic Factors for an
Ipsilateral Recurrence
© AGO
Oxford
e. V.
in der DGGG e.V. LoE
sowie
in der DKG e.V.  Resection margins 1a
Guidelines Breast  Age 1a
Version 2020.1
 Size 1a
 Grade 1a
 Comedo necrosis 1a
 Method of diagnosis 1a
 Focality 1a
 HER2-overexpression 1a
 ER/PgR (positive vs. negative) 1a
 Residual tumor-associated microcalcifications 2b
 Architecture 2b
 (modified) Van Nuys Prognostic Index 2b
 Palpable DCIS 2b
www.ago-online.de  Palpable and ER-, HER2+, Ki-67+ 2b
 DCIS-Score (9 Gene recurrence score) 2b
 MSKCC Nomogram 2b
 Intrinsic subtypes (luminal A, B, HER2+, triple negative) 2b
 DCIS Radiotherapy
Statements
© AGO e. V.
in der DGGG e.V.
 Radiotherapy has no impact on survival LOE 1a
sowie
in der DKG e.V.  Radiotherapy reduces the risk of ipsilateral (invasive and non
LOE 1a
Guidelines Breast
Version 2020.1
invasive) recurrences by 50 %
 Avoidance of invasive recurrence is probably not associated with
LOE 2b
survival benefit
 The absolute (individual) benefit of radiotherapy depends on the
individual risk of local recurrence
 The number needed to treat (for ipsilateral breast recurrence) is 9
(over all risk groups)
www.ago-online.de
 DCIS
Adjuvant Radiotherapy
© AGO
Oxford
e. V.
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.
Radiotherapy after:
 Breast conserving surgery (BCS)
Guidelines Breast
Version 2020.1 1a A ++
 Mastectomy 2b B --
Modality:
 Partial breast radiotherapy (PBI) (DCIS < 3 cm) 2a B +/-
 Hypofractionated radiotherapy regimens 2b D +/-*
 Radiotherapy boost on the tumor bed 2b D --
 Women younger than 45-50 years 2b C +/-
 Intraoperative Radiotherapy 2b C -
www.ago-online.de
Side effects and disadvantages must be weighed against risk reduction. Omitting radiotherapy implies elevated risk
for local recurrence without effect for overall survival even in the subset of „good risk” patients. Lack of level-1
evidence supporting the omission of adjuvant radiotherapy in selected low-risk cases: < 2.5 cm, low and
intermediate nuclear grade, mammographically detected
* Analysis in ongoing trials
 DCIS –
Adjuvant Systemic Treatment
© AGO e. V.  Adjuvant endocrine treatment has no impact on survival LOE 1a
in der DGGG e.V.
sowie
in der DKG e.V.  Endocrine treatment may have a small effect on ipsilateral
LOE 1a
Guidelines Breast invasive and DCIS recurrences
Version 2020.1

 Endocrine treatment for DCIS has an effect on contralateral

LOE 1a
invasive and non-invasive cancer
 The number needed to treat for any ipsilateral breast event is 15 LOE 1a

www.ago-online.de
 DCIS –
Adjuvant Systemic Treatment
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Tamoxifen (only ER+) 20mg 1a A +/-*
Version 2020.1
 Tamoxifen (only ER+) 5mg (long-term data missing) 2ba B +/-*
 Aromatase inhibitor (only ER+) in postmenopausal
1b A +/-*
women only
 Trastuzumab (only HER2+) 5 D --

www.ago-online.de

* Indication for treatment depends on risk factors, side effects and patient preference
 Low dose Tamoxifen (5mg)
in premalignant lesions
© AGO e. V.
in der DGGG e.V.
sowie
 N = 500
in der DKG e.V.

Guidelines Breast
Version 2020.1
 Follow up 5.69 years
Tamoxifen 5 mg 3y
DCIS (69%), LCIS (11%), R
ADH (20%) Placebo

 EFS: TAM 5.5% (14/253) vs. PLAC 11.3% (28/247)

 Severe adverse Event with same incidence (Endometrial
cancer TAM 1 vs. PLAC 0, thrombo-embolic event TAM
www.ago-online.de 1 vs. PLAC 1)
 Adherence TAM 65% vs. PLAC 61% Lazzeroni M et al: Breast 2019
 Therapy of Local DCIS Recurrence
after Tumorectomy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
After Radiation:
Version 2020.1
 Simple Mastectomy 3a C +
+ SLNE 5 D +
 Secondary breast conserving surgery 5 D +/-

Without radiation after first tumorectomy

 Treatment like primary disease 3 C ++

www.ago-online.de
Prognosis seems to be better for invasive recurrences than for primary
invasive breast cancer. About 50% of recurrences are invasive.
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

Breast Cancer Surgery

Oncological Aspects

www.ago-online.de
 Breast Cancer Surgery
Oncological Aspects
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  Versions 2002–2019:
Guidelines Breast
Version 2020.1
Bauerfeind / Blohmer / Böhme / Brunnert / Costa / Fersis / Gerber /
Hanf / Janni / Junkermann / Kaufmann / Kühn / Kümmel / Möbus / Nitz /
Rezai / Simon / Solomayer / Thomssen / Thill / Untch

 Version 2020:
Thomssen / Wöckel

www.ago-online.de
 Breast Cancer Surgery
Oncological Aspects
© AGO e. V.
in der DGGG e.V.
sowie
AGO: ++
in der DKG e.V.

Guidelines Breast
Version 2020.1
Surgery is one sub-step out of multiple steps in breast cancer
treatment. Thus, both diagnostic and oncological
expertise are an essential requirement for every breast surgeon.

www.ago-online.de
 Pre-therapeutic Assessment
of Breast and Axilla
© AGO e. V.
Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Clinical examination 5 D ++
Guidelines Breast
Version 2020.1  Mammography 2b B ++
 + Tomosynthesis (DBT) 3b B +
 + Contrast-enhanced mammography 3a B +/-
 Sonography (breast and axilla) 2b B ++
 MRI* 1b B +
 Minimally invasive biopsy** 1b A ++
 CNB of axillary lymph nodes if suspicious 2b B ++
 Breast-CT 5 D -
www.ago-online.de
* MRI-guided vacuum biopsy is mandatory in case of MRI-detected additional lesions. Individual decision for
patients at high familiar risk, with dense breast (density 3-4/diagnostic assessability C-D), lobular invasive
tumors, suspicion of multilocular disease. No reduction in re-excision rate.
**Histopathology of lesions if relevant for treatment
 Pre-therapeutic Staging
Oxford
© AGO e. V.
in der DGGG e.V. LoE GR AGO
sowie
in der DKG e.V.  History and clinical examination 5 D ++
Guidelines Breast
Version 2020.1 Additional diagnosis for patients with high metastatic potential and/or
symptoms (in decision making for chemotherapy and/or anti-HER2-therapy):
 CT scan of thorax/abdomen 2a B +
 Bone scan 2b B +
 Chest X-ray 5 C +/-
 Liver ultrasound 5 D +/-
 In case of suspicious lesions further diagnosis (e.g.
2a B +
liver-MRI, CEUS*, biopsy etc.)
www.ago-online.de
 FDG-PET or FDG-PET /CT 3a C +/-
 Whole body MRI 4 C +/-
* Contrast enhanced ultrasound
 Evidence of Surgical Procedure
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Version 2020.1
 Survival rates after lumpectomy + RT are equivalent
1a A
to those after (modified) radical mastectomy

 Local recurrence rates after skin sparing mastectomy

2b B
are equivalent to those after mastectomy

 Conservation of the NAC (nipple areola complex) is

an adequate surgical procedure, if R0 resection is 2b C
www.ago-online.de
achieved
 Breast Conservation:
Surgical Technical Aspects
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
 Non-palpable lesion
in der DKG e.V.

Guidelines Breast
Version 2020.1  Wire guided localisation 2b B ++
 Other procedures (Radionuclide guided localisation/RADAR
2a B +/-
reflection, Magnetic Seeds/RFID etc.)
 Specimen radiography or ultrasound 2b B ++
 Tumor-free margins required 2a A ++
(also in unfavorable biology, „no ink on tumor“ is sufficient)
 Immediate intraoperative re-excision for close margins
(specimen radiography or ultrasound and/or intra- 1c B ++
operative pathology)
 Re-excision required for involved margins (paraffin section) 3b C +
www.ago-online.de
 Therapeutic stereotactic excision alone 4 D --
 Ultrasound guided surgery to prevent re-excision 1a A +/-
 Intraoperative margin evaluation (with Margin Probe®) 1b A +/-
 Breast Conservation Surgery (BCS)
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Multicentric disease (MF/MZ)
Guidelines Breast 2b B +
Version 2020.1
(R0-Resection of all lesions)
 Positive microscopic margins after repeated excision 2b B --
 Inflammatory breast cancer 2b B --

For surgery after neoadjuvant chemotherapy

see chapter „neoadjuvant chemotherapy“

www.ago-online.de
 Primary Axillary Lymph Node Dissection
(ALND) I Oxford
LoE GR AGO
© AGO e. V.
in der DGGG e.V.  Endpoint: Survival 3 D -
sowie  Endpoint Staging 3 A -
in der DKG e.V.
 Endpoint: Locoregional control 2a A +/-
Guidelines Breast
Version 2020.1
 pN+ (pre-surgery) without neoadjuvant systemic therapy 2a B +
 cN0 pN0(sn)(i+) 1b A --
 cN0 pN1(mi) 2b B --
 cN0 pN 1(sn) ( cT1/2 , < 3 SN +, BCS + tangential radiation field,
1b A -
adequate systemic therapy)
 cN0 pN1 (sn) and mastectomy (no chestwall radiotherapy) 1b B +*
 cN0 pN1(sn) and mastectomy (T1/2, <3SN+) (chestwall radiotherapy) 5 D +/-*

 ALND indicated, but not feasible

 Radiotherapy according to AMAROS-trial (validated for cN0 pN1sn) 1b B +
www.ago-online.de

* Study participation recommended

 AxillarySurgery
Axillary Surgeryand
andNACT
NACT LoE
Oxford
GR
AGO

SLNE after NACT 2b B ++

SLNE before NACT 2b B +/-

© AGO e. V. cN-status pN-status N-status Surgical Procedure

in der DGGG e.V. (before NACT) (before NACT) (after NACT) (after NACT)
sowie
in der DKG e.V. cN0 pN0(sn) ycN0 None 1a A +
Guidelines Breast cN0 pN+(sn) according to ACOSOG Z0011 ycN0 None 1b B +
Version 2020.1

cN0 pN+(sn) different from ACOSOG Z0011 ycN0 ALND or Axillary RT 2b B +

ypN0 (sn) SLNE only 2b B ++

ALND 2b C +
ypN1mic (sn)
cN0 Not done (no SLNE) Axillary RT 5 D +/-
ALND 2b C ++
ypN1 (sn)
Axillary RT 5 D +/-
SLNE only* 2b B +/-
cN+ pN+CNB ycN0 TAD (TLNE + SLNE)* 2b B +
ALND* 2b B +
ALND 2b B ++
www.ago-online.de cN+ pN+CNB ycN+
Axillary RT 5 D -

NACT=Neoadjuvant chemotherapy; ALND=Axillary Lymph Node Dissection; SLNE=Sentinel Lymph Node Excision;
TAD=Targeted Axillary Dissection; TLNE=Targeted Lymph Node Excision; RT=Radiotherapy – *Trial participation recommended
 Improvement of the False-Negative Rate of SLNE
in Patients with pN+CNB before NACT and ycN0 after NACT
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Removal of > 2 SLNs
Guidelines Breast 2a B +
Version 2020.1
(SLNE, no untargeted axillary sampling)
 Combined tracer 2a B +/-
 IHC and serial sections to detect ITC or
2b B +
micrometastases
 Localization of pos. LN before NACT (clip/coil/tattoo) 2b B +*
 Targeted Axillary Dissection (TAD = TLNE + SLNE)** 2b B +*
 TLNE only 2b B +/-*
www.ago-online.de

* Study participation recommended ;

** TAD =Targeted axillary dissection; TLNE = Targeted lymph node excision; SLNE = Sentinel lymph node excision
 Reduction of individual failures
for SLNB in pN1 ypN0
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
 Predictive factors for axillary remission
pN1 (before NACT) to ypN0sn/TAD(after NACT)
 Young age
 Intrinsic Subtype (ER neg, HER 2 pos)
 Grade 3
 N1 (vs N2)
www.ago-online.de
 pCR (breast)
Kantor et al. Ann Surg Oncol 2018
 Sentinel Lymph Node Excision (SLNE)
Indications I
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Clinically / sonographically negative axilla (cN0) 1b A ++
Version 2020.1  Add CNB in cN1 (clinically/sonographically suspicious) in
order to enable SLNB
2a B +
 cT 1–2 2b A ++
 cT 3–4c 3b B +
 Multifocal / multicentric lesions 2b B +
 DCIS
 Mastectomy 3b B +
 BCT 3b B -
 DCIS in male 5 D +/-
www.ago-online.de  Male breast cancer 2b B +
 In elderly patients 3b B +
 Sentinel Lymph Node Excision (SNLE)
Indications II
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast  During pregnancy and / or breast feeding
Version 2020.1 3 C ++
(only 99mTc-colloid, no blue dye)
 After prior tumor excision 2b B +
 After prior major breast surgery
3b C +/-
(e.g. reduction mammoplasty)
 Ipsilateral breast recurrence after prior BCS
4 D -
and prior SNLE
 SLNE in the mammary internal chain 2b B -
 After axillary surgery 3b B +/-
www.ago-online.de
 Prophylactic bilateral / contralateral mastectomy 3b B --
 Inflammatory breast cancer 3b C -
 Sentinel Lymph Node Excision (SLNE)
Marking
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Version 2020.1
 99mTc Kolloid 1a A ++
 Preoperative lymphoscintigraphy (added infomation
1b A +
limited, but mandatory by legal regulations)*
 Patent blue dye 1a A +/-
 Methylen blue 4 D -
 Indocyanin green (ICG) 2a B +/-
 SPIO# 2a B +/-

www.ago-online.de * In Germany required for quality assurance of nuclear medicine

# SPIO: Superparamagnetic Iron Oxide
 Procedure after Neoadjuvant Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
 Early clip or coil marking of tumor (incl. detailed
Guidelines Breast
5 D ++
Version 2020.1
topographic documentation)
 Surgical removal of tumor/tumor bed 2b C ++
 Microscopically clear margins 2 B ++
 Tumor resection in new margins 2 C +

For „Surgery after neoadjuvant chemotherapy“

see chapter „Neoadjuvant chemotherapy“
www.ago-online.de
 Adjuvant Therapy after Primary Surgery
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Start adjuvant systemic therapy and radiotherapy (RT)
Guidelines Breast 1b A ++
Version 2020.1
as soon as possible (asap) after surgery
 Start of adjuvant chemotherapy +/- HER2 therapy
1b A ++
asap after surgery, prior to RT
 Without cytotoxic therapy +/- anti-HER2 therapy:
 Start RT 6–8 weeks after surgery 2b B ++
 Start endocrine therapy after surgery asap 5 D ++
 Endocrine therapy concurrent with radiotherapy 3b C +

www.ago-online.de
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Oncoplastic and
Reconstructive Surgery
 Plastic-reconstructive aspects after
mastectomy
© AGO e. V.
in der DGGG e.V.
sowie
▪ Versions 2002–2019:
in der DKG e.V.
Audretsch / Bauerfeind / Blohmer / Brunnert / Dall / Ditsch / Fersis /
Guidelines Breast
Version 2020.1 Friedrich/ Gerber / Hanf / Kümmel / Lux / Nitz / Rezai / Rody / Scharl /
Solbach / Thomssen

▪ Version 2020:
Blohmer / Kühn

www.ago-online.de
 Definition of oncoplastic surgical procedures
© AGO e. V.
in der DGGG e.V.
sowie
Use of plastic surgical techniques at the time of tumor
in der DKG e.V.

Guidelines Breast
removal to enable safe resection margins and to
Version 2020.1
preserve aesthetic breast contour.

Focus on favorable scar placement, adequate soft tissue

formation, choice of proper reconstruction procedure
(including in the context of radiation) and reconstruction
of the contralateral side to achieve symmetric results.
www.ago-online.de
 Oncoplastic Breast Conserving Surgery
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
▪ Tumor-adapted reduction mammaplasty 2a B +
Version 2020.1
▪ Local flap techniques 2a B +
▪ Partial mastectomy with tissue transfer 3b B +/-

www.ago-online.de
 Algorithm of Breast Reconstruction
© AGO e. V. Patient wishes to undergo breast reconstruction
in der DGGG e.V.
sowie
N.B.: Habitus, breast volume, wishes, previous surgery
in der DKG e.V.

Guidelines Breast
Version 2020.1
No postmastectomy radiotherapy Postmastectomy radiotherapy indicated

SSM/NSM and implantation Mastectomy Not suitable for autologous

or
MRM + tissue expander  Implant
or
not suitable for alloplastic
reconstruction or wish of patient
 autologous reconstruction
www.ago-online.de
à Radiotherapy
à Delayed autologous
reconstruction
To be discussed in individual cases:
Immediate autologous reconstruction
N.B.: Increased fibrosis rate
Delayed prothesis reconstruction
N.B.: Increased complication rate
reconstruction
E.g. too little subcutaneous fat,
wishes of patient
Direct prosthesis reconstruction or
two-staged implant-based
reconstruction:
MRM Tissue expander 
Implant
+ Radiotherapy
N.B.: Increased complication rate,
particularly capsular fibrosis
 Breast Reconstruction
Principles - AGO: ++
© AGO e. V.  Planning of reconstructive procedure by interdisciplinary tumor board before mastectomy
in der DGGG e.V.
sowie  Counseling regarding all surgical techniques, including advantages and disadvantages
in der DKG e.V.
 Offer second opinion
Guidelines Breast
Version 2020.1  Discussion of neoadjuvant treatment if unfavorable tumor-breast-relation
 Consideration of contralateral breast;
 discuss possible alignment / sequencing surgical procedures to produce symmetry;
usually after at least 3-6 months (Caveat: need for post-resections, consider effects
of radiotherapy for affected side)
 Preference for less stressful surgical technique with stable long-term esthetic result
(prefer BCS over mastectomy)
 Avoid delay of adjuvant therapy due to reconstruction
 Assessment of outcome (e.g. PROM)
 Oncologic safety is not impaired
www.ago-online.de
 Postmastectomy Reconstruction
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Use of silicone gel filled breast implants
Guidelines Breast 2a B +
Version 2020.1
one step or two steps after expander
 Safety comparable to saline implants 2b B
 Autologous tissue reconstruction 2a B +
 Pedicled tissue reconstruction 2a B +
 Free tissue reconstruction
2a B +
(including vascular anastomoses)
 Autologous tissue procedure plus implants 3a C +
www.ago-online.de

Caveat: BMI >30, smoking status, diabetes, radiotherapy, age, bilateral

mastectomy
 Timing of Reconstruction
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast ▪ Immediate Breast Reconstruction 3b B ++
Version 2020.1
▪ Mandatory: SSM/NSM
▪ Avoidance of a postmastectomy syndrome
▪ Delayed Breast Reconstruction 3b B ++
▪ No interference with adjuvant procedures (CHT, RT)
▪ Disadvantage: loss of skin envelope
▪ „Delayed-immediate“ Breast Reconstruction 3b B +/-

www.ago-online.de
 Timing of implant Based Reconstruction
and Radiotherapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Implant Reconstruktion (IR) 2a B +
Version 2020.1  IR without radiotherapy 2a B ++
 IR prior to radiotherapy 2a B +
 IR following radiotherapy 2b B +/-
 IR following secondary mastectomy
2a B +/-
(after BCS* with radiotherapy)
 Perioperative antibiotic prophylaxis
2b B +
 (at least 24 hours)

www.ago-online.de

* BCS: Breast Conserving Surgery

 Radiotherapy and
Implant-based Reconstruction
Caveat: High complication rate in combination with
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
radiotherapy (capsular contracture, revision surgery,
Guidelines Breast
Version 2020.1 reconstruction failure, reduced cosmetic outcome and
patient satisfaction)

Caveat: Lower patient satisfaction with implant-based

reconstruction plus radiotherapy compared to autologous
reconstruction plus radiotherapy

www.ago-online.de LoE 2b B
 Possible Associations between Implants
and rare Diseases
© AGO e. V.
 US FDA Breast Implant Postapproval Studies (LPAS)
in der DGGG e.V.
sowie Long-term Outcomes in 99,993 Patients
in der DKG e.V.
(Primary Augmentation: N= 71.937 / Primary Reconstruction: N= 9942)
Guidelines Breast
Version 2020.1 - 56% of implants were silicone implants
 Possible Associations:
- Sjogren syndrome: (SIR*8.14)
- scleroderma: (SIR 7.00)
- rheumatoid arthritis: (SIR5.96)
- stillbirth: (SIR4.50)
- melanoma: (SIR3.71)
 At 7 years, reoperation rate is 11.7% for primary augmentation, and 25% for
primary/revision reconstruction.
www.ago-online.de  One case of BI-ALCL

Associations need to be further analyzed with

*Standardized incidence ratio
patient-level data to provide conclusive evidence !
 Possible Associations between Implants
and rare Diseases
Rare Systemic Harms Compared With the General Population:
© AGO e. V.
in der DGGG e.V. Study Event Rate (Per General Population Event
sowie Manufacturer ,y Study 10,000 Person Yr) Rate SIR 95% CI
Events (Per 10,000 Person Yr) SIR P Value
in der DKG e.V.

Guidelines Breast Fibromyalgia Allergan 9 1.8 112.8 0.02 0.01–0.03 <0.001

Version 2020.1 Mentor 307 28.4 112.8 0.25 0.22–0.28 <0.001
Rheumatoid arthritis Allergan 4 0.8 5.4 0.15 0.04–0.38 <0.001
Mentor 349 32.2 5.4 5.96 5.35–6.62 <0.001
Scleroderma Mentor 46 4.2 0.6 7.00 5.12–9.34 <0.001
Sjogren syndrome Mentor 62 5.7 0.7 8.14 6.24–10.44 <0.001
Systemic lupus erythematosus Allergan 3 0.6 5.4 0.11 0.02–0.32 <0.001
Mentor 66 6.0 5.4 1.11 0.86–1.41 0.398
Cancer Allergan 80 16.0 41.3 0.39 0.31–0.48 <0.001
Mentor 532 63.8 41.3 1.54 1.42–1.68 <0.001
Breast cancer Mentor 116 13.9 12.5 1.11 0.92–1.33 0.26
Lung cancer Mentor 5 0.6 5.2 0.12 0.04–0.27 <0.001
Brain cancer Mentor 3 0.4 0.6 0.67 0.14–1.95 0.639
Melanoma Mentor 65 7.8 2.1 3.71 2.87–4.73 <0.001
Neurological disorder Allergan 18 3.6 22.5 0.16 0.09–0.25 <0.001
www.ago-online.de Mentor 394 35.8 22.5 1.59 1.44–1.76 <0.001
Multiple sclerosis Mentor 47 4.3 2.5 1.72 1.26–2.29 0.001
Myositis Mentor 17 1.5 0.8 1.88 1.09–3.00 0.018
Allergan follow-up 2 years
Mentor follow-up 7 years
 Breast Implant Associated Anaplastic Large
Cell Lymphoma (BIA-ALCL)
© AGO e. V.
in der DGGG e.V.
 Rare disease, 3 % of Non-Hodgkin Lymphomas, 0.04-0.5 % of all
sowie
in der DKG e.V.
malignant breast diseases
Guidelines Breast
Version 2020.1
 Estimated incidence 0.6-1.2 / 100.000 women with implants (median
age: 54 y)
 Mainly associated with textured implants
 Interval to diagnosis: 8 years (median)
 Clinical symptoms
 Swelling and seroma. (60 %)
 Solid tumor (17 %)
 Seroma and solid tumor (20 %)
 Histology: CD30+ / ALK-T-Cell Lymphoma
www.ago-online.de  Compulsory registration as SAE (§3 MPSV to BfArM)
 BIA-ALCL - Surfaces of Breast Implants
© AGO e. V.  The cause of BIA-ALCL is not established; however, it has been proposed that lymphomagenesis may
in der DGGG e.V.
sowie be driven by a chronic inflammatory reaction induced by capsule contents or surface. The risk for
in der DKG e.V.
BIA-ALCL has been shown to be significantly higher for implants with grade 3 and 4 surfaces.
Guidelines Breast
Version 2020.1

www.ago-online.de
 BIA-ALCL– Diagnosis
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Breast US (assessment of new seromas > 1 year after implant insert,
Guidelines Breast 3a D ++
Version 2020.1 solid lesion)
 Mamma-MRT in confirmed cases 3a D ++
 Staging (Imaging, e.g. CT, PET-CT) 3a D ++
 Cytology of late seromas
 - > 50 ml
 - Complete assessment 3a D ++
 - flow-cytology (T-cell clone)
 - BIA-ALCL specific cytologic diagnostic (CD 30+)
 Core needle biopsy in solid lesions
3a D ++
www.ago-online.de  Lymphoma assessment of resected tissue and histologic staging
 Documentation of the implant (manufacturer, size, volume, surface,
5 D ++
Batch-number) and enter in registry
 BIA-ALCL – Therapy
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast  Implant resection and complete capsulectomy including
Version 2020.1 3a C ++
tumorectomy
 Resection of suspicious lymph nodes, no routine use of
4 D ++
Sentinel-Node-Biopsy, no axillarx dissection
 Polychemotherapy (e.g. CHOP) in cases of extra capsular
4 D +
extension
 Radiotherapy in unresectable tumors 5 D +/-
 Case discussion in an interdisciplinary tumor board in the
5 D ++
www.ago-online.de
presence of a specialist for lymphomas
 Breast Implant-Associated
Anaplastic Large-Cell Lymphoma (BIA-ALCL)
- Summary of the Management (acc. to Noah 2017) -
© AGO e. V. Periprosthetic seroma or tumor mass > 1 year after implant Confirmed ALCL cases
in der DGGG e.V. placement
sowie
in der DKG e.V.
Tumor board discussion
Guidelines Breast
Exclude trauma or
Version 2020.1 infection
Complete operative caspulectomy, tumor excision
according to oncological standards Lymph node
Ultrasound / sonography removal in case of suspicion, no new implants,
possibly also contralaterally

Seroma: aspiration and cytology Complete Resection R1 or positive lymph

Tumor mass
(when suspicious: CD30-IHC) R0 nodes

Suspicious +ALCL Clinical follow-up.

Ultrasound and CT Chemotherapy; CHOP,
every 6 months for 2 possibly
years, then annually Immunotherapy
Operative exploration with
biopsy of the capsule Tumor board discussion for 5 years +/-

www.ago-online.de Radiatiotherapy
 Stage Adapted Therapy of BIA-ALCL
TNM Description

T= tumor extent
IA-IC/(IIA): surgical resection of
T1 Confined to effusion or a layer on luminal side of capsule capsula, implant, suspected nodular lesions and,
T2 Early capsule infiltration
only if suspicious, regional lymph nodes
© AGO e. V. no indication for mastectomy, sentinel node
in der DGGG e.V. T3 Cell aggreates or sheets infiltrating the capsule
sowie exstirpation or axillary dissection
in der DKG e.V. T4 Lymphoma infiltrates beyond the capsule

N= lymph node
Guidelines Breast
Version 2020.1 N0 No lymph node involvement IIA/IIB-IV: 2-18%
N1 One regional lympho nodes positive • surgical complet resection (see above)
N2 Multiple regional lymph nodes positive • CHO(E)P (Cyclophosphamide, Vincristin,
M= metastasis Doxorubicin,Prednison) +/- Etoposid
M0 No distant spread

M1 Spread to other organs /distant sides

• Brentuximab Vedotin (Adcetris®)
antibody-drug-conjugate (ADC) containing monoclonal
antibody against human CD30 antigen and 3-5 molecules
of cytostatic drug Monomethylauristatin E

and radiotherapy only in for patients with

incomplete resection and advanced stages
www.ago-online.de
 BIA-ALCL – EUSOMA-Recommendation
© AGO e. V.
in der DGGG e.V.
sowie
 Despite an increase of BIA-ALCL in association with texture implants
in der DKG e.V.
the use of textured implants is still permitted!
Guidelines Breast
Version 2020.1

„For the moment, textured implants can safely continue to be used with patient's fully informed
consent, and that women that have these type of implants already in place don't need to remove or
substitute them, which would undoubtedly cause harm to many tens of thousands of women, to
prevent an exceptionally rare, largely curable and currently poorly understood disease."

www.ago-online.de
 Tissue Replacement Techniques and Meshes
(Details of Implant Reconstruction)
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Autologous tissue
Guidelines Breast 3b C +
Version 2020.1
(e.g. autodermal graft, TDAP§,LDF *)
 Acellular dermal matrix (ADM) 2a B +#
 Synthetic meshes 2b B +#
 Pre- or subpectoral implant position comparable
2b B +#
(with or without meshes or ADM)

www.ago-online.de
§ Thoracodorsal Arteries Perforator flap
* Latissimus dorsi flap
# Participation in registry studies recommended
 Lipotransfer
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast  Lipotransfer following mastectomy and
Version 2020.1 2a B +
reconstruction
 Lipotransfer after BCS* 2a B +
 Autologous adipose derived stem cells (ASCs)-
4 C -
enriched fat grafting

www.ago-online.de

*BCS: Breast Conserving Surgery

 Postmastectomy Pedicled Reconstruction
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast Breast reconstruction (BR) with autologous tissue
Version 2020.1
 TRAM, Latissimus-dorsi-flap (both can be performed
3b C +
as a muscle-sparing technique)
 Delayed TRAM in patients at high-risk 3a B +
 Ipsilateral pedicled TRAM 3b A +
 Radiotherapy:
 BR following radiotherapy 2a B +
 BR prior to radiotherapy 2a B +/-
www.ago-online.de  (higher rates of fibrosis, wound healing problems,
liponecrosis and reduced aesthetic outcome)
 Free flaps for reconstruction
© AGO e. V.
Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
Type of free flap
Guidelines Breast
Version 2020.1  DIEP 2a B +
 Free TRAM 2a B +
 SIEA 3a C +/-
 Glutealis flaps (SGAP- / IGAP, FCI) 4 C +/-
 Free gracilis flap (TMG) 4 C +/-

Advantages
 DIEP and free TRAM are potentially muscle-sparing procedures. DIEP has a lower rate of
abdominal hernias.
Disadvantages
www.ago-online.de
 Time- and personnel consuming microsurgical procedures
 Intensified postoperative monitoring
 Higher reoperation rate
 Pre-reconstruction radiotherapy increases rate of vascular complications
 Pedicled versus free tissue transfer
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Muscle-sparing techniques and accuracy
Version 2020.1 of abdominal wall closure lead to low rates of late
3a A ++
donor site complications independent of method
used
 Autologous abdominal-based reconstructions have
highest satisfaction rates (PROM) in all patient
groups
 Donor site morbidity (e.g. impaired muscle function)
has to be taken into consideration with all flap
www.ago-online.de techniques
 Flap-implant combination
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
LDF* + Implant 2b C +
Version 2020.1  IR following RT 3b C +
 IR prior to RT 5 D -
Additional flap techniques + implant 5 C +/-
Advantages:
 TRAM: staged procedure preferable
 Improved implant coverage
 Suitable for irradiated tissue
Disadvantage:
www.ago-online.de  muscle contraction (LDF)

* LDF = Latissimus dorsi flap

 Skin-/nipple-sparing Mastectomy (SSM/NSM)
and Reconstruction
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Skin-/nipple-sparing Mastectomy (SSM/NSM)
Version 2020.1  Safe (same recurrence rate as MX) 2b B ++
 Higher QoL for patients 2b B ++
 NAC can be preserved under special conditions 2b B ++
 Feasible after mastopexy / reduction mammoplasty 4 C ++
 Use of ICG* to predict necrosis of the skin 1b B +
 Skin incisions - different possibilities:
 Periareolar
 Hemi-periareolar with/without medial/ lateral extension
 Reduction pattern: „inverted-T“ or vertical
www.ago-online.de
 Inferior lateral approach, inframammary fold
 Lowest incidence of complications 2b B +

* ICG = Indocyanine Green

 Risk-reducing bilateral mastectomy
for healthy women (RRBM)
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
▪ RRBM reduces breast cancer incidence 1b A ++
Version 2020.1 ▪ RRBM in deleterious BRCA1/2 mutation 2a B +*
▪ RRBM in high-risk situation without BRCA 1/2
mutation (individual decision depending on
4 D +/-*
personal- family history and mutational status – e.g.
high and moderate-risk genes, Hodgkin lymphoma)
▪ High risk and no BRCA counselling in specialized centre* 5 D --
▪ Non-directive counselling prior to RR-BM 2b B ++*
▪ RR-BM should be considered with other risk-reducing surgical
options incl. bilateral salpingoophorectomy (BSO) and in the 2a A ++*
www.ago-online.de
context of pre-existing diseases
▪ Further need for education of physicians regarding
1b A ++
possibilities and advantages of RRBM
* Counselling, risk prediction, and follow-up in specialized centers recommended
 Surgical Prevention for Healthy
Female BRCA1/2 Mutation Carriers
© AGO
Oxford
e. V.
in der DGGG e.V. LoE GR AGO
sowie
in der DKG e.V.  Risk-reducing bilateral salpingo-oophorectomy
2a B
Guidelines Breast
Version 2020.1
(RR-BSO)**
 Reduces OvCa incidence and mortality ++*
 Reduces overall mortality ++*
 Risk-reducing bilateral mastectomy (RR-BM) 2a B +*
 Reduces BC incidence
 Reduces BC mortality in BRCA1 mutation carriers***
2b B +*

*study participation recommended

www.ago-online.de
** The RRSO is recommended from about 35 years for BRCA1 and from about 40 years for BRCA2 mutation carriers,
taking into account the age of ovarian cancer diagnosis in the family and the family planning status.
*** No reduction in mortality could be shown for BRCA2 mutation carriers. RRM counselling should be individualised.
 Forms of risk-reducing (bilateral)
mastectomy (RRBM)
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
RRBM reduces breast cancer incidence;** bc-spec
Version 2020.1 mortality also likely reduced
 Simple mastectomy 2b B +
 RRBM by SSM* 2b C +
 RRBM by NSM* (NAC# sparing) 2b C +
 Contralateral prophylactic mastectomy 4 C +/-

www.ago-online.de

* SSM / NSM: Skin-/Nipple-Sparing Mastectomy

# NAC: nipple-areola complex
** depending on prior illnesses, e. g. pre-existing ovarian cancer 1-2% (stage III-IV)
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Adjuvant Endocrine Therapy
in Pre- and Postmenopausal Patients
 Adjuvant Endocrine Therapy in
Pre- and Postmenopausal Patients
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  Versions 2002–2019:
Guidelines Breast
Version 2020.1 Bauerfeind / Dall / Diel / Fersis / Fehm / Friedrichs / Gerber / Göring /
Hanf/ Harbeck / Huober / Jackisch / Lisboa / Lück / Lux / Maass / von
Minckwitz / Möbus / Müller / Oberhoff / Schaller / Scharl / Schneeweiss /
Schütz / Solomeyer / Stickeler / Thomssen / Untch /Fehm / Gerber

 Version 2020:
Nitz / Huober

www.ago-online.de
 Assessment of
Steroid Hormone Receptor Status
Oxford LoE: 1 GR: A AGO: ++
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Endocrine responsiveness: formerly known as hormone receptor positive
Immunohistochemistry (ER and / or PgR)
0% pos. cells: endocrine non responsive
1–9% pos. cells: doubtful endocrine responsiveness
≥ 10% pos. cells: endocrine responsive
Hormone receptor status unknown: endocrine responsive
www.ago-online.de
In case of ER negative / PR positive (> = 10% cells), consider
immunohistochemical re-evaluation
 Adjuvant Endocrine Therapy
Assessment of Menopausal Status
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast Assessment of menopausal status:
Version 2020.1

 Menstruation history ++
 FSH, E2 ++

www.ago-online.de
 Adjuvant Endocrine Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
Version 2020.1
Endocrine therapy:
 Endocrine responsive 1a A ++
 endocrine doubtful responsiveness 3b D +
 Endocrine therapy
1a A ++
Sequentially after CT
 Non-responsive: No endocrine therapy 1a A ++

www.ago-online.de
 General Principles in
Adjuvant Endocrine Therapy AGO ++
© AGO e. V.
 Adjuvant endocrine therapy is divided into initial therapy (years 0-5) and
in der DGGG e.V.
sowie
extended adjuvant therapy (EAT, years 6-15).
in der DKG e.V.

Guidelines Breast
 Standard treatment duration is 5 years.
Version 2020.1
 Extended therapy should be considered based on individual risks and
benefits.
 Duration, choice & sequence of AI or Tam mainly depend on menopausal
status, tolerability, and risk of recurrence.
 Switch to another better tolerated endocrine treatment (Tam or AI) is
better than stopping endocrine therapy altogether.
 AI should be used as first treatment in postmenopausal patients,
www.ago-online.de especially in case of lobular cancers and/or high risk of recurrence.
 To date, there is no sufficiently validated biomarker for identification of
patients at risk for early versus late recurrence.
 Premenopausal Patients
Initial Adjuvant Endocrine Therapy (Year 0-5)
© AGO e. V.
Oxford
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.  Tamoxifen* 5–10 years 1a A ++
Guidelines Breast
Version 2020.1
 GnRH alone 1a B +
(only, if relevant contraindication for Tam vs. no therapy at all)
 No indication for neo-/adjuvant chemotherapy
and preserved ovarian function
1b B ++
 Tamoxifen 1b B +/-
 Tamoxifen + OFS 1b B +/-
 AI + OFS
 Following neo-/adjuvant chemotherapy and preserved
ovarian function **
 Tamoxifen + OFS 5 years 1b B +
 in patients < 35 years 1b B ++
www.ago-online.de
 AI + OFS 1b B +/-
 in patients < 35 years 1b B +
OFS: ovarian function suppression; * as long as tolerated and the patient is clearly premenopausal
** If ovarian function resumes during 24 months
 TEXT /SOFT Joint Analysis
© AGO e. V. TEXT 5 yrs
in der DGGG e.V.
sowie
in der DKG e.V. Premenopausal Tamoxifen 20 mg/day Joint Analysis
Guidelines Breast
Patients with HR+ BC + OFS* (n = 1328)
Version 2020.1 ≤ 12 wks after surgery Exemestane 25 mg/day Tamoxifen + OFS*
(N = 2672) + OFS* (n = 1332) (n = 2344)

SOFT Tamoxifen 20 mg/day Exemestane + OFS*

Premenopausal + OFS* (n = 1016) (n = 2346)
patients with HR+ BC
≤ 12 wks after surgery Exemestane 25 mg/day
(if no chemo) or + OFS* (n = 1014)
*OFS
≤ 8 mos after chemo  TEXT: triptorelin 3.75 mg
(N = 3066) Tamoxifen 20 mg/day IM every 28 days for 6
www.ago-online.de mos, then optional
Median follow-up: 5.7 yrs bilateral oophorectomy
or irradiation
Nach Pagani O, et al. N Eng J Med, 371(2) 2014
 SOFT: choice of method
 Postmenopausal Patients
Initial Adjuvant Endocrine Therapy (Years 0-5)
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Aromatase Inhibitor (AI) for first 5 years 1a A ++
Version 2020.1  Non steroidal-AI in lobular cancer 2b B +
 High risk of recurrence

 Sequential therapy for first 5 years * ++

 Tam (2-3 yrs.) followed by AI to complete 5 years 1a A
 AI (2-3 yrs.) followed by Tamoxifen to complete 5 years 1b C

 Tamoxifen 20 mg/d for 5 years** 1a A +

www.ago-online.de
* in postmenopausal patients, AI should be integrated in the first five years
** Tamoxifen may be offered to very old patients or in patients with very low risk of recurrence or if
contraindications for AI are present
 Aromatase Inhibitor vs. Tamoxifen vs.
Sequentiell Therapy – 5 Years Upfront Therapie
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

www.ago-online.de

Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet. 2015 Oct 3;386(10001):1341-52.
 Premenopausal Patients
Extended Adjuvant Endocrine Therapy (EAT) (Years 6–10)
© AGO e. V.
in der DGGG e.V.
sowie Oxford
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Version 2020.1
In case of high risk of recurrence
 5 years Tamoxifen after 5 years Tamoxifen 1a A ++
 2–5 years AI after 5 years Tamoxifen in initially
premenopausal patients who obtain validated 1b B +
postmenopausal status during course of therapy
 5 years Tamoxifen after 5 years of endocrine therapy + OFS 5 D +

www.ago-online.de
 Postmenopausal Patients
Extended Adjuvant Endocrine Therapy (EAT) (Years 6–10)
© AGO e. V.
in der DGGG e.V. Oxford
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast In case of high risk of recurrence
Version 2020.1

 5 years Tamoxifen after 5 years Tamoxifen 1a A +

 2–5 years AI after 5 years Tamoxifen 1a A ++
 After initial AI-containing therapy (upfront or switch),
prolongation of endocrine therapy with AI for 2–5 years*
 High-risk and good tolerabilty of AI 1a A +
 Low-risk, poor tolerabilty of AI 1a A -
 Interruption of endocrine treatment up to 3 months during
1b B +/-
EAT
www.ago-online.de

* Up to date, no impact on OS
 Extended aromatase inhibitor treatment following 5 or more years of
endocrine therapy: a metaanalysis of 22192 women in 11 randomised
trials (EBCTCG)
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

www.ago-online.de

1 (new primary breast cancer, local and distant recurrence)

 Decision criteria for extended therapy
© AGO e. V.
in der DGGG e.V. Factors indicating a clinical benefit from EAT:
sowie
in der DKG e.V.  Adjuvant tamoxifen therapy only
Guidelines Breast  Condition after chemotherapy (indicating high risk)
Version 2020.1
 Positive lymph node status and /or T2/T3 tumors
 Elevated risk of recurrence based on immunohistochemical criteria or based on
multi-gene expression assays
 High CTS5-score
Further decision criteria:
 Wish of patient
 up to now well tolerated AI therapy,
 good bone health
 younger age
www.ago-online.de
 adherence
 Ovarian Protection and Fertility Preservation in
Premenopausal Patients Receiving (Neo)-Adjuvant
Chemotherapy (CT)
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Fertility preservation counselling including
Version 2020.1
referral of all potential patients to appropriate
++
reproductive specialists (further information
www.fertiprotekt.com)
 CT + GnRHa
(preservation of ovarian function)
1a A +
(GnRHa application > 2 weeks prior to chemo-
therapy, independent of hormone receptor status )
 CHT + GnRHa
1b A +/-
www.ago-online.de (preservation of fertility)
 Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation
of Ovarian Function and Fertility in Premenopausal Patients With Early Breast
Cancer: A Systematic Review and Meta-Analysis of Individual Patient–Level Data

© AGO e. V.
in der DGGG e.V.
N= 837 patients from 5 trial, median follow-up time 5.0 years (IQR, 3.0-6.3 years)
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Control GnRH HR (95%-CI) P-value

POI1,2 30.9% 14.1% 0.38; < 0.001

0.26 to 0.57
Pregnancy3 5.5% 10.3% 1.83; 0.03
1.06 to 3.15;
1premature ovarian insufficiency, 2 different definitions and time points were used
3 i n most trials POI and not pregnancy was defined as the primary endpoint

www.ago-online.de No significant differences in disease-free survival and overall survival

were observed between groups.
Lambertini M et al. J Clin Oncol 2018
 Adjuvant Endocrine Therapy
© AGO e. V. De-facto- AI-Therapie
HR für
in der DGGG e.V. Studie Therapien Vergleiche Jahre 0-5 Braun: Tamoxifen,
DFS
sowie (Jahre) (% )
in der DKG e.V. Jahre nach
1 2 3 4 5 6 7 8 9 10 15
Diagnose Grün: Tamoxifen oder AI,
Guidelines Breast Studien mit Tamoxifen nach 5 Jahren Tamoxifen
Version 2020.1 0,75 –
ATLAS * 5 vs 10
0,99 t
0 Blau: AI
0,75 –
ATTOM * 5 vs 10 0
0,99 t
Studien mit AI nach 5 Jahren Tamoxifen
Gestreift: Zeit der
MA. 17 * 5 vs 10 0,57 0 randomisierten
NSAPB B-33 * 5 vs 10 0,68 0 Intervention vs keine
ABCSG 6a * 5 vs 8 0,62 0
Studien mit erweiterter AI-Th. nach 5 Jahren endokrin inkl. AI
Therapie od. Plazebo,
DATA * 6 vs 9 0,79 100
NSABP B-42 * 5 vs 10 0,85 100 *: Randomisierungs-
MA.17R § 10 vs 15 0,66 100
Studien bzgl. optimaler Dauer in Jahr 5-10 zeitpunkt,
BOOG
2006-05 * 7,5 vs 10 0,92 88
IDEAL
§: MA17R nach 5 Jahren
ABCSG 16 * 7 vs 10 1,007 49
AI mit /ohne Tam zuvor
www.ago-online.de
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Adjuvant Cytotoxic and
Targeted Therapy
 Adjuvant Cytotoxic and Targeted Therapy
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  Versionen 2002 – 2019:
Guidelines Breast
Version 2020.1
Dall / Harbeck / Jackisch /Janni / Loibl / Lux/
von Minckwitz / Möbus / Müller / Nitz / Schmidt / Schneeweiss / Simon /
Schütz / Solomayer / Stickeler / Thill / Thomssen / Untch

 Version 2020:
Fehm / Stickeler

www.ago-online.de
 Subtype-specific Strategies
for Systemic Treatment
© AGO
AGO
e. V.
in der DGGG e.V. If chemotherapy is indicated,
sowie
in der DKG e.V. systemic treatment before surgery (neoadjuvant) should be preferred
Guidelines Breast HR+/HER2- and „low-risk”
Version 2020.1
 Endocrine therapy without chemotherapy ++
HR+/HER2- and „high-risk”
 Conventionally dosed AT- based chemotherapy (q3w) +
 Dose dense chemotherapy (including weekly schedule) ++
 Followed by endocrine therapy ++
HER2+
 Trastuzumab (plus Pertuzumab in N+ or NACT) ++
 Sequential A/T-based regimen with concurrent T + anti-HER2 therapy ++
 Anthracycline-free, platinum-containing regimen +
 Anthracycline-free, taxane-containing regimen +
Triple-negativ (TNBC)
www.ago-online.de
 Conventionally dosed AT-based chemotherapy +
 Dose dense chemotherapy (AT - based including weekly schedule) ++
 Neoadjuvant platinum-containing chemotherapy +
 Adjuvant Chemotherapy:
TNBC
© AGO e. V.
in der DGGG e.V.
sowie  Indication for chemotherapy in node-negative disease Oxford
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Version 2020.1  > 10 mm 2b B ++
 > 5–10 mm 2b B +
 ≤ 5 mm 2b B -

www.ago-online.de
 Adjuvant Chemotherapy
without Trastuzumab: Overview
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Dose-dense anthracycline / taxane based (incl.
Guidelines Breast 1a A ++
Version 2020.1
weekly) chemotherapy
 Conventional anthracycline-/taxane based (q3w) 1a A +
 „Tailored“ anthracycline-/taxane based 1b B +/-
 If anthracyclines cannot be given
 Docetaxel plus cyclophosphamide 1b B +
 Paclitaxel mono weekly 1b B +/-
 CMF 1a A +/-
 Low-dose maintenance chemo 1b B -
www.ago-online.de
 Gray R et al., Lancet 2019
© AGO e. V.
in der DGGG e.V.
Early Breast Cancer Trialists‘ Cooperative Group (EBCTCG)
sowie
in der DKG e.V. Increasing the dose-density of adjuvant chemotherapy: an EBCTCG meta-analysis
Guidelines Breast
Version 2020.1
Same chemotherapy drugs and doses (n = 10,004)

Recurrence-free survival: 10-y Gain 4.3% (95%-C.I. 2.2 – 6.5)

(RR = 0.83; 95%-C.I. 0.76 – 0.91; p<0.0001)
Overall survival: 10-y Gain 2.8% (95%-C.I. 0.8 – 4.8)
(RR = 0.86; 95%-C.I. 0.77 – 0.96; p=0.0054)

ER negative: 10-y Gain 4.7% (95%-C.I. 2.3 – 7.1)

www.ago-online.de ER positive: 10-y Gain 3.1% (95%-C.I. 1.5 – 4.7)
 Recommended Dose-dense and / or Dose-escalated,
Sequential Adjuvant Chemotherapy *
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
Dose-dense regimen
Version 2020.1
 A60 X4  Pac175 x4  C600 x4 q2w 1b A ++
 A60C q2w x4 Pac175 q2w x 4 1b B ++
 E90C q2w x4 Pac175 q2w x 4 1b A ++
 E90C q2w x4  Pac80 q1w x 12 1b B ++

Dose-dense and dose-escalated regimen (N ≥ 4+)

 E150Pac225C2500 q2w 1b A ++

www.ago-online.de

* G-CSF obligatory
 Recommended Conventional Regimens
for Adjuvant Chemotherapy
© AGO
* Extrapolation from doxorubicin trials Oxford
e. V.
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V. Anthracycline- / taxane-based regimen
Guidelines Breast
Version 2020.1  *EC q3w x 4  Pac q1w x 12 2b B ++
 AC q3w x 4  Pac q1w y 12 1b A ++
 AC  D A60C q3w x 4  D100 x 4 1b A +
 *EC  D E90C q3w x 4  D100 x 4 1b B +
 DAC D75A50C q3w x 6 1b A +
Anthracycline-free regimen
 DC corresponds to EC  D D75 C600 x 6 1b B +
 DC >> 4 x AC D75C600 x 6 1b B +
 Pac mono P80 q1w x 12 1b B +/-
www.ago-online.de
 CMF 1a A +/-
Taxane-free regimen (if pN0)
 FE100C x 6 F500E100C500 x 6 2b(a) B +
 Adjuvant Chemotherapy
Other Drugs
© AGO e. V.
Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast  Capecitabine-containing regimen in TNBC 1a B +/-
 in general
Version 2020.1
1aa A -
 postneoadjuvant in non-pCR patients* 1aa A +

 Platinum-containing regimen in TNBC 5 D +

 5- fluorouracile added to EC/AC 1b A --

www.ago-online.de

*no platinum pretreatment

 Van Mackelenbergh M et al., SABCS 2019,
abstr. GS1-07
© AGO e. V. Effects of capecitabine as part of neo-/adjuvant chemotherapy
in der DGGG e.V.
sowie Meta-analysis of individual patient data from 12 randomized trials (n=15,457)
in der DKG e.V.

Guidelines Breast
Version 2020.1
HR for DFS overall 0.952 (95%-C.I. 0.895-1.012, p=0.115)
X add. 0.888 (95%-C.I. 0.817-0.965, p=0.005)
X instead 1.035 (95%-C.I. 0.945-1.134, p=0.455)
HR for OS overall 0.892 (95%-C.I. 0.824-0.965, p=0.005)
X add. 0.837 (95%-C.I. 0.751-0.933, p=0.001)
X instead 0.957 (95%-C.I. 0.853-1.073, p=0.450)
Significance only for TNBC overall DFS 0.886 (95%-C.I. 0.789-0.994, p=0.040)
OS 0.828 (95%-C.I. 0.720-0.952, p=0.008)
www.ago-online.de
X add.: DFS 0.818 (95%-C.I. 0.713-0.938, p=0.004)
OS 0.778 (95%-C.I. 0.657-0.921, p=0.004)
 Adjuvant Treatment
with Trastuzumab +/- Pertuzumab
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
 Trastuzumab + Pertuzumab
Version 2020.1
 pN+ 1ba B +
 pN- 1ba B +/-

 Trastuzumab in node-negative disease

(if chemotherapy is indicated)
 > 10 mm 1a A ++
 > 5–10 mm 2b B +
 ≤ 5 mm 2b B +/-
www.ago-online.de
 Aphinity-Trial - Update
Clinical benefit of the dual blockade with trastuzumab / pertuzumab

© AGO e. V.
in der DGGG e.V.
HR (95%-CI) for IDFS 6-yr-IDFS rate
sowie
in der DKG e.V. Group Primary analysis Update Pertuzumab Placebo Absolute benefit
Guidelines Breast
(2017) * (2019)** arm arm 95%-CI
Version 2020.1
ITT 0,81 (0,66-1,00) 0,76 (0,64 -0,91) 90,6% 87,8% 2,8% (1,0-4,6)

N+ 0,77 (0,62-0,96) 0,72 (0,59-0,87) 87,9% 83,4% 4,5% (1,9-7,1)

N0 1,13 (0,58-1,86) 1,02 (0,69-1,53) 95,0% 94,9% 0,1% (-2,0 -2,2)

HR pos 0,86 (0,56-1,13) 0,73 (0,59 – 0,92) 91,2% 88,2% 3,0% (0,8-5,2)

HR neg 0,76 (0,56-1,04) 0,83 (0,63-1,10) 89,5% 87,0% 2,5% (-0,7-5,6)

* FU: 45,5 mths; ** FU: 74,1 mths

www.ago-online.de
OS difference after 74.1 mths of median follow-up did not reach statistical significance

Mod. Nach Piccart M et al. SABCS 2019; abstr. GS1-04

 Adjuvant treatment
with trastuzumab
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
Start of treatment
Version 2020.1
 Simultaneously with taxanes 1a A ++
 Sequentially up to 3 months after chemotherapy 1b B +
 s.c. = i.v. 1a A ++

Duration
 For 1 year 1a A ++
 For 0.5 years 1a A +
www.ago-online.de  For 2 years 1b A -
 Adjuvant Treatment with Trastuzumab +/-
Pertuzumab: Chemotherapy regimen
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
Trastuzumab simultaneously with
Version 2020.1  paclitaxel / docetaxel after AC / EC 1a A ++
 P q1w 12 x in pT < 2 cm, pN0 2b B +
 docetaxel and carboplatin 1b A +

Trastuzumab + Pertuzumab simultaneously with

 paclitaxel q1w (or docetaxel q3w) after EC/AC 1b B ++
 docetaxel+ carboplatin 1b B +
 taxanes dose-dense 2b B +*
www.ago-online.de

Radiotherapy concurrently with Trastuzumab 2b B +

 Adjuvant Therapy With
Other Targeted Agents
© AGO e. V.
in der DGGG e.V. Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast
Version 2020.1
 Lapatinib 1ba B -
 (delayed adjuvant treatment) 1b B -
 Lapatinib + Trastuzumab 1ba B -
 Neratinib* (one year) after completing a year of
1b B +
adjuvant trastuzumab (if HR-positive)
 Bevacizumab 1b B --

www.ago-online.de

* In addition to standard endocrine treatment

 Postneoadjuvant Therapy
Oxford
© AGO e. V.
in der DGGG e.V.
LoE GR AGO
sowie
in der DKG e.V. HR-positive (pCR and non-pCR)
Guidelines Breast
 Endocrine therapy according to menopausal status (see. ch. 10) 1a A ++
Version 2020.1  Capecitabine (in case of non-pCR) 3b C +/-
HER2-positive (in case of pCR)
 Low-risk: Trastuzumab (to complete 12 months) 2a C ++
 High-risk (N+): Trastuzumab + Pertuzumab (to complete 12
2b C +
months)
HER2-positive (in case of non-pCR)
 T-DM1 1b B +
 Neratinib after 1 year* Trastuzumab (HR-positive) 3b B +/-
 Trastuzumab + Pertuzumab (to complete 12 months) 2b C +/-
www.ago-online.de
Triple negative (TNBC) (if non-pCR)
 Capecitabine (up to 8 courses)** 1b B +
* in combination with standard endocrine therapy
** without platin based previous therapy
 Biosimilars
Genaral Considerations
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Biosimilars that are used for treatment (i.e. trastuzumab) and supportive
care of breast cancer (i.e G-CSF) must be approved by the respective
regulatory authorities (EMA, FDA ) after passing the stringent development
and validation processes required before being used in daily practise.*

www.ago-online.de

* Thill M et al. Einführung und Verwendung von biosimilaren Antikörpern in der Therapie des Mammakarzinoms.
Geburtshilfe Frauenheilkd 2018; DOI: 10.1055/s-0043-118761
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Neoadjuvant
(Primary) Systemic Therapy
 Neoadjuvant Systemic Therapy
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  Versions 2002–2019:
Guidelines Breast
Version 2020.1
Bauerfeind / Blohmer / Costa / Dall / Fersis /
Friedrich / Göhring / Harbeck / Heinrich / Huober / Jackisch / Kaufmann /
Liedtke / Loibl / Lux /
von Minckwitz / Müller / Mundhenke / Nitz / Schneeweiss / Schütz /
Solomayer / Untch

 Version 2020:
Jackisch / Schneeweiss

www.ago-online.de
 Subtype-specific Strategies
for Systemic Treatment
© AGO e. V.
AGO
in der DGGG e.V.
sowie If chemotherapy is indicated systemic treatment before surgery (neoadjuvant)
in der DKG e.V.
should be preferred
Guidelines Breast
Version 2020.1 HR+/HER2- and „low-risk”
 Endocrine therapy without chemotherapy ++
HR+/HER2- and „high-risk”
 Conventionally dosed AT- based chemotherapy (q3w) +
 Dose dense chemotherapy (including weekly schedule) ++
 Followed by endocrine therapy ++
HER2+
 Trastuzumab (plus Pertuzumab in N+ or NST) ++
 Sequential A/T-based regimen with concurrent T + anti-HER2 therapy ++
 Anthracycline-free, platinum-containing regimen +
 Anthracycline-free, taxane-containing regimen +
www.ago-online.de Triple-negative (TNBC)
 Conventionally dosed AT-based chemotherapy +
 Dose dense chemotherapy (AT - based including weekly schedule) ++
 Neoadjuvant platinum-containing chemotherapy +
 HER2+ Early Breast Cancer
Neo-/adjuvant and postneoadjuvant Therapy
© AGO e. V.
Adjuvant Therapy: Neoadjuvant Therapy³ Postneoadjuvant Therapy4
in der DGGG e.V. low risk of recurrence Trastuzumab + Pertuzumab Trastuzumab +/- Pertuzumab
sowie or T-DM1
in der DKG e.V. Rezidivrisiko
Paclitaxelweekly x 12 + Trastuzumab1
Guidelines Breast In case of pCR:
Version 2020.1
• elderly or fragile patients • Node-positive (cN+/pN+)
• Trastuzumab
or
• Trastuzumab + Pertuzumab
• pT1, pN0 or
- Node-positive prior NST
Adjuvant Therapy:
high risk of recurrence - Irrespective of ER-status
CHT + Trastuzumab + Pertuzumab² • cT > 2
In case of non-pCR:
• Node-positive (pN+) • T-DM1
• Irrespective of ER-status5

www.ago-online.de

Total duration of anti-HER2-therapy: 1 year

1.Tolaney SM, et al. J Clin Oncol April 2019; 2. von Minckwitz G, et al. N Engl J Med 2017; 377:122–131 (inkl. Suppl.); 3. Gianni L, et al. Lancet Oncol 2012;13:25-32;
4. von Minckwitz G, et al. N Engl J Med 2019; 380:617-628, 5. Piccart M, et al. SABCS 2019 (abs GS1-04)
 Neoadjuvant Systemic Chemotherapy
Clinical Benefit
Oxford
© AGO e. V.
in der DGGG e.V. LoE GR AGO
sowie
in der DKG e.V.  Leads to improvement of prognosis by individualization of 1b A
Guidelines Breast post-neoadjuvant therapy
Version 2019.1
 Survival is similar after neoadjuvant (preoperative, primary)
and adjuvant systemic therapy (with same regimen and
1a A
number of cycles), if the postneoadjuvant therapy is not
stratified according to pathologic response
 Pathological complete response is associated with improved
1b A
survival
 Can achieve operability in primary inoperable tumors 1b A
 Improved options for breast conserving surgery 1b A
www.ago-online.de  Decreases rate of axillary lymph node dissection 3b C
 Allows individualization of therapy according to mid-course
1b B
treatment effect
 Neoadjuvant Systemic
Chemotherapy - Indications
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Inflammatory breast cancer 2b B ++
Version 2020.1
 Inoperable breast cancer 1c A ++
 Large operable breast cancer requiring mastectomy
and adjuvant chemotherapy with the goal of breast 1b B ++
conservation
 If similar postoperative adjuvant chemotherapy ++
1b A
is indicated

www.ago-online.de
 To allow a risk adapted postoperative therapy 1b A ++
 Neoadjuvant Systemic Chemotherapy
Response Prediction I
© AGO e. V.
in der DGGG e.V. Factor LoEOx2 CTS GR AGO
sowie
001
in der DKG e.V.

Guidelines Breast
 Young age 1a B A +
Version 2020.1
 cT1 / cT2 tumors o. N0 o. G3 1a B A ++
 Negative hormone receptor status 1a B A ++
 ER+ and negative PgR-status 2a B B ++
 Triple negative breast cancer 1a B A ++
 Positive HER2 status 1a B A ++
 Non-lobular tumor type 1a B A +
 Early clinical response 1b B A +

www.ago-online.de
 Neoadjuvant Systemic Therapy
Response Prediction II
© AGO e. V.
in der DGGG e.V.
sowie Factor LoE2009 CTS GR AGO
in der DKG e.V.

Guidelines Breast  Multigene signatures III C B +/-

Version 2020.1
 Ki-67 I B A +
 Tumor infiltrating lymphocytes* I B B +
 PIK3CA mutation in HER2 positive BC I B B +/-
 gBRCA II B B +
 Homologous recombination deficiency IV C C +/-

www.ago-online.de

* LPBC is defined as dense lymphocytic infiltration of inner peritumoral stroma outside of invasion front
(> 50% of stromal area are covered by lymphocytes)
 Neoadjuvant Systemic Chemotherapy
Recommended Regimens and Schedules
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Standard protocols used in the adjuvant setting
Guidelines Breast 1a A ++
Version 2020.1
with a duration of at least 18 weeks*

 Taxane followed by anthracycline 1a A +

 Platinum in TNBC (irrespective of BRCA status) 1a B +

1b B +
 Nab-Paclitaxel weekly instead of Paclitaxel weekly

www.ago-online.de

* See chapter Adjuvant Chemotherapy

 Neoadjuvant Systemic Therapy
Recommended Methods of Monitoring of Response
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Breast ultrasound 2b B ++
Version 2020.1
 Palpation 2b B ++
 Mammography 2b B ++
 MRI 2b B +
 PET(-CT) 2b B +/-
 Clip tumor region 5 D ++
 Clip placement in pN+ 3 C +/-

www.ago-online.de
 Neoadjuvant Targeted Therapy
in HER2 Positive Tumors
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast  Trastuzumab in combination with chemotherapy 1b A ++
Version 2020.1

 Pertuzumab + trastuzumab in combination with 2b B ++

chemotherapy
2b B +/-
 Two anti-HER2 agents without chemotherapy

www.ago-online.de
 Neoadjuvant Systemic Therapy
Procedures in Case of Early Response
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
In case of early response following 6 to 12 weeks of
Version 2020.1
neoadjuvant chemotherapy:

 Complete all chemotherapy before surgery i.e. ≥ 18

1b A ++
weeks of treatment

 In case of response after 2 cycles of TAC in HR positive

2b C +
breast cancer consider 8 instead of 6 cycles
of TAC
www.ago-online.de
 Neoadjuvant Systemic Therapy
Procedures in Case of No Early Response
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
In case of no change:
Version 2020.1  Completion of neoadjuvant chemotherapy (NST)
2b C ++
followed by surgery
 Continuation of NST with non cross-resistant
2b B +
regimen
 AC or EC x 4 → D x 4 or Pw x 12 2b B +
 DAC x 2 → NX x 4 1b B +

In case of progressive disease:

www.ago-online.de
 Stop NST and proceed to surgery or radiotherapy 4 D ++
 Additional adjuvant chemotherapy with non
4 D +/-
cross-resistant regimen
 Oxford
Axillary
Axillary Interventions
Interventions inin NST
NACT LoE GR
AGO

SLNE following NST 2b B ++

SLNE prior NST 2b B +/-

© AGO
Further surgical procedures depending on SLNE status
e. V.
in der DGGG e.V. cN-status pN-status N-status Surgical Procedure
sowie
in der DKG e.V.
(before NST) (before NST) (after NST) (after NST)

Guidelines Breast
cN0 pN0(sn) ycN0 None 1a A +
Version 2020.1
cN0 pN+(sn) according to ACOSOG Z0011 ycN0 None 1b B +
cN0 pN+(sn) not according to ACOSOG Z0011 ycN0 ALND or Axillary RT 2b B +
ypN0 (sn) SLNE only 2b B ++
ALND 2b C +
ypN1mic (sn)
cN0 Not done Axillary RT 5 D +/-
ALND 2b C ++
ypN1 (sn)
Axillary RT 5 D +/-
SLNE only* 2b B +/-
cN+ pN+CNB ycN0 TAD (TLNE + SLNE)* 2b B +
ALND* 2b B +
ALND 2 B ++
www.ago-online.de cN+ pN+CNB ycN+
Axillary RT 5 D -

NST=Neoadjuvant Systemic Therapy; ALND=Axillary Lymph Node Dissection; SLNE=Sentinel Lymph Node Excision;
TAD=Targeted Axillary Dissection; TLNE=Targeted Lymph Node Excision; RT=Radiotherapy – *Trial participation recommended
 Neoadjuvant Systemic Therapy
Loco-regional Surgery
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast  Clip tumor region before NST 5 D ++
Version 2020.1

2b C ++
 Appropriate surgery following NST
2 B ++
 Microscopically clear margins

 Tumor resection according to most recent imaging 2 B +

result

www.ago-online.de
 Neoadjuvant Systemic Therapy
Indications for Mastectomy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Positive margins after repeated excisions 3b C ++
Version 2020.1

5 D ++
 Radiotherapy not feasible

 In case of clinical complete response

 Inflammatory breast cancer (in case of pCR) 2b C +/-
 Multicentric lesions 2b C +/-
 cT4a-c breast cancer 2b B +/-

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 Neoadjuvant Systemic Therapy
Timing of Diagnosis, Surgery and Radiotherapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Version 2020.1
Initiation of therapy
Necessary delay of therapy does not impact prognosis 2b B
(even if > 4 weeks)

Surgery
After nadir of leucocyte count 2b B ++
(2 to 4 weeks after last course of chemotherapy)

www.ago-online.de
Radiotherapy within 2–3 months after surgery 2b B ++
 Neoadjuvant Endocrine Therapy in Patients
with Endocrine-responsive Breast Cancer
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Postmenopausal patients:
Version 2020.1  Who are inoperable and cannot / will not receive chemotherapy 2a B +
 Optimizes the option for breast conserving therapy 1b A +
 Aromatase inhibitors (for > 3 months) 1aa B +
 Aromatase inhibitor + lapatinib (HER2+ BC) 2b B +/-
 Premenopausal patients
 Who are inoperable and cannot / will not receive chemotherapy 5 C +
 Tamoxifen 2b C +
 Aromatase inhibitors + LHRHa 1b C +/-
 Concurrent chemo-endocrine therapy 1b A -
 Prognostic score:
www.ago-online.de  PEPI: pTN-Stage, ER expression and Ki-67 expression after 1b B +
neoadjuvant endocrine therapy
a Optimal duration of neoadjuvant endocrine therapy is unknown.
No long term results for neoadjuvant endocrine therapy (vs. adjuvant endocrine therapy)
 Postneoadjuvant Therapy
Oxford
© AGO e. V.
in der DGGG e.V.
LoE GR AGO
sowie
in der DKG e.V. HR-positive (pCR and non-pCR)
Guidelines Breast
 Endocrine therapy according to menopausal status (see. ch. 10) 1a A ++
Version 2020.1  Capecitabine (in case of non-pCR) 3b C +/-
HER2-positive (in case of pCR)
 Low-risk: Trastuzumab (to complete 12 months) 2a C ++
 High-risk (N+): Trastuzumab + Pertuzumab (to complete 12
2b C +
months)
HER2-positive (in case of non-pCR)
 T-DM1 1b B +
 Neratinib after 1 year* Trastuzumab (HR-positive) 3b B +/-
 Trastuzumab + Pertuzumab (to complete 12 months) 2b C +/-
www.ago-online.de
Triple negative (TNBC) (if non-pCR)
 Capecitabine (up to 8 courses)** 1b B +
* in combination with standard endocrine therapy
** without platin based previous therapy
 Take Home Message - NST
© AGO e. V.
in der DGGG e.V.  Neoadjuvant systemic therapy offers an established treatment option for patients with
sowie
in der DKG e.V. early breast cancer if chemotherapy is indicated
Guidelines Breast
Version 2020.1
 The pathologic response offers important prognostic information
 Surgical procedures after NST follows the same guidelines as compared to upfront
surgery
 The options in axillary interventions follow a complex algorithm (see slide 16 of this
chapter
 In case of non-pCR there is the option to improve prognosis by postneoadjuvant
treatment in HER2+, TNBC or high-risk HR+ HER2- breast cancer by adapted
postneaodjuvant therapy
 If postneoadjuvante endocrine therapy is indicated therapy is independend of the
www.ago-online.de
response to NST
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Adjuvant Radiotherapy
 Adjuvant Radiotherapy (RT)
© AGO e. V.
in der DGGG e.V.
sowie
 Versions 2002 – 2019:
in der DKG e.V.
Blohmer / Budach / Friedrichs / Göhring / Huober/ Janni / Kühn / Möbus
Guidelines Breast
Version 2020.1 / Rody / Scharl / Seegenschmiedt / Souchon / Thomssen / Untch / Wenz

 Version 2019:
Budach / Krug / Kühn

www.ago-online.de
 Preliminary Note
© AGO e. V.
in der DGGG e.V.  The recommendations on adjuvant radiotherapy for breast
sowie
in der DKG e.V. cancer are based on a consensus discussion between AGO and
Guidelines Breast
Version 2020.1 DEGRO experts
 For technical radiotherapy details, we refer to the corresponding
updated DEGRO practical guidelines

www.ago-online.de
 Radiotherapy (RT) after Breast Conserving Surgery
(Invasive Cancer): Whole Breast Irradiation
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Radiotherapy of the affected breast 1a A ++
Version 2020.1
 Hypofractionated radiotherapy (total dose
approximately 40 Gy in 15-16 fractions within 1a A ++
3-5 weeks
 Conventionally fractionated radiotherapy (total dose
about 50 Gy in approx. 25-28 fractions in about 5-6 1a B +
weeks)
 In case of life expectancy <10 years and pT1, pN0, R0,
ER/PR-positive, HER2-negative, endocrine therapy (all
www.ago-online.de criteria), radiotherapy can be omitted after individual 1a B +
counseling, resulting in an increased risk for in-breast
recurrence
 BCS >=70y <4cm cN0 : Tamoxifen vs. Tamoxifen + RT
Time:1994-1999, since 8/1996 only pT1cN0 ER/PR+ or unknown allowed

© AGO e. V. @10 yrs Tamoxifen plus

in der DGGG e.V. Tamoxifen Hazard Ratio
sowie (95% C.I.) Radiotherapy
in der DKG e.V.
HR=0.18
Guidelines Breast Local recurrence- 90% 98%
Version 2020.1 (95% CI, 0.07 to
free (=8%) (85%-93%) (96%-99%)
0.42; P < .001)
HR=0.50
Mastectomy- 96% 98%
(95% CI, 0.17 to
free (93% - 98%) (96% - 99%)
1.48; n.s.)
HR=1.20
Distant 95% 95%
(95% CI, 0.63 to
metastasis-free (91% - 97%) (92% - 97%)
2.32; n.s)
HR=0.95
66% 67%
Overall survival (95% CI, 0.77 to
(61% - 71%) (62% - 72%)
www.ago-online.de 1.18; n.s.)

Hughes KE et al J Clin Oncol 2013; 31:2382-2387

 Radiotherapy (RT) after Breast Conserving Surgery
(Invasive Cancer) – Boost Irradiation
Oxford
© AGO e. V.
in der DGGG e.V. LoE GR AGO
sowie
in der DKG e.V.  Boost-RT (improves local control, no survival benefit)
Guidelines Breast  Premenopausal 1b B ++
Version 2020.1
 Postmenopausal, if >T1*, G3, HER2-positive, triple negative, EIC
2b B +
(at least 1 factor)
 Techniques
 Percutaneous boost (photons, electrons) as sequential boost 1a A ++
 Multicatheter brachytherapy-boost 1a A ++
 Percutaneous boost as simultaneous integrated boost (with
2b B +
normofractionated whole-breast irradiation)
 Percutaneous boost as simultaneous integrated boost (with
2b B +/-
hypofractionated whole-breast irradiation)
 Intraoperative boost irradiation (followed by whole-breast
2b B +
www.ago-online.de irradiation)

* continuous parameter with regard to risk of relapse

 EORTC 22881-10882: Boost vs no Boost
(Endpoint: Ipsilateral Breast Recurrence)
© AGO e. V. @20 yrs Boost No boost Hazard Ratio
in der DGGG e.V. (95% C.I.) (n=2.661) (n=2.657) (95% C.I.)
sowie
in der DKG e.V. Overall Survival 59.7% 61.1% HR 1.05
(=-1.4%) (56.3–63.0) (57.6–64.3) (0.92–1.19) n.s.
Guidelines Breast
Version 2020.1
Cumulative Risk of Ipsilateral Breast Tumour Recurrence
All patients 12.0% 16.4% HR=0.65
(9.8–14.4) (14.1–18.8) (0.52–0.81); p<0.0001

≤40 years 24.4% 36.0% HR=0.56

(=11.6%) (14.9–33.8) (25.8–46.2) (0.34–0.92); p=0.003

41–50 years 13.5% 19.4% HR=0.66

(=5.9%) (9.5–17.5) (14.7–24.1%) (0.45–0.98); p=0.007

51–60 years 10.3% 13.2% HR=0.69

(=2.96%) (6.3–14.3) (9.8–16.7) (0.46–1.04); p=0.020

>60 years 9.7% 12.7% HR=0.66

www.ago-online.de (=3.0%) (5.0–14.4) (7.4–18.0) (0.42–1.04); p=0.019

(Median F/U 17.2 y) acc. to: Bartelink et al. Lancet Oncol 2015; 16: 47–56
 EORTC 22881-10882: Boost vs no Boost
(Endpoint: Any First Recurrence)
© AGO e. V. @15 yrs/20 yrs Boost No boost Hazard Ratio
in der DGGG e.V. (95% C.I.) (n=2.661) (n=2.657) (95% C.I.)
sowie
in der DKG e.V.
Overall Survival 59.7% 61.1% HR 1.05
Guidelines Breast (= - 1.4%) (56.3–63.0) (57.6–64.3) (0.92–1.19) n.s.
Version 2020.1
Cumulative Risk of Any First Recurrence
All patients @15y 28.1% 32.1% HR=0.92
(≥4%) @20y 32,8% 38.7% (0.81-1.04), n.s.
≤40 years @15y 41.5% 48.1% HR=0.80
(>6%) @20y 49.5% 56.8% (0.56-1.15) , n.s.
@15y 34.0% 35.6% HR=0.91
41–50 years
@20y 38.6% 44.2% (0.71-1.16), n.s.
@15y 28.5% 28.7% HR=0.96
51–60 years
@20y 34.7% 36.2% (0.76-1.21), n.s.
@15y 27.4% 29.1% HR=0.94
www.ago-online.de >60 years
@20y 32.1% 32.8% (0.74-1.19), n.s.

(Median F/U 17.2 y) acc. Bartelink et al. Lancet Oncol 2015; 16: 47–56. Suppl.
 Radiotherapy (RT) after Breast Conserving Surgery
(Invasive Cancer) – Partial Breast Irradiation (PBI)
© AGO
Oxford
e. V.
in der DGGG e.V. LoE GR AGO
 Intraoperative Radiotherapy (low-risk)*
sowie
in der DKG e.V.

Guidelines Breast  As sole radiotherapy, during first breast surgery (IORT 50 kV, IOERT)
Version 2020.1
 >50 years 1b A +/-
 >70 years 1b A +
 Postoperative partial breast irradiation (low-risk)*
 Interstitial Multicatheter-Brachytherapy 1b A +
 Intracavitary balloon-technique 2b B -
 Intensity-modulated radiotherapy (IMRT) (5x6 Gy in 2 weeks) 1b A +
 3D-conformal radiotherapy (15x2.67 Gy in 3 weeks) 1b A +
 3D-conformal radiotherapy (10x3.8 Gy in 2 weeks) 2b B +/-
 3D-conformal radiotherapy (10x3.85 Gy in 1 week) 1b A +/-

www.ago-online.de For definition of target volume and practical conduct see DEGRO practical guidelines

* only for pT1 pN0 R0 G1-2, HR+, non-lobular, >50 years, no extensive DCIS
 New data on partial breast irradiation
© AGO e. V. NSABP B-39/RTOG 0413 (Vicini FA et al. Lancet. 2019 Dec 14;394(10215):2155-2164.)
in der DGGG e.V.
sowie
• Randomised phase III equivalence trial, 4216 pat., 2005-2013, DCIS or invasive carcinoma ≤ 3
in der DKG e.V. cm, 0-3 involved lymph nodes, age >18 y
Guidelines Breast • 50 Gy/25 fr. +/- boost vs. APBI with
Version 2020.1
• 38.5 Gy/10 fr. in one week (external beam irradiation)
• 34 Gy/10 fr. in one week (Multicatheter- or Single lumen-Brachytherapy)
• “We observed an HR of 1.22 with a 90% CI of 0.94–1.58, which did not meet the equivalence
criteria and favoured whole-breast irradiation. The 10-year cumulative incidence of IBTR was
3.9% (95% CI 3.1–5.0) in the whole-breast irradiation group and 4.6% (3.7–5.7) in the APBI
group for an absolute difference of 0.7%.”
• “Significantly more evaluable patients in the APBI group had recurrence-free interval events
than patients in the whole-breast irradiation group (figure 3). The 10-year point estimate of
recurrence-free interval for the whole breast irradiation group was 93·4% (95% CI 92·1–94·6),
and in the APBI group it was 91·8% (90·4–93·0; figure 3)”.
www.ago-online.de
• "Our findings support whole-breast irradiation but the absolute outcome difference compared
with APBI is small, so partial breast irradiation might also be an acceptable treatment for some
patients. “
 New data on partial breast irradiation
© AGO e. V. RAPID (Whelan TJ et al. Lancet. 2019 Dec 14;394(10215):2165-2172.)
in der DGGG e.V.
sowie
• Randomised phase III non-inferiority trial, 2135 pat., 2006-2011, DCIS or invasive carcinoma ≤ 3
in der DKG e.V. cm, pN0, age ≥40 y., no ILC
Guidelines Breast • 42.56/16 fr. or 50 Gy/25 fr. +/- Boost vs. APBI 38.5 Gy/10 fr. in one week (external beam
Version 2020.1
irradiation)
• “In patients treated with APBI, the 5 year cumulative rate of IBTR was 2·3% (95% CI 1·4–3·2)
and the 8 year cumulative rate was 3·0% (1·9–4·0). In patients treated with whole breast
irradiation, the 5 year cumulative rate of IBTR was 1·7% (0·9–2·5) and the 8 year cumulative
rate was 2·8% (1·8–3·9; figure 2). The HR for APBI versus whole breast irradiation was 1·27 (90%
CI 0·84–1·91). Thus, the upper bound of the estimated 90% CI did not exceed the non-
inferiority margin of 2·02.”
• “Late radiation toxicity (grade ≥2 […]) was more common in patients treated with APBI (346
[32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001).
Adverse cosmesis […] was more common in patients treated with APBI than in those treated
www.ago-online.de
by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5–15·0), 5 years
(16·5%, 12·5–20·4), and 7 years (17·7%, 12·9–22·3).”
 Postmastectomy Radiotherapy
(PMRT)* to the Chest Wall
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
 > 3 tumor infiltrated lymph nodes (LN) 1a A ++
Version 2020.1
 1–3 tumor infiltrated LN (high-risk) 1a A +
 1–3 tumor infiltrated LN (low-risk*) 5 D +/-
 T3 / T4 1a A ++
 pT3 pN0 R0 (and no additional risk factors) 2b B +/-
 If R0 is impossible to reach (for invasive tumor) 1a A ++
 In young pts with high-risk features 2b B ++
The indications for PMRT and regional RT are
1a A
www.ago-online.de independent of adjuvant systemic treatment

* For definition of low-risk, see next slide Radiotherapy of the Chest Wall After Mastectomy (PMRT)
 Radiotherapy of the Chest Wall After Mastectomy (PMRT) in
Case of 1-3 Axillary Lymph Node Metastases
© AGO e. V. PMRT PMRT PMRT
in der DGGG e.V.
sowie
can be omitted to be discussed recommended
in der DKG e.V. LoE 3b B AGO + LoE 3b B AGO +/- LoE 3b B AGO +
Guidelines Breast
Version 2020.1 ≥45 y. AND >25% pos. ax. Lnn in case of axillary
ER pos, G1, HER2 neg, pT1
dissection OR
(at least 3 criteria present)
<45 y. AND (ER neg. OR>25% pos. ax. Lnn in case
Kyndi et al. 2009 Patients, who of axillary dissection OR medial tumor location)
don‘t fulfill Truong et al. 2005
the mentioned <40 y. OR
criteria for HER2 pos. OR
high or low lymphovascular invasion
risk Shen H et al. 2015
G3 OR
lymphovascular invasion OR
www.ago-online.de triple negative
Different publications
Comment: In case of an indication for radiotherapy of regional lymph nodes,
radiotherapy of the chest wall should also be administered
 Boost in PMRT
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 An additional boost irradiation to a part of the chest wall has not 2a B
Guidelines Breast
Version 2020.1 been shown to improve DSS and overall survival
 An additional boost irradiation to a part of the chest wall should be 5 D ++
given in case of of R1/R2-resection, if secondary resection is not
feasible
 In case of tumor extention to the pectoral resection margin, but no 5 D ++
clinical signs of extention beyond the fascia, the resection margin
should be regarded as R0 (provided, that the pectoral fascia was
resected). A boost radiotherapy is not required in this situation

www.ago-online.de
 Radiotherapy after axillary lymph node dissection or
negative sentinel lymph node excision
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Oxford
Guidelines Breast
Version 2020.1 LoE GR AGO
 Tumor residuals after axillary dissection 5 D ++
 Sentinel node negative 1b B --
 Extracapsular tumor spread (ECS) 2b B -
 Axillary micrometastases or isolated cells found in
1b B --
regional lymph nodes

www.ago-online.de
 Radiotherapy of axillary lymph nodes in patients with positive
sentinel-lymph nodes**, who did not undergo axillary dissection
Oxford
© AGO e. V.
in der DGGG e.V.
LoE GR AGO
sowie
in der DKG e.V. BCS and ACOSOG Z0011-criteria+ met
Guidelines Breast  Radiotherapy of the breast including LN level 1 + 2 2b B +*
Version 2020.1
to 5 mm below the axillary vein (PTV)
BCS and ACOSOG Z0011-criteria+ not met
1b B ++*
 Radiotherapy of the axillary lymph nodes (analog AMAROS)
ME and chest wall RT indicated and ACOSOG Z011-criteria+ not met or
ME and chest wall RT not planned 1b B ++
 Radiotherapy of the axillary lymph nodes (analog AMAROS)
>=3 pos. SLN
www.ago-online.de
 Radiotherapy of the axillary lymph nodes (analog AMAROS) 1b B +
+ = <T3, no palpable LN, R0, 1-2 positive SN, no
* = Study participation recommended
** = Macrometastases extracapsular extention, no NACT
 Dose in the axillary LN-levels I + II using different RT-
techniques
mean encompassed
© AGO e. V. ACOSOG Z0011 Trial RT-volume
LN level 1 dose* volumen**
in der DGGG e.V.
45% micrometast. in the exp. arm % of patientis
sowie
in der DKG e.V.
AMAROS >95% >95%
high tangent 86% 79%
supra-

AMAROS
Guidelines Breast
Version 2020.1
clavicular 17% standard tangent 66% 51%
IMRT+ 29% 1%
„high tangent“ II 53%
axillary vein
I LN-level 2
AMAROS >95% >95%
„standard breast 28% high tangent 71% 51%
tangent“ standard tangent 44% 26%
IMRT+ 7% 0%
* in relation to the prescribed dose in the breast
** % volume receiving the prescribed dose
www.ago-online.de 2% no RT + Lee et al. Medicine 2016 (3)

Data from 228/856 pat. Jagsi (2): “The results of Z0011 should not be extrapolated to patients who receive RT using
partial-breast or prone techniques, in which substantially less of the axilla is included”
 Radiotherapy (RT) of Other Locoregional
Lymph Node Areas (SCG/ICG)
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast RT to supra-/infraclavicular lymphatic regions

Version 2020.1

 ≥ 4 positive axillary lymph nodes (LN) or involved LN in level

1b A ++
III or in supra-/infraclavicular LN

 1–3 positive axillary lymph nodes1 in case of 2a B +

- central or medial tumor and G2-3 or ER/PgR-negative
- premenopausal patient and G2-3 or ER/PgR-negative

 pN0 with central or medial tumors, if premenopausal and

2a B +/-
www.ago-online.de
G2-3 and ER/PgR-negative

1 not applicable for micrometastases

 Radiotherapy (RT) of Other Locoregional
Lymph Node Areas (IMN)
© AGO
Oxford
e. V.
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.
Internal mammary lymph node region (IMN)
Guidelines Breast
Version 2020.1  pN0 high-risk with central or medial tumor 1b B +/-
and premenopausal and G2-3 and ER/PgR-negative
 1–3 positive axillary lymph nodes1 in case of 2a B +
- central or medial tumor and G2-3 or ER/PgR-negative
- premenopausal patient and G2-3 or ER/PgR-negative
 ≥ 4 positive axillary lymph nodes 2a B +
 involved internal mammary lymph nodes 2a B +
 In case of cardiac risk factors or if trastuzumab is given 2b A --
www.ago-online.de

1 not applicable for micrometastases

 Fractionation of Radiotherapy in Case of
Regional Nodal Irradiation
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Conventionally fractionated radiotherapy
Version 2020.1
(total dose about 50 Gy in approx. 25-28 fractions 1a A ++
within 5–6 weeks)
 Hypofractionated radiotherapy
(total dose approx.´40–43.5 Gy in 15-16 fractions 2b B +/-
within 3–5 weeks)

www.ago-online.de
 Hypofractionated post-mastectomy
radiotherapy and regional nodal irradiation
© AGO e. V. Wang et al. Lancet Oncol. 2019 Mar;20(3):352-360.
in der DGGG e.V.
sowie
• Randomised phase III non-inferiority trial, 820 pat., 2008-2016, T3/4 and/or ≥4 involved lymph
in der DKG e.V. nodes, 50 Gy/25 fr. vs. 43.5 Gy/15 fr.
Guidelines Breast • 98% 2D-planned radiotherapy, no treatment of the internal mammary lymph nodes
Version 2020.1
• “The 5-year cumulative incidence of locoregional recurrence was 8.3% (90% CI 5.8–10.7) in the
hypo- fractionated radiotherapy group compared with 8·1% (90% CI 5.4–10.6) in the
conventional fractionated radiotherapy group (absolute difference 0.2%, 90% CI –3.0 to 2.6; HR
1.10, 90% CI 0.72 to 1.69; figure 2).
• ”In conclusion, this study provides high-level evidence for the clinical use of hypofractionated
postmastectomy radiotherapy for patients with high-risk breast cancer. It can be recommended
in clinical practice to patients who do not plan breast reconstruction and will not receive
internal mammary node irradiation.”

www.ago-online.de
 Multivariate Analysis of Overall Survival: Effect of
Radiotherapy of the Internal Mammaria Lymph Nodes
© AGO e. V. (median follow-up 10.9 yrs)
in der DGGG e.V.
sowie
in der DKG e.V.
Adjuvant treatment n* Hazard ratio (95%CI)
Guidelines Breast 0.91
Version 2020.1 No adjuvant reported 625
(0.59 - 1.39)
1.05
Chemotherapy 954
(0.84 - 1.32)
0.82
Endocrine therapy 1185
(0.63 - 1.06)
Both (endocrine th. and 0.72
1200
chemotherapy) (0.55 – 0.94)
0.88
Total 4004
(0.76 – 1.01)
www.ago-online.de
* missing data on 40 patients

Poortmans et al. ECCO Amsterdam 2013

 Radiotherapy following NACT
© AGO e. V.
Pretreatment Posttreatment RT-BCS PMRT RT-RN
Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
Locally advanced pCR / no pCR yes yes yes 1a/1a/1a A/A/A ++/++/++
Guidelines Breast
Version 2020.1 ypT1+ o. ypN1
cT1/2 cN1+*
+ (no pCR)
yes yes yes 1a/2b/2b A/B/B ++/+/+

Increased risk of
cT1/2 cN1+* ypT0/is ypN0 yes 2b/2b/2b B/B/B +/+/+
relapse1

cT1/2 cN0
(Sonogr.bligat)
ypT0/is ypN0 Ja nein nein 2b/2b/2b A/B/B +/-/-

Locally advanced: T3-4 or cN2-N3,

BCS: Breast conserving surgery, PMRT: Post mastectomy radiotherapy, RN: Regional nodes
1 Criteria for increased risk of relapse:

 pN0 premenopausal high risk: central or medium tumor localization, and

(G2-3 and ER/PgR-negative)
www.ago-online.de  pretreatment pN1a/ cN+* high risk: central or medium tumor localization and
(G2-3 or ER/PgR-negative) or premenopausal, lateral tumor localization and
(G2-3 or ER/PgR-negative)
* = confirmed by core biopsy
 Molecular predictors and use of radiotherapy
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast
Version 2020.1
 Results of gene expression profiling should not be
2b B ++
used for indication of radiotherapy

www.ago-online.de
 Use of concomitant Systemic Therapy
with adjuvant locoregional Radiotherapy
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast
Version 2020.1
 Trastuzumab/Pertuzumab* 1a A ++
 T-DM1 1b A +
 Tamoxifen 2b B +
 Aromatase inhibitors 2b B +
 Checkpoint inhibitors 2b C +
 Capecitabine 2b B +**

www.ago-online.de
* concurrent Trastuzumab/Pertuzumab and parasternal radiotherapy should be avoided
** with hypofractionated RT apporx. 40 Gy, consider dose reduction of Capecitabine, Pat. with high risk for
locoregional recurrence
 Simultaneous Capecitabine with locoregional
Radiotherapy
© AGO e. V. Woodward et al. Int J Radiat Oncol Biol Phys. 2017 Nov 15;99(4):777-783
in der DGGG e.V.
sowie
• Prospective phase trial, 32 pat. with LABC, sim. def./neoadj. chemoradiotherapy, median total
in der DKG e.V. dose 66 Gy
Guidelines Breast • “The first 9 patients analyzed […] received CAP 825 mg/m2 twice daily continuously beginning
Version 2020.1
on the first day of RT. Because of observed excess grade 3 toxicity the protocol was amended,
and subsequent patients received CAP only on RT days (5 days per week).”
• “Noncontinuous CAP dosing was much better tolerated than continuous dosing. Thirteen of 26
patients (50%) had grade ≥3 and higher treatment-related dermatologic toxicity. “

Alhanafy et al. Menoufia Medical Journal 2015, 28:325-332

• Randomised phase II-trial, 100 pat., adj. Radiotherapy 40 Gy/15 fr. +/- CAP 825 mg/m2 Mo-Fr,
LABC
• “ […] concurrent capecitabine was feasible with a high percent of patients (96%), […] only two
out of 50 (4%) patients had capecitabine dose modification …”.
• “All early toxicities were GI/GII. Radiation dermatitis had a peak incidence in the last few
www.ago-online.de
fractions of the radiation therapy and the week after radiotherapy; no treatment interruption
was needed and the incidence was close in both groups”.
• Radiation dermatitis grade I 14% vs. 18%; grade 2 4% vs. 4%
 Smoking and Risk
of secondary lung cancer
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Increased risk of lung cancer secondary to breast
Guidelines Breast
1a A
Version 2020.1
cancer radiotherapy in smokers
 Inform patients about risk ++
 Recommend to stop smoking ++

www.ago-online.de
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1 Supportive Care and
Management of Side Effects

www.ago-online.de
 Supportive Care and
Management of Side Effects
© AGO e. V.
in der DGGG e.V.
 Versionen 2002–2019:
sowie
in der DKG e.V. Albert / Bauerfeind / Brunnert / Bischoff / Costa / Dall / Diel / Fersis /
Guidelines Breast
Version 2020.1
Friedrich / Friedrichs / Gerber / Göhring / Hanf / Harbeck / Heinrich /
Huober / Jackisch / Lisboa / Lück / Lüftner / von Minckwitz / Möbus
/Müller / Nitz / Oberhoff / Rody / Schaller / Scharl / Schmidt /
Schneeweiss / Schütz / Solomayer / Souchon / Stickeler / Thomssen /
Untch
 Version 2020:
Müller / Albert

www.ago-online.de
 Content
© AGO e. V.
in der DGGG e.V.
 Guidelines
sowie
in der DKG e.V.  Assessment of toxicity
Guidelines Breast
Version 2020.1  Incidence of side effects (according technical product information;
MedDRA-standard)
 Side effects according organ systems
 Incidence, prevention, therapy
 Substance specific side effects
 Targeted drugs
 Further issues
www.ago-online.de  Pain management, palliative care
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
 Guideline - environment

www.ago-online.de
 Guideline Environment
© AGO e. V.
in der DGGG e.V.
Specific national and international guidelines deal with various aspects of evidence-
sowie
in der DKG e.V.
based supportive therapy of cancer patients
Guidelines Breast
Version 2020.1 Without claiming completeness, such guidelines will be quoted, with an emphasis on
German guidelines.
Aspects concerning breast cancer patients will especially be highlighted.
The „Arbeitsgemeinschaft Supportive Maßnahmen in der Onkologie, Rehabilitation
und Sozialmedizin der DKG“ should especially be highlighted
(http://www.onkosupport.de).
Multidisciplinary S 3 guidelines of the AWMF (Reg.-Nr. 032-054OL):

www.ago-online.de  S3-Leitlinie: Supportive Therapie bei onkologischen Patientinnen

Langversion 1.1 –April 2017 AWMF-Registernummer: 032/054OL
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
 Assessment of toxicity
 Acute toxicity (NCI-CTCAE)
 Long term toxicity (ICPC, ICD-GM)

www.ago-online.de
 Assessment of toxicity
© AGO e. V.
in der DGGG e.V.
Acute Toxicity (according to WHO1 or NCI-CTC²)
sowie
in der DKG e.V. Acute toxicities should be asked for and documented after every
LoE 5 D AGO ++
Guidelines Breast treatment course
Version 2020.1
Grade Information required
0 none organs involved
1 mild type of toxicity
2 moderate time interval after treatment
3 severe effect on general health status
4 life threatening treatment required
5 death recovery achieved
Long term toxicity (= secondary diseases after tumour therapy)
Long term surveillance and documentation in regular intervals
www.ago-online.de (acc. ICPC³ following symptoms or acc. ICD-10-GM4 following LoE 5 D AGO ++
diagnoses)
 Acute Toxicity (NCI CTCAE vs 5.0, 2017)
© AGO e. V.  Grade 1
in der DGGG e.V.
sowie Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not
in der DKG e.V.
indicated.
Guidelines Breast
Version 2020.1  Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate
instrumental ADL*.
 Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or
prolongation of hospitalization indicated; disabling; limiting self care ADL**.
 Grade 4
Life-threatening consequences; urgent intervention indicated.
 Grade 5
Death related to AE.
Activities of Daily Living (ADL)
www.ago-online.de
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing
money, etc.
** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and
not bedridden.
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
 Incidence of side effects
(according to technical product information by
MedDRA* classification)

www.ago-online.de

* MedDRA - Medical Dictionary for Regulatory Activities

 Chemotherapy – Acute Toxicities I
SYSTEM ORGAN CLASS
DRUGS

BLOOD & YMPH.

AND NSPECIFIED

IMMUNE YSTEM

AND NUTRITION
BEN., ALIGNANT

EYE DISORDERS.
© AGO

SYST. ISORDERS
e. V.

INFESTATIONS

(INCL CYSTS &

METABOLISM

HOT FLUSHES
PSYCHIATRIC
NEOPLASMS
in der DGGG e.V.

(ALLERGIES)
INFECTIONS

ENDOCRINE

DISOR. INCL
DISORDERS

DISORDERS

DISORDERS

DISORDERS

DISORDERS

DISORDERS

DISORDERS
LABYRINTH

VASCULAR
NERVOUS
sowie

EAR AND

CARDIAC
POLYPS)

SYSTEM
in der DKG e.V.

AND
Guidelines Breast
Version 2020.1 Alkylating antineoplastic agent
Cyclophosphamide 4 2 5 5 1 - 1 3 2 3 3 3
Anti-Metabolites
Methotrexate 1 - 4 3 3 - 3 4 2 - 1 2
5-Fluorouracil* 5 - 5 2 2 5 - 3 3 - 5 3
Capecitabine 4 3 (Lipoma) 4 3 - 5 4 4 4 3 3 4
Gemcitabine 4 - 5 1 - 4 -: 4 - - 2 2
Platinum-complexes
Cisplatinum 4 2 5 3 2 5 - 4 2 5 4 4
Carboplatin 4 - 5 4 - - - 4 4 4 4 -
Anthracyclines / Anthrachinones
Epi-/Doxorubicin 5 3 5 1-2 - 1-5 - - 4 - 4 5
Liposom. Doxorubicin 5 - 5 - - 5 3 4 (4) - 4 4
PEG-lipos. Doxorubicin 4 - 4 - - 5 - 4 4 - 4 -
Mitoxanthrone 5 3 5 3 - 4 - 4 3 3 4 3
Taxanes
Paclitaxel 5 1 5 5 - 1 1 5 1 1 4 5
nab-Paclitaxel 4 - 5 3 - 5 4 5 4 4 4 4
www.ago-online.de Docetaxel 5 - 5 5 - 5 - 5 - - 4 4
Further tubulin-targeting drugs
Vinorelbine IV (PO) 5(5) - -(5) 2(-) - - -(5) -(5) -(4) - 2(3) 3(4)
Eribulin 4 - 4 - -: 5 4 5 4 4 4 4
Listing and grading of side effects was performed according the MedDRA-classification with the following categories of frequency: 1. Very rarely (<1/10,000); 2. rarely (≥ 1/1,000 to <
1/10,000); 3. occasionally (≥ 1/1,000 to < 1/100); 4. frequently (≥ 1/100 to < 1/10); 5. very frequently (≥ 1/10). - unknown (based on available data incidence not assessable)
 Chemotherapy – Acute Toxicities II
SYSTEM ORGAN CLASS

MUSCULOSKELETA

TISSUE DISORDERS

SPECIAL FEATURES
GASTROINT.DISOR

PREGN., PUERPER.
HORAC. & MEDIA-
© AGO

GENERAL DISORD.
e. V.

RENAL& URINARY

REPRODUCT. SYS.

FAMILIAL GENET.
L & CONNECTIVE
SKIN & SUBCUT.
HEPATOBILIARY

STRATION SITE
in der DGGG e.V.

& PERINATAL

CONDITIONS
TIS. DISORD.
D. (NAUSEA,
sowie

STINAL DIS.

(ALOPECIA)
DISORDERS

DISORDERS

DISORDERS

DISORDERS
& ADMINI-
RESPIRAT.,

CONGEN.,
& BREAST
in der DKG e.V.

CONDIT.
EMESIS)
Guidelines Breast
Version 2020.1 DRUG

- unknown (based on available data incidence not assessable)

Alkylating antineoplastic agent
Cyclophosphamide 2 4 4 5 - 5 - 4 5 - Hyponatriaemia
Anti-Metabolitee
Methotrexate 4 5 5 4 3 3 - 3 1 - Mucositis, risk of “third space”-toxicity
5-Fluorouracil 5 5 3 5 - - - - 5 - Risk DPD-deficiency: light 5%, severe 0,1%; diarrhea, heart
Capecitabine 4 5 4 5 4 3 - 3 5 - Hand-foot-syndrome (HFS), risk of DPD-deficiency; heart
Gemcitabine 5 5 5 5 4 5 - - 5 - Flu-like symptoms, edema, heart
Platinum-complexes
Cisplatinum 4 5 4 4 - 5 - 3 5 - Nephrotoxicity, ototoxicity, CIPN
Carboplatin 4 5 - 4 4 4 - - 4 - Colitis (nephrotoxicity)
Anthracyclines / Anthrachinones
Epi-/Doxorubicin 2 5 - 5 1 4 1 5 - Cardiotoxicity (CHF), sec. malign. diseases, extravasation
Lipo. Doxorubicin 4 5 4 5 4 3 - (4) 5 -
PEG-lipo. Doxo. 4 5 - 5 4 - - 4 5 - Palmar and plantar erythema (PPE)
Mitoxanthrone 4 5 3 5 - 3 - 3 4 - Sec. AML, cardiomyopathy
Taxanes
Paclitaxel 2 5 1 5 5 - - - 5 - Peripheral neuropathy (CIPN); hypersensitivity, myalgia
nab-Paclitaxel 4 5 3 5 5 3 - 3 5 - Peripheral neuropathy (CIPN)
www.ago-online.de Docetaxel 5 5 - 5 5 - - - 5 - Fluid retention, paronychia, colitis, myalgie
Further tubulin-targeting drugs
Vinorelbine IV (PO) 3(4) 2 (5) 5(4) 2(5) -(4) 2(4) - - - - Phlebitis, GI-Tox (PO), CIPN
Eribulin 5 5 4 5 5 4 - - 5 - Constipation, CIPN
Listing and grading of side effects was performed according the MedDRA-classification with the following categories of frequency: 1. Very rarely (<1/10,000);
2. rarely (≥ 1/1,000 to < 1/10,000); 3. occasionally (≥ 1/1,000 to < 1/100); 4. frequently (≥ 1/100 to < 1/10); 5. very frequently (≥ 1/10).
 Endocrine Therapy – Toxicities

UNSPECIFIED (INCL

METABOLISM AND

INCL HOT FLUSHES

NEOPLASMS BEN.,

NERVOUS SYSTEM

VASCULAR DISOR.
BLOOD & LYMPH.
MALIGNANT AND

IMMUNE SYSTEM
SYST. DISORDERS
INFECTIONS AND

CYSTS & POLYPS)

EYE DISORDERS.
© AGO e. V.

INFESTATIONS

PSYCHIATRIC
(ALLERGIES)

ENDOCRINE
DISORDERS

DISORDERS

DISORDERS

DISORDERS

DISORDERS

DISORDERS

DISORDERS
LABYRINTH
NUTRITION
in der DGGG e.V.

EAR AND

CARDIAC
sowie
in der DKG e.V.
DRUG
Guidelines Breast SERM
Version 2020.1 Tamoxifen - 3 4 - 3 5 - 4 4 - - 4
AI
Anastrozole - - - - - 4 5 5 4 - 4 5
Exemestane 4 4 5 4 5
Letrozole 3 - 3 - - 5 4 4 3 - 3 5
SERD
Fulvestrant 4 - 3 4 - 4 - 4 - - - 4

TISSUE DISORDERS

& PERINAT. COND.

& MEDIASTIN. DIS.

MUSCULOSKELETA

SPECIAL FEATURES
PREGN., PUERPER.
RESPIR.., THORAC.

(NAUSEA, EMESIS)

RENAL& URINARY

ADMINISTRATION

&GENET. DISORD.
REPRODUCT. SYS.

CONGEN., FAMIL.
GASTROINT. DIS..

SITE CONDITIONS
SUBCUT.TIS. DIS.

L & CONNECTIVE

GENERAL DIS. &

HEPATOBILIARY
DISORDERS

DISORDERS

DISORDERS
(ALOPECIA)

& BREAST
SKIN &

DRUG
SERM
Tamoxifen 3 5 4 5 4 - - 5 5 1 Hot flushes; rarely: endometrial Ca (>55y); thrombosis
AI
Anastrozole - 5 4 5 5 - - 5 5 - Hot flushes, arthralgia, osteoporosis; cognition
Exemestane 5 5 5 5 - Hot flushes, arthralgia, osteoporosis; cognition
www.ago-online.de Letrozole 3 4 3 5 5 3 - 4 5 - Hot flushes, arthralgia, osteoporosis; cognition
SERD
Fulvestrant - 5 5 4 4 4 - 3 5 - Hitzewallungen
Listing and grading of side effects was performed according the MedDRA-classification with the following categories of frequency:
1. Very rarely (<1/10,000); 2. rarely (≥ 1/1,000 to < 1/10,000); 3. occasionally (≥ 1/1,000 to < 1/100); 4. frequently (≥ 1/100 to < 1/10); 5. very frequently (≥ 1/10).
- unknown (based on available data incidence not assessable)
 Side effects according Organ Systems
Incidence, Prevention, Therapy
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
1. Infections and infestations
 General prophylaxis for infections
 Hepatitis B virus screening

www.ago-online.de
 Prophylaxis of Infections
rarely applicable to patients with solid tumors (e.g. BC)
ASCO Practice Guideline „Antimicrobial Prophylaxis...“ 2018
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast  Avoidance of highly infection-risking
Version 2020.1 5 D +
behavior or situations
 Prophylactic treatment in low-risk patients 1a B -
 Prophylactic treatment in high-risk* patients
(e.g. according to NCCN Guidelines) with
 Antibiotics 1a A ++
 Anti-fungal agents (triazole) 1a B +/-
 Virostatics in solid tumors 5 D -
 Granulocyte colony-stimulating factors 1a A ++
www.ago-online.de

* High risk: estimated duration of neutropenia < 100/µl > 7d

 Hepatitis B virus screening before
chemotherapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
Version 2020.1
 Hepatitis B virus screening before adjuvant chemotherapy
2c B +
(HBsAG, anti-HBC)
In case of positive serology or reactivation:
 Interruption of chemotherapy 5 D ++
 Prophylactic therapy with virustatic drugs if HBV-DNA
1b A ++
detected (according AGIHO/DGHO – recommendations)

www.ago-online.de
 Hepatitis C virus screening before chemotherapy 5 D +/-
 Interaction Hepatitis B and Tumour Therapy
© AGO e. V. Dx cure
in der DGGG e.V. (neo)adj.
sowie breast prolong. DFS
in der DKG e.V. CT
Guidelines Breast
cancer prolong. OS
Version 2020.1 dose- risk of recurrence  risk of death for
reduction (local/metast.) breast cancer 

chron. reactivation liver failure risk of death

HepB HCC for hepatitis 

„Number needed to screen“ in Germany:

www.ago-online.de
Prevalence 0.5%-1% (general population): 100 to 200
Prevalence 3.6% (migrants): 28
 AGIHO / DGHO – recommendations on
Hepatitis B virus screening in oncology
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

www.ago-online.de

Sandherr M et al. Ann Hematol. 2015 Sep;94(9):1441-50

 International recommendations on Hepatitis B virus screening
Recommendations of Various Authoritative Bodies Regarding Screening for
Hepatitis B to Mitigate the Risk of HBV Reactivation
© AGO e. V. Organization Recommendation Tests to Be Done
in der DGGG e.V. Centers for Disease Control and Persons needing immunosuppressive therapy, including chemotherapy, HBsAg, anti-HBc, anti-HBs
sowie
in der DKG e.V. Prevention immunosuppression related to organ transplantation, and immunosuppresssion
for rheumatologic or gastroenterologic disorders
Guidelines Breast
Version 2020.1
American Academy of Dermatology Hepatitis B reactivation after treatment with tumor necrosis factor inhibitors has Not stated
been reported; in the appropriate clinical setting, patients should be screened for
hepatitis B infection.
American Association for All patients before beginning immunosuppressive therapy HBsAg, anti-HBc
the Study of Liver Diseases
Asian Pacific Association Before receiving immunosuppression or chemotherapy, patients should be HBsAg, anti-HBc
for the Study of the Liver screened for HBsAg. Patients who are going to receive biologic agents such as anti-
CD20 or anti-tumor necrosis factor-α should be screened for anti-HBc.

European Association for the Study of All candidates for chemotherapy and immunosuppressive therapy should be HBsAg, anti-HBc
the Liver screened.
American Society of Clinical Oncology Physicians may consider screening patients belonging to groups at heightened risk Consider HBsAg, consider
for chronic HBV infection or if highly immunosuppressive therapy is anti-HBc
www.ago-online.de recommended.
US Preventive Services Screen persons who are immunosuppressed. HBsAg
Task Force

Di Bisceglie AM et al. Hepatology. 2015 Feb;61(2):703-11.

 Side Effects According Organ Systems
Incidence, Prevention, Therapy
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
2. Neoplasms benign, malignant and
unspecified (incl. cysts and polyps)

www.ago-online.de
 Secondary Malignancies I
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR
in der DKG e.V.
 With regard to solid tumors, chemotherapy induced secondary
Guidelines Breast 2a
Version 2020.1
malignancies are rare events
 Alkylating agents increase the risk of leukemia dose-
2a
dependently to a total of 0.2–0.4 % within 10–15 years
 Anthracycline-containing regimens increase the risk of MDS and
2a
leukemia to 0.2–1.7 % within 8 to 10 years
 PARP-inhibitors are associated with an increased risk of AML
2b
and MDS to 0.5–1%
 Radiotherapy increases the risk of leukemia by 0.2–0.4% in
2b
www.ago-online.de patients treated with anthracycline-containing chemotherapy
 Tamoxifen approximately doubles the risk for developing
2b
endometrial cancer (in pts. older than 55y at start of therapy)
 Secondary Malignancies II
(After Radiotherapy)
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE
Guidelines Breast
Version 2020.1
 Radiotherapy (PMRT, BET) may moderately enhance the risk of
ipsilateral lung cancer and angiosarcoma (10-15 / 10.000) 5–10 1a
years after treatment

 Enhanced risk especially among ever smokers 2b

 No difference of secondary malignancy between PBI und WBI 2c

www.ago-online.de
 Side Effects According Organ Systems
Incidence, Prevention, Therapy
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
3. Blood and Lymphatic System Disorders
 Anemia
 Neutropenia
 Febrile Neutropenia (FN)

www.ago-online.de
 Anemia – Indications for Therapy with
Erythropoiesis-stimulating agents (ESAs)
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast  Indicated in asymptomatic anemia 1a B -
Version 2020.1
 Therapy and secondary prophylaxis in CT-induced
1a A +
anemia
 Adjuvant setting 1b A +
 Neoadjuvant/metastatic setting 1a A +/-
 In dose-dense / dose-escalated CT (iddETC) 1b A +
 Treatment start at Hb-levels < 10 g/dL 1a A +
 Target Hb 11–12 g/dL 1a A +
 Improvement of outcome (DFS, OS) 1a B --
www.ago-online.de  Risk of thromboembolic events is increased by use of
1a A
ESAs
 Phase III Study of Epoetin Alfa Versus Best Standard of Care
in Anemia Patients with Metastatic Breast Cancer
© AGO e. V. N=2.098 Pat., Hb <11g/dl; non inferiority study.
in der DGGG e.V.
sowie
in der DKG e.V.
Prespecified upper non inferiority margin = 1.15
Guidelines Breast
Version 2020.1
PFS OS (median) ORR RBC TVE
(median) transfusions
Epo Invest.* IRC** 17,2 Mon 50% 5,8% 2,8%
7,4 Mon 7,6 Mon
BSC 7,4 Mon. 7,6 Mon. 17,4 Mon 51% 11,4% 1,4%
HR: 1,09 HR: 1,02 HR: 1,06 OR: 0,95 p<.001 p=.04
Upper CI: Upper CI:
1,20 1,146

* Investigator determined
** Independent review committee
www.ago-online.de

J Clin Oncol 2016 (34): 1197-1209

 Practical Use of ESAs
© AGO e. V.
in der DGGG e.V.  Epoetin α and Darbepoetin are equieffective
sowie
in der DKG e.V.  Dosage:
Guidelines Breast
Version 2020.1
 Epoetin α: 150 IU/kg 3 x weekly s.c. or
40.000 IU 1 x /week s.c. or
80.000 IU q2w s.c. or
120.000 IU q3w s.c.
 Epoetin ß: 30.000 IE weekly s.c.
 Darbepoetin: 2,25 µg/kg s.c. weekly or 500 µg s.c. q3w
 Weekly hematologic blood controls
 Dose reduction if Hb-increase > 1g/dl within 2 weeks
 Dose increase if Hb-increase < 1g/dl within 4-6 weeks
 In case of FID (“functional iron deficiency”) iron supplementation,
www.ago-online.de
preferably i.v.
 Stop ESA-treatment if there is no Hb increase after 9 weeks
 Granulocyte Colony-stimulating Factors
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Primary prophylaxis for expected febrile neutropenia
Version 2020.1 (FNP)
 If expected risk for FNP 10–20% 1b B +/-
 In case of individual risk factors 3b C +
 If expected risk for FNP >20% (e.g. DAC, dose-dense CT) 1a A ++
 Secondary prophylaxis during chemotherapy
1b A ++
(previous FNP or neutropenia grade IV > 7 days)
 Therapeutic use for FNP 1a A +/-
 Start related to chemotherapy and duration
 Pegfilgrastim day 2 1b A ++
www.ago-online.de
 Lipegfilgrastim day 2 1b A ++
 Filgrastim/Lenograstim from day 2–3 until
1b A ++
ANC > 2–3 x 109
 Management of Febrile Neutropenia
c.f. Recommendations by Arbeitsgemeinschaft Infektionen in der Hämatologie und
Onkologie (AGIHO) der Deutschen Gesellschaft für Hämatologie und Onkologie e.V. (DGHO)
www.dgho-infektionen.de
© AGO e. V.
in der DGGG e.V. Definition (oral temperature of >38.5°C or two consecutive readings of >38°C for 2 h in a
sowie
in der DKG e.V. patient with an ANC of <500 cells/mm3 or expected to fall to <500 cells/mm3)
Guidelines Breast
Version 2020.1
Oxford
LoE GR AGO
 Clinical examination 5 D ++
 Daily evaluation 5 D ++
 Hospitalization of high-risk patients 1b A ++
 Homecare in low-risk patients 1b A +
 Differential blood count 5 D ++
 Blood cultures 5 D ++
 Imaging of lungs 3 C ++
 Immediate initially empiric antibiotic therapy 1a A ++
www.ago-online.de
 Empiric antifungal therapy 4–7d in case of failure of
1b A ++
antibiotic therapy
 G-CSF for treatment (not prophylactic) 2b B +/-
 Empirical Antibiotic Therapy
© AGO e. V.
in der DGGG e.V. The recommendations for empirical antibiotic therapy are currently changing
sowie
in der DKG e.V. because of infection biological findings.
Guidelines Breast
Version 2020.1
Current recommendations should be referred to regularly and adjusted to
within personal professional judgement.
The “Arbeitsgemeinschaft Infektionen in der Hämatologie und Onkologie
(AGIHO) der Deutschen Gesellschaft für Hämatologie und Onkologie e.V.
(DGHO) www.dgho-infektionen.de“ is a source for regular consultation.

www.ago-online.de
 EORTC and ASCO G-CSF
Guideline-Based FN Risk Assessment
© AGO
Step 1: Assess frequency of FN associated with the planned chemotherapy regimen
e. V.
in der DGGG e.V.
sowie
in der DKG e.V. FN risk ≥20% FN risk 10-20% FN risk <10%
Guidelines Breast
Version 2020.1 Step 2: Assess factors that may increase the risk of FN:

High risk: Age >65 years

Increased risk: Advanced disease
(level I and II evidence) History of prior FN Reass
No antibiotic prophylaxis ess at
Other Factors: Poor performance (ECOG > 1) each
(level III and IV Female gender cycle
evidence) Haemoglobin <12 g/dL
Liver, renal or cardiovascular disease
Nutritional status
Step 3: Define the patient’s overall FN risk for planned chemotherapy regimen

www.ago-online.de
Overall FN risk ≥20% Overall FN risk <20%

Prophylactic G-CSF recommended G-CSF prophylaxis not indicated

 Side Effects According Organ Systems
Incidence, Prevention, Therapy
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
4. Endocrine disorders

www.ago-online.de
 Therapy-associated
Amenorrhea (CRA, CIA, TIA)
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE
in der DKG e.V.
 CRA may be permanent or temporary (depending on age of the
Guidelines Breast 2b
Version 2020.1
patient and type of chemotherapy)
 The risk of CRA increases with patient‘s age and duration of the
2b
chemotherapy
 CRA is an imperfect surrogate for
5
menopause and fertility
 Adjuvant endocrine therapy with GnRHa induces reversible
5
amenorrhea, but delays conception to a less fertile period
 Ovarian reserve of women who remain premenopausal
2b
www.ago-online.de after CTX is reduced
 CRA is associated with improved outcome (DFS/OS) 1b
Synonym: Chemotherapy related or induced / Treatment induced Amenorrhea (CRA, CIA, TIA)
 Side Effects According Organ Systems
Incidence, Prevention, Therapy
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
5. Psychiatric Disorders
 Depression
 Fatigue
 Cognitive impairment
 Sleep disturbances

www.ago-online.de
 (Therapy-Associated)
Depression
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Depression is an often reported adverse event in breast
Guidelines Breast 2a B
Version 2020.1
cancer patients (20–30%)
 Psychological interventions are effective to improve
mood, but not survival in distressed and depressed 1b A
patients
 Antidepressents have shown to improve depression in
1b A
breast cancer patients
 Regular exercise participation can prevent depression in
2b B +
breast cancer survivors
www.ago-online.de
 (Therapy-Related)
Fatigue
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Version 2020.1  Fatigue frequent in breast cancer patients (30–60%) 2a B
 Exclusion of somatic reasons (anemia, tumor burden,
1a A ++
co-morbidity, medication) for fatigue
 Psycho-social interventions specifically addressing
1a A ++
fatigue efficient in reducing fatigue
 Physical exercise can improve fatigue 1b D +
 Diet, Yoga can improve fatigue 2b B +
 Methylphenidate can improve fatigue 1a D +
www.ago-online.de
 (Therapy-Associated)
Cognitive Impairment
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR
Guidelines Breast  Therapy-related cognitive deficits (“chemobrain”) frequently
Version 2020.1 2a B
described (16–75%)
 Cognitive-behavioral therapy beneficial for cognitive function 2b B
 Methylphenidate may improve cognitive function in cancer
3a C
patients
 Under therapy with aromatase inhibitors, deterioriation of
1a B
cognitive performance was observed (espec. verbal memory)

www.ago-online.de
 (Therapy-Associated)
Sleep Disturbances
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
 Sleep disturbances are a common problem in breast
Version 2020.1
2a B
cancer patients during and after therapy (20–70%)

 Behavioral therapies demonstrated efficacy in treatment

1b A ++
of insomnia and improved quality of life

www.ago-online.de
 Side Effects According Organ Systems
Incidence, Prevention, Therapy
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
6. Nervous system disorders
 Chemotherapy-Induced Peripheral Neuropathy
(CIPN)

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 Chemotherapy-Induced Peripheral
Neuropathy (CIPN)
© AGO e. V.
in der DGGG e.V.
 Incidence with taxanes:
sowie  Grade 1–2: 20–50 %
in der DKG e.V.
 Grade 3–4: 6–20 %
Guidelines Breast
Version 2020.1
 Risk factors: type and dose of chemotherapy, BMI, reduced physical activity
 Individual risk factors
 Diabetes mellitus
 Nutritive-toxic compounds part. alcohol
 Renal failure
 Hypothyreosis
 Collagenoses / vasculitis
 Vitamine deficiency
 HIV-Infection
www.ago-online.de
 CMT-Gen mutations
Unclear:
 Other genetic factors (SNPs, mutations)
 Chemotherapy-induced Peripheral Neuropathy
– Prevention –
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
Non drug-based prevention
Guidelines Breast
Version 2020.1  Functional training (physical fitness, sensomotoric stimulation
5 D +
training etc.)
 Compression treatment (tight surgical gloves, compression stockings) 2b B +
 Cooling gloves and stockings 2ba B +/-
 Elektro-acupuncture 1b B -
Drug-based prevention
 Venlafaxine 2a C +/-
 Palmitoylethanolamine (PEA) topically or PO 5 D +/-
 Α-lipoic-acid (thioctic acid), amifostine, amitriptyline, acetyl-L-car-nitine,
www.ago-online.de carbamazepine, electrolyte solutions, glutathione, Goshajinkigan (GJG), 1b A -
oxcarbazepine, vitamine B, vitamine E, or other compounds1
1 For list of not recommended drugs, see Hershman et al. 2014
 Chemotherapy-induced Peripheral Neuropathy
– Therapy –
Oxford
© AGO e. V.
in der DGGG e.V.
LoE GR AGO
sowie
in der DKG e.V. Non drug-based therapy
Guidelines Breast  Functional training (physical fitness, sensomotoric stimulation
Version 2020.1 2a C +
training etc.)
 Physiotherapy / physical treatment 5 D +
 acupuncture 2b B +
Drug-based therapy
 Menthol locally (1%), capsaicin/lidocain locally 5 D +
 Baclofen/amitryptiline/ketamin-gel 2b B +
 Duloxetine for therapy of CIPN-induced pain 1b B +
 Opioids for therapy of CIPN-induced pain 5 D +
 Palmitoylethanolamine (PEA) topically or PO. 5 D +/-
 Venlafaxine 5 D +/-
www.ago-online.de  Gabapentin, pregabaline 1b B +/-
 Amitryptiline/ nortripyline, imipramine/desipramine 1b B +/-
 Acetyl-L-carnitine, lamotrigine, or other compounds1 1b B -
1 For list of not recommended drugs, see Hershman et al. 2014
 Side Effects According Organ Systems
Incidence, Prevention, Therapy
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
7. Cardiac Disorders

www.ago-online.de
 Cardiotoxicity as Long-term Side Effect
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.  Equivalent cardiotoxicity of doxorubicin and epirubicin at recommended dose
2b B
Guidelines Breast levels (450–500 and 900–1000 mg/m² cum. dose, resp.)
Version 2020.1
 Liposome encapsulated anthracyclines (doxorubicin) induce less cardiotoxicity 1b B
 Anthracycline- or trastuzumab-associated cardiotoxicity may occur
2b B
earlier/more frequently:
 Elderly patients
 Obesity
 Hypertension
 Hypercholesterolemia
 Pre-existing cardiac diseases (incl. borderline LVEF)
 Diabetes mellitus
 Monitoring of cardiac function:
www.ago-online.de
 Standardized echocardiography (LVEF or SF in %) 3b C +
 Troponin I as marker of cardiac toxicicty 2b B +/-
 Betablocker-prohylaxis during anthracycline therapy 2a B +/-
 Adjuvant Trastuzumab
Cardiac Monitoring for CHF
© AGO e. V.
in der DGGG e.V.
sowie
Oxford LoE: 5 GR: D AGO: ++
in der DKG e.V.

Guidelines Breast Before start of trastuzumab

Version 2020.1  History, physical examination (edema, Assessment
hepatomegaly)
 Echocardiography (alternative to MUGA) of LVEF

During trastuzumab
Regular assessment of
 Heart rate increase > 15% above individual base level
 Body weight increase ≥ 2 kg/week
 Cardiac signs and symptoms

3 monthly assessment of LVEF

www.ago-online.de
 Feasibility of Treatment Combinations
Considering Toxicities
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast Regarding cardiac toxicity

Version 2020.1
 Trastuzumab simultaneous to radiotherapy 2b B +
 Trastuzumab simultaneous to epirubicin 2b B +/-
 Trastuzumab simultaneous to doxorubicin 2b B -
 Anthracycline simultaneous to radiotherapy 2c C -
Regarding lung and breast fibrosis
 Tamoxifen simultaneous to radiotherapy 3 C +/-
www.ago-online.de  Chemotherapy simultaneous to radiotherapy 1b B -
 Side Effects of Trastuzumab/Pertuzumab:
Algorithm in Case of Cardiac Toxicity
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

www.ago-online.de
 Side Effects According Organ Systems
Incidence, Prevention, Therapy
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
8. Gastrointestinal Disorders
 Nausea, Emesis
 Mucositis
 Stomatitis (Everolimus)
 Diarrhea
 Constipation
www.ago-online.de
 Antiemetic Therapy
http://www.mascc.org/antiemetic-guidelines
www.onkosupport.de
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
 After assessment of emetic potential of
Guidelines Breast
5 D ++
Version 2020.1
chemotherapy protocol
 Neurokinin-1-receptor-antagonists 1b A ++
 Dexamethasone 1a A ++
 5-HT3-antagonists 1b A ++
 Fixed antiemetic combination therapy 1b A ++
 Rescue Medication
• Olanzapine 1b A +

 Levomepromazine, benzodiazepines
www.ago-online.de 3b C +
 Cannabinoids, ginger
 Antiemetic Therapy
https://www.mascc.org/antiemetic-guidelines
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

www.ago-online.de
 Antiemetic Therapy
https://www.mascc.org/antiemetic-guidelines
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

www.ago-online.de
 Supportive Therapy
Antiemetics
Wirkstoffgruppe Substanz Dosierung Nebenwirkungen Potenzial
© AGO e. V. Serotonin- Ondansetron 8 mg i.v., 2 x 4-8 mg p.o Kopfschmerzen, Diarrhoe, sehr hoch
in der DGGG e.V. antagonisten Tropisetron 5 mg i.v., 5 mg p.o. Flushsymptomatik
sowie Granisetron 1-3 mg i.v. Transaminasenanstieg
in der DKG e.V. Palonosetron 0, 25 mg i.v. Darmatonie in hoher
Dosierung
Guidelines Breast
Version 2020.1 NK1-Antagonisten Aprepitant 125 mg d1, Cytochrom-P-450- Aktivierung mit Dosis-reduktion von sehr hoch
80 mg d 2-3 p.o. Dexamethason (2 x 8 mg).
Fosaprepitant 150 mg d1 i.v. Keine Kombination mit Astemizol, Terfenadin, Cisaprid
Rolapitant 180 mg d1 p.o.
Dopamin- Metoclopramid bis zu 120 mg/24h als Dyskinesien hoch
antagonisten/ Dauerinfusion od. als Tropfen (Antidot:Biperiden)
substituierte
Benzamide bis zu 300 mg i.v. oder
Alizaprid p.o./24 h ( 6 Amp. od. 6 Tbl.) Angstreaktion, Depressionen,
Diarrhoe
Oxazapine Olanzepin 10mg/d for d1-4 Sedation, weight gain hoch
Ggf. 5mg/d for d1-4
Phenothiazine/ Haloperidol 1-3 mg 4 x/d Sedation, Senkung der mäßig
Krampfschwelle, transiente
Butyrophenone Leberwerterhöhung
Corticosteroide Dexamethason 8-20 mg i.v. 1-3 x/d Blutzuckerentgleisung, mäßig
psychotische Reaktionen,
Prednisolon 100-250 mg i.v. 1-3 x/d Flush, Blutdruckanstieg
www.ago-online.de
Benzodiazepine Diazepam bis zu 20 mg/d Sedation, gering
Lorazepam 0,5-1,0 mg/d Atemdepression
NEPA (Netupitant fixe Kombinations NE 300 mg PA 0,5 mg sehr hoch
and Palonosetron) partner (oral)
 Mucositis Prevention
http://www.mascc.org/assets/documents/MukositisGuidelinesMASCC2006(dtV).pdf
Multidisciplinary S 3 guidelines of the AWMF (Reg.-Nr. 032-054OL):
„Supportive Therapie bei onkologischen Patientinnen – interdisziplinäre Querschnittsleitlinie“, released 11.11.2016

© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Standardized mouth hygiene for prophylaxis of oral mucositis should
Guidelines Breast
Version 2020.1 be adhered to by all age groups and during all cancer-related 2b ++
therapies with any risk for oral mucositis.
This entails:
1. Patient:
 Regular mouth washs (H2O, NaCl)
 Soft tooth brushs
 Interdental care: flossing or using interdental brush
 Avoidance of alcohol, tobacco, hot food, sour food
 Regular screening for lesions
2. Risk adjusted prophylaxis by dentist
3. Continuous clinical control
www.ago-online.de
There is no evidence with regard to the use of one of the following compounds: allopurinol, capsaicin, glutamine,
honey, camomile, camomile oil or extract, chewing gum, kefir, methadone, nystatin, pentoxifylline, povidone-
iodine, vitamine A/E/combinationes
 Prevention of Everolimus-Induced Stomatitis
Using Dexamethasone Mouthwash
© AGO e. V.
in der DGGG e.V.  Study design: single arm phase II-trial (SWISH)
sowie
in der DKG e.V.
 Cohort: 92 pts., treated with everolimus 10 mg and exemestane
Guidelines Breast
Version 2020.1 25 mg
 Schedule: 10 mL of alcohol-free dexamethasone 15 mg per 5 mL
oral solution (swish for 2 min and spit) for at least 8–12 weeks*
 Results: after 13 wks exposition all-grade incidence of stomatitis
27% (BOLERO 67%), ≥ grade 2 events 9% (BOLERO 27%)

* Alternatively Hydrocortison: Hydrocortisonacetat-Suspension 0,5 % with Lidocainhydrochlorid and

www.ago-online.de Dexpanthenol (Germany: Arzneibuchrezeptur NRF 7.14.)

Rugo et al., Lancet Oncol 2017, , Jones et al. Oncologist 2019

 Mucositis
http://www.mascc.org/assets/documents/MukositisGuidelinesMASCC2006(dtV).pdf

© AGO e. V.  Desinfecting / antiphlogistic measures: :

in der DGGG e.V.
sowie
Mouth rinsing with infusions of chamomile or salvia, extracts of chamomile, etheric oils, polyvidon-iodine,
in der DKG e.V. hexetidine. Local therapy with crystal violet solution 0.5% or tinctura myrrhei, H. mometasonfuroate + propylene
Guidelines Breast
glycol
Version 2020.1
 Mucosa protecting measures (during / after application of chemotherapy):
Sucking ice cubes (especially from pineapple juice) during 5-fluorouracile- or HD-melphalane. Calcium folinate
(Leucovorin-mouth gel®) every 4–6 hrs for HD-methotrexate:
do not start earlier than 24 hours after end of MTX-Infusion (otherwise potential loss of efficacy of MTX!).
Dexpanthenole (Panthenol®-Solution. 5%) mouth rinsing.

 Local antimycotic treatment:

Amphotericin B, nystatin, fluconazole

 Local antiviral treatment

Aminoquinuride / tetracaine-HCl , Aciclovir®

www.ago-online.de  Local anaesthesia:

Benzocaine, Doxepin 0,5% p.o.

 Pain Therapy: Opioids if indicated

 Diarrhea
© AGO e. V.
in der DGGG e.V.  Adsorbent agents
sowie
in der DKG e.V.  Carbo medicinalis; caoline / pectine, Al-Mg-silicate hydrate
Guidelines Breast
Version 2020.1
 Analgetics, opioids
 Loperamide; codeine, morphine IV, tintura opii (tinture of opium), butylscopolamine
 Pseudomembranous colitis
 Metronidazole or (if not effective) vancomycin

www.ago-online.de
 Constipation
Important Side Effect of Opioid Treatment

© AGO e. V.
in der DGGG e.V.  Bulging agents
sowie
in der DKG e.V.  Psylium, flaxseed (shredded)
Guidelines Breast
Version 2020.1
 Osmotic laxatives
 Macrogol > Lactulose (Cochrane review LoE 1a, AGO +)
 Oral radio-opaque material: ultima ratio e.g. sodium amidotrizoate
 Sorbitol
 Motility stimulating laxatives
 Senna, Ricinus (Castrol Oil), Bisacodyl, sodium-picosulfate

 Emollients (Internal lubricants e.g. paraffin)

 Opioid-receptor-antagonists (in opioid-related constipation)
 Methylnaltrexone
www.ago-online.de
 Side Effects According Organ Systems
Incidence, Prevention, Therapy
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
9. Skin & Subcutaneous Tissue Disorders
(Alopecia)

www.ago-online.de
 Skin toxicities
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast  Avoidance of chemotherapy-induced alopecia by
Version 2020.1
1b +/-
cooling the patient‘s scalp*
 Prophylaxis of hand-foot-syndrome using urea
1b +
containing lotions (5-10%)
 Prophylaxis of nail changes and hand-foot-syndrome
2b +
by cooling hands during application of docetaxel

www.ago-online.de

* Substance- and regimen specific

 Scalp Cooling: Scalp Cooling Alopecia
Prevention Trial (SCALP) and metaanalyses
© AGO e. V.
in der DGGG e.V. AGO: +/- LOE 2b B
sowie
in der DKG e.V. ▪ Nangia J, Wang T, Osborne C, et al. Effect of Scalp Cooling Device on Alopecia in
Guidelines Breast Women Undergoing Chemotherapy for Breast Cancer: The SCALP Randomized
Version 2020.1
Clinical Trial JAMA. 2017 Feb 14;317(6):596-605.
Primary Outcome: hair preservation
Cooling: 50.5 % success vs. 49.5 % failure
Non-cooling: 0 % success vs. 100 % failure
Fisher’s exact test p < 0.001

Two Metaanalyses: AGO: +/- LOE 1b

▪ Scalp cooling reduced relative risk (RR) of alopecia by 43% (RR, 0.57; 95% CI, 0.45-
0.72; I2 = 11%; P < .00001). (Rugo & Voigt, Clinical Breast Cancer 2018; 18(1): 19-28.)
www.ago-online.de
▪ Incidence rate of scalp metastasis (SC vs. no-SC) 0.61% vs. 0.41%; P = 0.43. (Rugo &
Voigt; BCRT 2017)
 Side Effects According Organ Systems
Incidence, Prevention, Therapy
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
10. MUSCULOSKELETAL & CONNECTIVE TISSUE
DISORDERS
(see Chapter Osteooncology)

www.ago-online.de
 Side Effects According Organ Systems
Incidence, Prevention, Therapy
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
11. General Disorders & Administration Site
Conditions

www.ago-online.de
 Extravasation of Potentially Necrotizing Compounds
(Anthracyclines, Taxanes, Vinorelbine)
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Version 2020.1  Dexrazoxane for treatment of anthracycline-
extravasations 2b B ++
(exception: liposomal Anthracyclines)
 Hyaluronic acid for treatment of taxane/
3b D ++
vinorelbine-extravasations

www.ago-online.de
 Extravasation of Chemotherapy
Role of Dexrazoxane/Hyaluronic Acid
© AGO e. V. Dexrazoxane for treatment of anthracyclines paravasates
in der DGGG e.V.
sowie Day 1: 1000 mg/m² (max. 2000 mg), IV 1–2 hrs
in der DKG e.V.
Day 2: 1000 mg/m² (max. 2000 mg), IV 1–2 hrs
Guidelines Breast
Version 2020.1 Day 3: 500 mg/m² (max. 1000 mg), IV 1–2 hrs

Otherwise or if treatment with dexrazoxane is not indicated, following measures are recommended:
1. Local cooling: ice packs for 15 min every 6 hrs, for at least 3 days, alternatively: 24 h continuous ice cooling
2. Local application (with swab) of dimethylsulfoxid 99% (DMSO) every 3-4 hours for at least 3 days (better 14
days), allow it to air dry. The interval may be extended to 6 hours from day 4 onward.

Hyaluronic Acid in case of Taxan/Vinorelbin Paravasates:

 1–10 Amp a 150 IU
 1 ml dissolvent (z.B. NaCl 0.9%)
 Local anaesthesia
www.ago-online.de  No thermotherapy after taxanes
 Dry warmth 4 x daily 20 min during vincaalkaloids
 Substance-Specific Side Effects
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1  Antibodies and Antibody-Drug-Conjugates (ADC)
 CDK 4/6-Inhibitors
 PARP-Inhibitors
 Small molecules (TKI, mTOR.Inihibitor)
 Immun-Checkpoint-Antibodies
 PI3-Kinase-Inhibitoren (Alpelisib)

www.ago-online.de
 Key-Toxicities – Antibodies and
Antibody-Drug-Conjugates (ADC)
Oxford
© AGO e. V.
in der DGGG e.V.
LoE GR AGO
sowie
in der DKG e.V.
Trastuzumab
Guidelines Breast  Cardiotoxicity in the adjuvant setting (1.0–2.0%) 1b A
Version 2020.1
 Troponin I may identify patients at risk for cardiotoxicity 2b B
Pertuzumab
 Skin rash, diarrhea, mucositis 1b A
Trastuzumab-Emtansine (T-DM1)
 Thrombocytopenia, hepatotoxicity, pyrexia, headache, pneumonitis,
1b A
neuropathy
Bevacizumab
 Hypertonus, proteinuria, bleeding, left ventricular dysfunction, 2b B
www.ago-online.de Trastuzumab-Deruxtecan
 Interstitelle Lungenerkrankung, Neutropenie, Übelkeit 2b B
 Toxicities of New Substances – CDK 4/6 Inhibitors
(Palbociclib/Ribociclib/Abemaciclib)
© AGO e. V. UE, % All Grades Grade 3 Grade 4
in der DGGG e.V.
sowie
Neutropenia 79,5/74,3/41,3 56,1/49,7/19,6 10,4/9,6/1,5
in der DKG e.V. Leukopenia 39,0/32,9/20,8 24,1/19,8/7,3 0,7/1,2/0,3
Guidelines Breast Anemia 24,1/18,6/28,4 5,2/0,9/5,8 0,2/0,3/0
Version 2020.1
Thrombocytopenia 15,5/5,7/10,0 1,4/0,6/2,0 0,2/0/<1,0
Fatigue 37,4/36,5/40,1 1,8/2,1/1,8 0/0,3/0
Nausea 35,1/51,5/38,5 0,2/2,4/0,9 0/0/0
Vomiting 15,5/29,3/28,4 0,5/3,6/1,2 0/0/0
Diarrhea 26,1/35,0/81,3 1,4/1,2/9,5 0/0/0
Alopecia 32,9/33,2/26,6 - -
Exantheme 17,8/17,1/14,0 0,9/0,6/<1,0 0/0/0
ALT elevated 9,9/15,6/15,6 1,7/7,5/5,8 0,1/1,8/0,3
AST elevated 9,7/15,0/15,0 2,5/4,8/3,0 0/0,9/0
Infections 60/50,3/39,1 6,0/3,6/4,0 1/0,6/0,9
QT-prolongation N.A./7,5/N.A. N.A./3,0/N.A. N.A./0/N.A.
www.ago-online.de Palbociclib/Ribociclib/Abemaciclib
 QT interval prolongation:
Ribociclib vs Placebo
 Post-baseline QT interval prolongation > 480 msec: 6.9% vs 1.2%
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. (incidence Ribo vs Placebo)
Guidelines Breast
Version 2020.1
 Post-baseline QT interval prolongation > 500 msec: 1.5% vs 0.3%
 Therapy discontinuation for QT interval prolongation:
0.3% vs 0.6%
 QT interval prolongation is not associated with symptoms; however, QT
interval prolongation stands for an elevated risk of life-threatening
arrhythmia “torsades de pointes” (TdP)

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 Toxicities of new compounds: mTOR-Inhibitor
– Everolimus –
UE, % All grades (%) grade >/=3 (%)
© AGO e. V. Stomatitis 11,6 1,6
in der DGGG e.V.
sowie
Exanthema 7,4 0,02
in der DKG e.V. Anemia 3,3 1,3
Guidelines Breast Fatigue 6,8 0,8
Version 2020.1 Nausea 5,6 0
Emesis / Vomiting 2,9 0
Diarrhea 6,2 0,02
Loss of appetite 6,0 0,02
Headache 3,9 0
Weight loss 3,9 0
Dyspnea 3,8 0,08
Arthralgia 3,3 0
Epistaxis 3,1 0
Edema 2,9 0
Constipation 2,6
Pyrexia 2,9 0
www.ago-online.de Cough 4,5 0
ALT Elevated 2,6 0
Pneumonitis 0,2 0
Asthenia 2,4 0,04
Dysgeusia 4,3 0
 Toxicities of new compounds: PARP-Inhibitors
– Olaparib, Talazoparib –
© AGO e. V.
in der DGGG e.V.
Olaparib Talazoparib
sowie AE. % all grades grade AE. % all grades grade
in der DKG e.V. (%) >/=3 (%) (%) >/=3 (%)
Guidelines Breast AE, overall 97.1 36.6 AE, overall 98,6 31,8
Version 2020.1 Neutropenia 27.3 9.3 neutropenia 34,6 20.9
Anemia 40.0 16.1 Anemia 52.8 39,2
Fatigue 28.8 2.9 Fatigue 50,3 1,7
Nausea 58.0 0 Nuasea 48,6 0,3
Emesis 29.8 0 Emesis 24,8 2,4
Diarrhea 20.5 0.5 Diarrhea 22,0 0,7
Appetite loss 16.1 0 Appetite loss 21,3 0,3
Headache 20.0 1 Headache 32,5 1,7
Pyrexia 14.1 0 Back pain 21,0 2,4
Cough 17.1 0 Dyspnea 17,5 2,4
ALT elevated 11.2 1.5 Pleural effusion 2,1 1,7
AST elevated 9.3 2.4 PPE 1,4 0,3
PPE 0.5
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Treatm. discontinuation 4.9
 Toxicities of new compounds: antiHER2-TKI
– Neratinib, Lapatinib –
© AGO e. V.
in der DGGG e.V. Lapatinib Neratinib
sowie
in der DKG e.V. AE, % All grades Grade >/=3 AE, % Alle Grade Grad >/=3
Guidelines Breast Diarrhea 61% 6% Diarrhea 90 40,1
Version 2020.1
Nausea 18% 4% Nausea 43 2
Rash 60% 6% Abdominal pain 36 2
Fatigue 16% 4% Fatigue 27 2
Cardiac 3% < 1% SAE Emesis 26 3
Hepatobiliary 8% Exanthema 18 0,6
All AE % 92% SAE 6% Stomatitis 14 0,6
Appetite loss 12 0,2
Dyspepsia 10 0,4
ALAT elevated 9 1,2
ASAT elevated 7 0,7
Nail disorders 8 0,3
Dry skin 6 0
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LoE AGO
Primary Prophylaxis with loperamide 2b B ++
 Toxicities of new compounds: PIK3CA -
alpelisib
© AGO e. V. Alpelisib+Fulvestrant
in der DGGG e.V.
sowie
in der DKG e.V. UE, % All Grade Grad >/=3
Hypergycemia 63,7% 32,7%
Regard recommendations for
Guidelines Breast
Version 2020.1
Diarrhea 57,7% 6,7%
management of side effects (Diabetes
Nausea 44,7% 2,5%
mellitus, hyperglycemia, Insulin resistance
und metabolic syndrom)
Decreased appetite 35,6% < 1% SAE
Rush 35,5% 9,9%

Vomiting 27,1% < 1% SAE LoE AGO

Weight loss 26,8% 3,9%
2b B ++
Stomatitis 24,6% 2,5%
Fatique 24,3% 3,5

www.ago-online.de Asthenia 20,4% 1,8

Alopecia 19,7% 0
Andre F, et al N Engl J Med 2019;380:1929-1940
Mucositis 18,3% 2,1
 Immune Checkpoint Inhibitors

 Therapeutic approaches (antibodies)

© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  PD1 /PD-L1
Guidelines Breast PD1
Version 2020.1
 nivolumab
 pembrolizumab
PDL1
 atezolizumab
 durvalumab
 avelumab

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 Immune Checkpoint Inhibitors
Time Course of Adverse Events, ex. Nivolumab
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

pneumonitis
rash

hypothyroidism

hepatitis

www.ago-online.de

Haanen J et al. Ann Oncol 2017; 28 (suppl 4): 119-142

 Immune Checkpoint Inhibitors
– side effects –
 Adverse events ≥ grade 3
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  diarrhea
Guidelines Breast
 fatigue
Version 2020.1  skin lesions (maculopapular exanthema, vitiligo, epidermolysis)
 pneumonitis
 colitis
 hypophysitis
 hepatitis
 nephritis
 thyreoiditis (hyper-/hypothyroidism)
 Guillain-Barré syndrome
 cardiomyopathy
 myopathy – myalgia – rhabdomyolysis
www.ago-online.de  uveitis
 Immune Checkpoint Inhibitors
Toxicities (Total in %)
© AGO e. V. atezolizumab nivolumab pembrolizumab
in der DGGG e.V.
sowie diarrhea 18.6% 13% 18%
in der DKG e.V.

Guidelines Breast
colitis 1.1% 2% 1%
Version 2020.1
exanthema 18.6% 15% <1%
hepatoxicity 0.3% 1% 0.5%
hypophysitis <0.1% <1% 0.5%
pneumonitis 3.1% 3% 2.9%
hyper- 1.7% hyper -1% hyper- 1.2%
thyroid dysfunction
hypo- 4.7% hypo- 4% hypo- 8.3%
nephritis <1% 1% 0.7%
neuropathy 0.2% <1% <1%

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Atezolizumab technical product information 2018; Nivolumab, safety management BMS 2014; Pembrolizumab PI 2014
 Immune Checkpoint Inhibitors
Principles of Adverse Event Management
© AGO e. V. CTC AE-Grade Management
in der DGGG e.V.
sowie  supportive therapy
in der DKG e.V.
 close examination
Guidelines Breast
1  exclusion of infective complications
Version 2020.1
 patient information
Like grade 1 but
2  intermission of therapy until recovery of all irAE to grades 0-1
 consider corticosteroids
 supportive therapy
 IV steroids (e.g. 1-2 mg/kg prednisolone)
In case of no improvement within 48 h:
 consider additional immunosuppressive therapy (infliximab, MMF)
3  consider further organ specific diagnostics (eg. colonoscopy)
 consider specialists consultations
 exclusion or treatment of infection
 stop of treatment, re-initiation after recovery to CTC AE grades 0, 1
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 slow reduction of steroids (3-6 weeks)
4 Like grade 3 but persistent withdrawal of therapy
 Management of Pneumonitis
PD1/ PDL1 Inhibitors
© AGO
I° (asymptomatic,
e. V.
in der DGGG e.V. morphological signs on CT Continue Consider controls by imaging
sowie
in der DKG e.V. scan)
Guidelines Breast
Version 2020.1 II° (oligosymptomatic, oral methylprednisolone
Withhold
coughing/exertional dyspnea) at 0,5-1 mg/kg * †

III° (dyspnea at rest, IV methylprednisolone

Withhold
oxygen substitution) at 1-2 mg/kg † ‡

IV° (life-threatening, IV methylprednisolone

indication for tracheotomy/ Stop at 1-2 mg/kg, consider infliximab/
intubation) MMF/endoxane after 48 -72h ‡

* Prophylactic antibiotic therapy with ciprofloxacin 500 mg bid orally, ulcus prophylaxis with PPI,
www.ago-online.de oral substitution of potassium. In case of no improvement, treat like for pneumonitis III°
† in case of improvement reduce steroids over 1 month
‡ > pneumonitits III°bronchoscopy plus lavage / consider biopsy
Courtesy, A.Schneeweiss, NCT, UFK Heidelberg, 2017
 Management of Nephritis
PD1/PDL1-Inhibitors
© AGO e. V.
in der DGGG e.V. Monitoring; exclude prerenal/
sowie I° (Creatine to 2 mg/dL) Continue
in der DKG e.V.
postrenal failure
Guidelines Breast
Version 2020.1
oral methylprednisolone
II° (Creatine to 3 mg/dL) Withhold
at 0,5-1 mg/kg * †

IV methylprednisolone
III° (Creatine > 3 mg/dL) Withhold
at 1-2 mg/kg † ‡

IV° need of dialysis:

Treatment according the
(hypervolemia/ hyperkalemia/ Stop
nephrologist`s consideration
azothemia/ pericarditis)
* Prophylactic antibiotic therapy with ciprofloxacin 500 mg bid orally, ulcus prophylaxis with PPI, oral
www.ago-online.de substitution of potassium. In case of no improvement treat like for nephritis III°
† in case of improvement reduce steroids over 1 month
‡ > nephritis III°refer to nephrologist for biopsy
Courtesy, A.Schneeweiss, NCT, UFK Heidelberg, 2017
 Management of Hypophysitis
PD1/PDL1-Inhibitors
© AGO e. V. TSH/fT3/ fT4 suppressed methylpredisolone
in der DGGG e.V.
sowie +/- hyperkalemia ACTH †, cortisone in serum, 1-2 mg/kg IV*ǃ
in der DKG e.V. +/- hypoglycemia 24h-urine: cortisone, PRL †, Further hormone
+/- hypotension IGF-1 †, FSH/ LH
Guidelines Breast
Version 2020.1 +/- fatigue (premenopause), ECG, vital
substitution
-> susp. autoimmune signs followed by MRI of the (L-thyroxin) based on
hypophysitis/central M. pituitary gland‡ endocrinologist`s
Addison recommendation
† ACTH: adrenocorticotropic hormone, PRL: prolactin, IGF-1: insulin growth factor-1
‡ MRI of the pituitary gland
* Prophylaktisch antibiotic therapy with ciprofloxacin 500 mg bid orally, ulcus prophylaxis with PPI, oral
substitution of potassium
ǃ Under reduction of methylprednisolone (cave: reduced bioavailability of oral steroids) to levels of 8 mg/d orally
-> switch to hydrocortisone as maintenance (15-10-5 mg daily);
no ACTH controls
Addison emergency card via Department of Endocrinology; ->in stress situations (fever, deterioration of general
www.ago-online.de
condition) triple dose to 45-30-15 mg daily
Consider treatment with checkpoint inhibitors at clinical discretion

Courtesy, A.Schneeweiss, NCT, UFK Heidelberg, 2017

 Management of Hepatitis
PD1/PDL1-Inhibitors
© AGO e. V. I° (ALAT/ASAT< 3 x ULN and/or Serum controls before each
in der DGGG e.V.
total bilirubin < 1,5 x ULN)
Continue
sowie treatment
in der DKG e.V.

Guidelines Breast II° (ALAT/ASAT < 5 x ULN and/or persisting longer than 5 days:
Version 2020.1
total bilirubin < 3 x ULN)
Withhold oral methylprednisolone 1 mg/kg * †

III° (ALAT/ASAT > 5 x ULN and/or IV methylprednisolone

total bilirubin > 3 x ULN)
Withhold
2 mg/kg †
IV methylprednisolone 2 mg/kg,
IV° (ALAT/ASAT > 20 x ULN and/or
total bilirubin > 10 x ULN)
Stop consider add-on
MMF 1000 mg bid after 48h
* Prophylactic antibiotic therapy with ciprofloxacin 500 mg bid orally, ulcus prophylaxis with PPI, oral
substitution of potassium. Cave: reduced bioavailability of oral steroids, in case of no improvement treat like
hepatitis III°
† Diagnostics with ultrasound/ abdominal CT scan, HBV-/ HCV-/ CMV-/ EBV serology, electrophoresis, ANA,
www.ago-online.de
ANCA, ASMA, AMA, anti-LKM1, anti-SLA, consider liver biopsy. In case of improvement, reduce
methlyprednisolone to 1 mg/kg IV (2 weeks) followed by steroid tapering (1 month), start checkpoint inhibitor
only at 10 mg/d prednisolone (8 mg/d methylprednisolone)
Courtesy, A.Schneeweiss, NCT, UFK Heidelberg, 2017
 Management of Colitis
PD1/PDL1-Inhibitors
© AGO e. V. symptomatic therapy
in der DGGG e.V. Diarrhea I° (bis 3 x daily) Continue
sowie (loperamide)
in der DKG e.V.

Guidelines Breast duration of more than 5 days:

Version 2020.1 Diarrhea II° (4-6 x daily) Withhold oral methylprednisolone 1 mg/kg *

IV methylprednisolone
Diarrhea III° (7-10 x tgl daily) Withhold
2 mg/kg †

IV methylprednisolone 2 mg/kg
Diarrhea IV° (>10 x tgl daily) Stop
+ consider infliximab 5 mg/kg ‡
* Stool diagnostics (exclude C-diff.). Prophylactic antibiotic therapy with ciprofloxacin 500 mg bid orally, ulcus prophylaxis with PPI, oral
substitution of potassium. Cave: reduced bioavailability of oral steroids, in case of no improvement treat like diarrhea III°
† Diagnostic colonoscopy with biopsy, abdomincal CT scan in case of left-sided colitis (exclude diverticulitis). In case of improvement,
reduce methlyprednisolone to 1 mg/kg IV (2 weeks) followed by steroid tapering (1 month), start checkpoint inhibitor only at 10
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mg/d prednisolone (8 mg/d methylprednisolone)
‡ pre-therapeutic HBV/ HCV/ CMV/ Tb-(Quantiferon) serology, infliximab contraindicated in case of perforation/ sepsis; application 2h
IV via 1,2 µm filter (up to 15% infusion reactions), consider retreatment on day 15

Courtesy, A.Schneeweiss, NCT, UFK Heidelberg, 2017

 Management of Thyreoiditis
PD1/PDL1-Inhibitors
© AGO e. V.
in der DGGG e.V. Endocrinological therapy:
sowie
carbimazol 10 mg/d ǃ
in der DKG e.V.
Thyreoglobulin, MAKs Based on symptoms
Guidelines Breast †, TAKs †, TRAKs †, ECG, escalation of carbimazol to
Version 2020.1 TSH suppressed, fT3/
vital signs, 20 mg/d +/- propranolol 5
fT4 increased –
followed by ultrasound mg bid +/-
consider autoimmune methylprendisolone 1-2
of the thyroid gland to
thyreoiditis mg/kg IV*
exclude nodes /
In severe cases inpatient
proof of hyperemia ‡ management for IV
thiamazol

† MAKs: anti-TPO antibody, TAKs: anti-thyreoglobulin antibody, TRAKs: anti-TSH-receptor antibody

‡ ultrasound of the thyroid gland
ǃ Under carbimazol, withhold treatment with checkpoint inhibitor and start weekly controls of TSH/ fT3/ fT4/
www.ago-online.de blood count, ALAT/ASAT/AP, continue IO therapy with decreasing fT3/ fT4
* Prophylactic antibiotic therapy with ciprofloxacin 500 mg bid orally, ulcus prophylaxis with PPI, oral
substitution of potassium. Cave: reduced bioavailability of oral steroids,
Courtesy, A.Schneeweiss, NCT, UFK Heidelberg, 2017
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1  Further supportive and palliative issues
 Nutrition
 Pain management
 Palliative Care

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 Nutrition deficiency

 Nutrient deficiency is a common medical problem affecting 15-40% of

© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. cancer patients. It impairs their quality of life and can affect the success of
Guidelines Breast
Version 2020.1
treatment.
 Integration of nutritional advice into clinical management recommended
 For nutrition see S3 guideline Palliative care and supportive therapy

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 Analgesia
© AGO e. V.  Non-opioids; WHO Step 1
in der DGGG e.V.
sowie Diclofenac resinate, ibuprofen and / or metamizole,
in der DKG e.V.

Guidelines Breast
paracetamol (acetaminophen)
Version 2020.1
 Mild opioids; WHO Step 2
Tramadol (preferentially „retard“-formulations)
or tilidine / naloxone (also as „retard“-formulations)
 Strong opioids; WHO Step 3
Morphine, buprenorphine (sublingual or transdermal), fentanyl
(transdermal), hydromorphone, oxycodone, as a back-up levomethadone.
The dose of opioids should be titrated step by step according to the
analgetic effect.
 Additional drugs – „adjuvants“
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Canabinoide, Gabapentin, pregabalin, carbamazepine, amitriptyline,

bisphosphonates
 Palliative Care

 All patients should be offered palliative care after the diagnosis of a non-
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. curable cancer, regardless of whether a tumour-specific therapy is carried
Guidelines Breast
Version 2020.1
out.
 Specialized palliative care should be integrated into oncological decision-
making processes, e.g. by participating in interdisciplinary tumor
conferences.
 Patients with incurable cancer who are cared for in structures of
specialized palliative care (palliative care ward, specialized outpatient care
such as SAPV) should have access to oncological councelling.

https://www.leitlinienprogramm-onkologie.de/leitlinien/palliativmedizin/
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 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Breast Cancer:
Specific Situations
 Breast Cancer:
Specific Situations
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  Versions 2005–2019:
Guidelines Breast
Version 2020.1
Dall / Fehm / Fersis / Friedrich / Gerber / Göhring /
Harbeck / Huober / Janni / Loibl / Lück / Lux / Maass /
Mundhenke / Müller / Oberhoff / Rody / Scharl / Schneeweiss / Schütz /
Sinn / Solomayer / Stickeler / Thomssen

 Version 2020:
Ditsch / Kolberg-Liedtke

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 Breast Cancer:
Specific Situations

© AGO e. V.
in der DGGG e.V. Young patients
sowie
in der DKG e.V.  Pregnancy- and breast-feeding-associated BC

Guidelines Breast
Version 2020.1 Elderly patients
 Male patients
 Inflammatory BC
 Occult Breast Cancer (Cancer of unknown primary – axillary CUP)
 Paget‘s disease
 Malignant and Borderline Phyllodes Tumor
 Angiosarcoma
www.ago-online.de  Breast Implant-Associated Anaplastic Large-Cell Lymphoma (BIA-ALCL)
 Metaplastic breast cancer
 Breast Cancer in
Young Women ≤ 40 Years
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast  Aggressive biological behavior with worse prognosis 2a B

Version 2020.1
 Local therapy independent of young age 2b B +
 Guidelines adapted (neo-)adjuvant systemic
1b A ++
treatment (see respective chapters)
 GnRHa as ovarian protection
1a B +
(see chapter gynecological problems)
 Genetic and fertility counseling 2b B ++
 Contraception counseling 2b B ++
www.ago-online.de
 Breast Cancer During Pregnancy*
or Breast Feeding – Diagnostics and Surgery
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Breast imaging and biopsy like in non-pregnant 4 C ++
Version 2020.1
 Staging if indicated (bone scan after delivery) 5 D +
 Full body MRI (without contrast agent) 4 C +/-
 Surgery like in non-pregnant patients 4 C ++
 Sentinel node excision (technetium only) 4 C +
 SLNE during 1st trimester 5 D +/-
 Sensitivity and specificity not established (during lactation);
4 C ++
breast feeding should be avoided for 24 hrs

 Blue dye (not tested in pregnant animals or humans) 4 C --

www.ago-online.de

* Participation in register study recommended

 Breast Cancer During Pregnancy
- (Neo-)adjuvant Therapy -
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast  Radiation therapy during pregnancy 4 C -
 (Neo-)adjuvant chemotherapy only after first
Version 2020.1

++
trimester (indication as in non-pregnant)
 Anthracyclines: AC, EC 2b B ++
 Taxanes 2b B +
 Platinum salts (carboplatin, cisplatin) 4 C +/-
 MTX (e.g. CMF) 4 D --
 Endocrine treatment 4 D --
 HER2-targeted treatment 3a C --
www.ago-online.de
 Bisphosphonates, denosumab 4 D -
 Breast Cancer During Pregnancy*
– Delivery and Breast-Feeding –
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Delivery should be postponed until sufficient
Guidelines Breast 2b C ++
Version 2020.1
fetal maturation (avoid iatrogenic prematurity)
 Termination of pregnancy does not improve
3b C
maternal outcome
 Delivery mode like in healthy women; avoid delivery
4 C ++
during chemotherapy-induced leucocyte nadir
 If further systemic therapy is needed after delivery,
breast feeding may be contra-indicated depending on 5 D ++
www.ago-online.de drug toxicities

* Participation in register study recommended

 Breast Cancer and Pregnancy
– Family Planning –
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 After breast cancer diagnosis, reproductive
Guidelines Breast
5 D ++
Version 2020.1
techniques can be used to induce pregnancy
 Success rates for getting pregnant and for
delivering a child lower in breast cancer patients 5 D ++
compared to non-cancer patients
 Breast cancer patients of reproductive age
should be offered fertility counseling before 5 D ++
starting any kind of treatment
 Breast cancer patients should not be advised
www.ago-online.de against getting pregnant independent of their tumor‘s 5 D ++
hormone receptor status
 Pregnancy Associated
Breast Cancer*: Outcome
© AGO e. V.
in der DGGG e.V. Oxford
sowie
in der DKG e.V. LoE
Guidelines Breast
Version 2020.1
 BC during pregnancy / lactation
 Adequate treatment is essential 3a

 Pregnancy and lactation after BC

 Outcome not compromised 3a

www.ago-online.de

* Participation in register study recommended

 Geriatric Assessment
© AGO e. V.
in der DGGG e.V.
 No specific algorithm is available
 Ability to tolerate treatment varies greatly („functional reserve“)
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
 Comprehensive geriatric assessment (CGA) describes a multidisciplinary
evaluation of independent predictors of morbidity and mortality for older
individuals
 Physical, mental, and psycho-social health
 Basic activities of daily living (dressing, bathing, meal preparation, medication management, etc.)
 Living arrangements, social network, access to support services
 Assessment tools:
 Charlson Comorbidity Index (widely used; good predictor over a 10-year period)
 12 prognostic indicators to estimate 4-year mortality risk
 Short screening tests (more qualitative evaluation)
 IADL (IADL = The Lawton Instrumental Activities of Daily Living Scale with 8 domains of function, that
www.ago-online.de are measured), G8
 Geriatric Prognostic Index (GPI), 3 parameters in oncological patients (psychological distress or acute
disease, >3 prescribed drugs, neuropsychological problems)
 Treatment for Fit Elderly Patients
(Life Expectancy > 5 yrs. and Acceptable Comorbidities)

© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Clinical geriatric assessment 2b B ++
Version 2020.1
 Treatment according to guidelines 2a C ++
 Surgery similar to „younger“ age 2b B ++
 Endocrine treatment (endocrine responsive) 1a A ++
 Chemotherapy (standard regimens)
 < 70 years 1a A +
 > 70 years (especially N+, ER/PgR-) 2a C +*
 Radiotherapy 1a A +
 Omit radiotherapy after BCS if low-risk and endocrine
1b B +
treatment
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 Trastuzumab 2b C +

* Study participation recommended

 Treatment for Frail Patients
(Life Expectancy <5 yrs, Substantial Comorbidities)

© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Reduced standard treatment 2b C ++
Version 2020.1
 Options extrapolated from trials in elderly:
 No breast surgery (consider endocrine options) 2b C +
 No axillary clearing (≥ 60 y, cN0, HR-pos) 2b B +
 No radiotherapy ( ≥ 65 y, pT1, pN0, HR-pos) 1b B ++
 Hypofractionated radiotherapy 2b B +
 No chemotherapy if >70y and negative risk-benefit analysis 2b C +

www.ago-online.de
 Male Breast Cancer: Diagnostic
Work-Up and Loco-Regional Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Diagnostic work-up as in women 4 C +
Version 2020.1  Mammography 3b C +/-
 Ultrasound 2b B ++
 Standard-surgery: Mastectomy 4 C ++*
 BCT is an option (tumor/breast relation) 4 C +*
 Sentinel-node excision (SNE) 2b B +
 Radiotherapy as in women
4 C +
(consider tumor/breast relation!)
 Genetic counseling if one additional relative affected
2b B ++
(breast/ovarian cancer)
www.ago-online.de
 Screening for 2nd malignancies according to guidelines GCP ++
* Participation in register study recommended
 Male Breast Cancer:
Systemic Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Adjuvant chemotherapy as in women 2a B ++
Version 2020.1
 HER2-targeted therapy (if HER2-positive) 5 D ++
 Endocrine therapy 4 D ++
 Tamoxifen 2b B ++
 Aromatase inhibitors (adjuvant) 2b B -*
 Aromatase inhibitors (metastatic BC) 4 C +/-
 GnRHa and AI (metastatic BC) 4 C +*
 Fulvestrant (metastatic BC) 4 C +/-
 CDK4/6i (in combination) * 2b B +
 Palliative chemotherapy as in women 4 C ++
www.ago-online.de

* Study participation recommended

 Benefit from Trimodal Treatment in
Inflammatory Breast Cancer
© AGO e. V. Median survival probability
in der DGGG e.V.
sowie Trimodal therapy 72 months p<0.05
in der DKG e.V.
Surgery alone 26 months
Guidelines Breast
Version 2020.1
Overall survival-probability (OS) 10 years-OS 5 years-OS
Trimodal therapy 55.4% 37.3%
Surgery & chemotherapy 42.9% 28.5%
Surgery & radiotherapy 40.7% 23.5%
Surgery alone 16.5%
Multivariate analysis of OS Hazard Ratio 95% CI
Surgery & chemotherapy &
1.00 -
RT (trimodal therapy)
Surgery & chemotherapy 1.64 1.46 to 1.84
www.ago-online.de
Surgery & radiotherapy 1.47 0.96 to 2.24
Surgery alone 2.28 1.80 to 2.89
Rueth et al. J Clin Oncol 2014; 32:2018–2024
 Primary inflammatory breast cancer
© AGO e. V.
in der DGGG e.V.
5yr- OS
sowie
in der DKG e.V.

Guidelines Breast pCR 77%

p<0.0001
Version 2020.1

Non-pCR 54%

TN-IBC 37%
p<0.0001
other biologic subtypes (HR+/HER2−,
60%
HR+/HER2+, HR−/HER2+)

 N=8.550
 On multivariable analysis, TNBC, positive margins, and not receiving either
www.ago-online.de chemotherapy, hormonal therapy or radiotherapy were independently
associated with poor 5-year survival (p < 0.0001).
 Inflammatory Breast Cancer (IBC, cT4d)
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Invasive BC and clinical signs of inflammation
Version 2020.1 (e.g. ≥ 1/3 of the breast affected) determine ++
stage cT4d
 Staging 2c B ++
 Skin punch biopsy (at least 2; detection rate < 75%) 2c B +
 Treatment according to guidelines (neoadjuvant or
2c B ++
adjuvant – as in non-IBC)
 Mastectomy after chemotherapy 2c B +
 Breast conserving therapy in case of pCR (individual) 2b C +/-
 Sentinel excision only 3b C -
www.ago-online.de
 Radiotherapy (PMRT) 2c B ++
 Axillary Metastasis in Occult Breast Cancer
(Cancer of Unknown Primary – Axillary CUP)
 Incidence: < 1% of metastatic axillary disease
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  In > 95% occult breast cancer, < 5% other primary
 Immunhistology
Guidelines Breast
Version 2020.1

ER-positive: 55%
HER2 3+: 35%
Triple-negative: 38%
 Nodal status:
 1 - 3 Ln-Met. in 48%
> 3 Ln-Met in 52%
 Outcome similar or better than in breast cancer with similar tumor
www.ago-online.de
biology and tumor stage
 Axillary Metastasis in Occult Breast Cancer (Axillary
CUP) Imaging Diagnostics
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Mammography, Breast-ultrasound, Breast-MRI 3 B ++
Version 2020.1
 Exclude contralateral cancer 3 B ++
 Exclude non-breast malignancy, especially
in case of TNBC (e.g. skin, female genital tract, 5 D ++
lung, thyroid gland, stomach)
 Staging (CT thorax / abdomen,
3 B ++
thyroid scintigraphy, HNT-exam)
 PET / PET-CT 3b B +

www.ago-online.de
 Axillary Metastasis in Occult Breast Cancer (ex. CUP)
Pathology, molecular pathology

© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 ER, PgR, HER2, GATA3 5 D ++
Version 2020.1
 Exclusion of other primary malignancies in case of
triple-negative phenotype or unusual histology, e.g.
5 D ++
lung, female genital tract, HNT tumors,
neuroendocrine ca.
 Gene expression profiling for determination
or primary site 2c B +/-
(e.g. CUPprint, Pathwork, TOT, Theros CTID)
 NGS, epigenetics for determination of primary site
2c B +/-
www.ago-online.de (Panel-Sequencing, e.g. EPICup)
 Prognostic gene expression tests 5 D --
 Axillary Metastasis in Occult Breast Cancer
(Axillary CUP): Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Axillary dissection 3a C ++
Version 2020.1
 Mastectomy if breast MRI is negative 3a C -
 (Neo-) adjuvant systemic therapy according
5 D ++
to breast cancer guidelines (AGO)
 Breast irradiation if breast MRI is negative 2c B +
 Irradiation of regional lymph nodes according to
3b B +
breast cancer guidelines (AGO)

www.ago-online.de
 Paget‘s Disease of the Breast
© AGO e. V.  Definition: Paget‘s disease of the breast is characterized by an intraepidermal
in der DGGG e.V.
sowie tumor manifestation originating in intraductal or invasive breast cancer.
in der DKG e.V.

Guidelines Breast
 Clinical presentation: skin eczema of the nipple, areola and surrounding skin;
Version 2020.1 thickening, pigmentation and scaly skin

Feature Frequency
Presentation Paget‘s disease with invasive Ca. (37 - 58%)
Paget‘s disease mit DCIS (30 - 63%)
Isolated Paget‘s disease (4 - 7%)
Isolated Paget‘s disease with invasion (rare)
IHC HER2-positive (83 - 97%)
ER-positive (10 - 14%)
AR-positive (71 - 88%)
www.ago-online.de
Prognosis and tumor Better in isolated Paget‘s disease
biology Worse if in combination with invasive breast cancer or DCIS
compared to isolated Paget‘s disease
 Paget‘s Disease of the Breast Diagnosis
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Histological verification by skin biopsy ++
Version 2020.1
 Mammography, sonography 4 D ++
 MRI of the breast if other imaging negative 4 C +
 Immunohistochemistry (ER, PgR, HER2, Ck7)
5 D ++
to detect benign and HER2-negative cases

www.ago-online.de
 Paget‘s Disease of the Breast - Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Paget‘s disease with underlying disease
Version 2020.1
(invasive breast cancer, DCIS)
 Therapy according to standard of underlying disease 5 D ++
 Surgery must achieve R0 1c B ++

 Isolated Paget‘s disease of the NAC:

 Surgery must achieve R0 1c B ++
 Surgical resection only, no adjuvant radiotherapy 4 D ++
 Sentinel-node excision (SNE) 2b B --

www.ago-online.de
 Borderline and Malignant Phyllodes Tumor
 Name derived from greek term of “Phyllon” (leaf) due to its lobulated
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. histological aspect
Guidelines Breast
Version 2020.1
 Differential diagnosis may be problematic on core biopsy
 Resection margin is independent prognostic parameter
 Comparable rates of recurrence in association with BCT or mastectomy
 In-Breast recurrence relatively frequently seen (10 - 30%)
 Distant metastasis relatively rare (< 10%) and almost exclusively seen in
malignant phyllodes tumor.
 Adverse pathological criteria: marked stromal cellularity and overgrowth,
increased nuclear atypia, presence of large necrohemorrhagic areas, and
www.ago-online.de
high mitotic activity associated with increased risk of distant recurrence
 Phyllodes tumor
© AGO e. V.  Fibroepithelial tumors of the breast: frequency 0.3 – 1% of all primary brteast tumors
in der DGGG e.V.
sowie
in der DKG e.V. parameter frequencies
Guidelines Breast
Version 2020.1
Grading (3-STEP histological grading Benign (75%)
system) Borderline (16%)
Malignant (9%)
Median age at time of diagnosis Benign PT: 39 y
Borderline PT: 45 y
Malignant PT: 47 y
Local recurrence Benign PT: 4 – 17%
Borderline PT: 14 – 25%
Malignant PT: 23 – 30%
Metastasis Benign PT: <1%
www.ago-online.de Borderline: PT: 1.6%
Malignant PT: 16-22%
10y OS: 86–90% (range: 57–100%) depending on subtype and unfavorable histological criteria
 Borderline and Malignant Phyllodes Tumor
Diagnosis
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Mammography, sonography 3 C ++
Version 2020.1
 Diagnosis on core biopsy, grade determination on
3 C ++
resection specimen
 Breast MRI 3 C +/-
 Staging only malignant PT (CT thorax, skeletal system) 5 D ++

www.ago-online.de
 Borderline and Malignant Phyllodes Tumor
Surgery
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Version 2020.1
 Benign phyllodes tumor: complete resection 2b B ++
 Borderline /malignant phyllodes tumor: resection 2b B ++
margin ≥1mm
 Borderline /malignant phyllodes tumor: resection 2b B +
margin >10mm (local control)
 SNE / Axillary dissection when cN0 4 C --
 Treatment of local recurrence
 R0 resection or simple mastectomy 4 C ++
www.ago-online.de
 Borderline and Malignant Phyllodes Tumor
Adjuvant Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Adjuvant radiotherapy (younger age, increased tumor
Guidelines Breast 2b B +/-
Version 2020.1
volume > 5 cm, close resection margin)
 Systemic adjuvant therapy (chemo, endocrine) 4 C --
 Treatment of local recurrence
 R0 resection or simple mastectomy 4 C +
 Radiotherapy, chemotherapy after R1 resection 4 C +/-
 Distant metastasis (very rare)
 Treatment like soft tissue sarcomas 4 C ++

www.ago-online.de
 Sarcomas of the Breast
 Not infrequently associated with familial syndromes (Li-Fraumeni,
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. familial adenomatous polyposis, neurofibromatosis type 1)
Guidelines Breast
Version 2020.1
 Primary sarcomas: angiosarcoma, undifferentiated sarcoma,
leiomyosarcoma, liposarcoma, osteosarcoma
 Secondary malignancies of the breast:
 Radiotherapy-Associated Angiosarcoma
 Breast Implant Associated Large-Cell Anaplastic Lymphoma (BI-ALCL)
 Rare: intramammary sarcoma metastases
 Staging: TNM (UICC) or AJCC scheme of the soft tissue sarcoma analogous
to sarcoma of the breast
www.ago-online.de  Grading: Analogous to the FNCLCC system for sarcoma or according to
Rosen (1988) for angiosarcomas
 Primary Angiosarcoma of the Breast

© AGO e. V.
in der DGGG e.V. Most common primary sarcoma of the breast
sowie
in der DKG e.V.  Young age (median: 24–46 years)

Guidelines Breast
Version 2020.1 Indistinct tumor borders
 Large tumor (median: 5–7 cm)
 Uncharacteristic findings on mammography and sonography
 High local recurrence risk, even after mastectomy
 More unfavorable prognosis than other primary sarcoma of the breast

www.ago-online.de
 Primary Angiosarcoma of the Breast*
Diagnosis
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Mammography, sonography to determine extent of
Guidelines Breast 3a C --
Version 2020.1
disease
 Preoperative MRI to determine the extent of disease 3a C ++
 Diagnosis by core biopsy 3a C ++
 Diagnosis by FNB 3a C --
 Staging (CT thorax & abd.; angiosarcoma: MRI brain) 4 D ++
 Prognostic factors: size, grade, margins 3a C ++

www.ago-online.de

* Therapy in specialized centers recommended

 Primary Angiosarcoma of the Breast*
Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Surgery with wide clear margins, mostly as
Guidelines Breast 2b C ++
Version 2020.1
mastectomy
 Breast-conserving therapy 3a C -
 SNB or axillary dissection if cN0 3a C --
 Adjuvant chemotherapy
4 C +/-
(anthracycline/taxane-based)
 Adjuvant radiotherapy if high risk (size > 5 cm, R1) 4 C +/-

www.ago-online.de

* Therapy in specialized centres recommended

 Secondary (Radiotherapy-associated)
Angiosarcoma of the Breast
 Cumulative incidence of radiotherapy-associated sarcoma: 3.2 per 1,000
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. after 15 years
Guidelines Breast
Version 2020.1
 Clinical presentation
 > 5 years after BCT or mastectomy with irradiation
 usually intracutaneously or subcutaneously in the irradiation area with livid
discoloration
 multiple foci
 most often in advanced stages (II–III)
 metastasis mostly pulmonary
 lymph node metastasis possible
 Prognosis is more unfavorable than in non-radiotherapy-associated
sarcoma
www.ago-online.de
 Survival: after 5 yrs up to 50.5%, after 10 yrs up to 25.2%
 Secondary Angiosarcoma
of the Breast Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Secondary mastectomy 3a C ++
Version 2020.1
 Adjuvant chemotherapy
2b B +/-
(anthracycline/taxane-based)
 Adjuvant radiotherapy if high risk
2b B +/-
(size > 5 cm, R1)
 Regional hyperthermia (to improve local control)
2b B +/-
plus chemotherapy and/or radiotherapy

www.ago-online.de
 Angiosarcoma of the Breast
Treatment of Local Recurrence and Metastases
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
Treatment of Local Recurrence:
Version 2020.1  R0 resection 4 C ++
 Adjuvant radiotherapy for high-risk patients
4 C +/-
(tumor size > 5 cm, R1)
Distant Metastases / Unresectable Tumors:
 Treatment like soft tissue sarcomas 4 C ++
 Paclitaxel weekly / liposomal doxorubicin (as in angiosarcoma) 2b B +
 Antiangiogenic treatment (e.g. in angiosarcoma) 4 C +/-

www.ago-online.de
 Breast Implant Associated Anaplastic Large
Cell Lymphoma (BIA-ALCL)
 Rare disease, 3 % of Non-Hodgkin Lymphomas, 0.04-0.5 % of all malignant
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. breast diseases
Guidelines Breast
Version 2020.1
 Estimated incidence 0.6-1.2 / 100.000 women with implants (median age:
54 y)
 Mainly associated with textured implants
 Interval to diagnosis: 8 years (median)
 Clinical symptoms
 Swelling and seroma. (60 %)
 Solid tumor (17 %)
 Seroma and solid tumor (20 %)
 Histology: CD30+ / ALK-T-Cell Lymphoma
www.ago-online.de
 Compulsory registration as SAE (§3 MPSV to BfArM
 BIA-ALCL - Surfaces of Breast Implants
© AGO e. V.  The cause of BIA-ALCL is not established; however, it has been proposed that lymphomagenesis
in der DGGG e.V.
sowie
may be driven by a chronic inflammatory reaction induced by capsule contents or surface. The risk
in der DKG e.V. for BIA-ALCL has been shown to be significantly higher for implants with grade 3 and 4 surfaces.
Guidelines Breast
Version 2020.1

www.ago-online.de
 BIA-ALCL– Diagnosis
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Breast US (assessment of new seromas > 1 year after implant insert,
Guidelines Breast 3a D ++
Version 2020.1 solid lesion)
 Mamma-MRT in confirmed cases 3a D ++
 Staging (Imaging, e.g. CT, PET-CT) 3a D ++
 Cytology of late seromas
- > 50 ml
- Complete assessment 3a D ++
- flow-cytology (T-cell clone)
- BIA-ALCL specific cytologic diagnostic (CD 30+)
 Core needle biopsy in solid lesions
3a D ++
www.ago-online.de  Lymphoma assessment of resected tissue and histologic staging
 Documentation of the implant (manufacturer, size, volume, surface,
5 D ++
Batch-number) and enter in registry
 BIA-ALCL – Therapy
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast  Implant resection and complete capsulectomy
Version 2020.1 3a C ++
including tumorectomy
 Resection of suspicious lymph nodes, no routine use
4 D ++
of Sentinel-Node-Biopsy, no axillarx dissection
 Polychemotherapie (z.B. CHOP) bei extrakapsulärer
4 D +
Tumorausbreitung
 Radiotherapy in unresectable tumors 5 D +/-
 Case discussion in an interdisciplinary tumor board in
5 D ++
www.ago-online.de the presence of a specialist for lymphomas
 Breast Implant-Associated
Anaplastic Large-Cell Lymphoma (BIA-ALCL)
- Summary of the Management (acc. to Noah 2017) -
© AGO e. V. Periprosthetic seroma or tumor mass > 1 year after Confirmed ALCL cases
in der DGGG e.V. implant placement
sowie
in der DKG e.V.
Tumor board discussion
Guidelines Breast Exclude trauma or
Version 2020.1 infection
Complete operative caspulectomy, tumor
excision according to oncological standards
Ultrasound / sonography Lymph node removal in case of suspicion, no
new implants, possibly also contralaterally
Seroma: aspiration and
cytology Tumor mass Complete R1 or positive
Resection R0 lymph nodes
(when suspicious: CD30-IHC)

Suspicious +ALCL Clinical follow-up.

Ultrasound and CT Chemotherapy;
every 6 months for CHOP, possibly
2 years, then Immunotherapy
Operative exploration
with biopsy of the Tumor board discussion annually for 5 years +/-
capsule
www.ago-online.de Radiatiotherapy
 Stage Adapted Therapy of BIA-ALCL
TNM Description

T= tumor extent
IA-IC/(IIA): surgical resection of
T1 Confined to effusion or a layer on luminal side of capsule capsula, implant, suspected nodular lesions and,
T2 Early capsule infiltration only if suspicious, regional lymph nodes
© AGO e. V. no indication for mastectomy, sentinel node
in der DGGG e.V. T3 Cell aggreates or sheets infiltrating the capsule
sowie exstirpation or axillary dissection
in der DKG e.V. T4 Lymphoma infiltrates beyond the capsule

Guidelines Breast N= lymph node

Version 2020.1 N0 No lymph node involvement IIA/IIB-IV: 2-18%
N1 One regional lympho nodes positive • surgical complet resection (see above)
N2 Multiple regional lymph nodes positive • CHO(E)P (Cyclophosphamide, Vincristin,
M= metastasis Doxorubicin,Prednison) +/- Etoposid
M0 No distant spread

M1 Spread to other organs /distant sides

• Brentuximab Vedotin (Adcetris®)
antibody-drug-conjugate (ADC) containing
monoclonal antibody against human CD30 antigen
and 3-5 molecules of cytostatic drug
Monomethylauristatin E

and radiotherapy only in for patients with

www.ago-online.de incomplete resection and advanced stages
 BIA-ALCL – EUSOMA-Recommendation
© AGO e. V.
in der DGGG e.V.  Despite an increase of BIA-ALCL in association with texture implants the
sowie
in der DKG e.V. use of textured implants is still permitted!
Guidelines Breast
Version 2020.1

„For the moment, textured implants can safely continue to be used with patient's fully informed
consent, and that women that have these type of implants already in place don't need to remove or
substitute them, which would undoubtedly cause harm to many tens of thousands of women, to
prevent an exceptionally rare, largely curable and currently poorly understood disease."

www.ago-online.de
 Metaplastic Breast Cancer
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Imaging and histology for diagnosis according to
Guidelines Breast
5 D ++
Version 2020.1
standard
 Staging including chest and abdominal CT
4 C ++
(hematogenous metastasis)
 Surgical treatment according to standard
(more often MRM needed due to advanced 4 C ++
tumor stage)
 SNB 4 C +
 Adjuvant chemotherapy (tumors more
4 C +
www.ago-online.de chemoresistant)
 Adjuvant endocrine standard therapy 4 C +/-
 Adjuvant standard radiotherapy 4 C +
 Metaplastic Breast Cancer
© AGO
Incidence: 0,2–5 % of all breast cancers (1)
e. V. Histology: epithelial and mesenchymal components with two to three different components within a tumor;
in der DGGG e.V.
sowie high proliferation rate; subtypes: according to WHO (4)
in der DKG e.V.
Metaplastic carcinoma of no special type Low-grade adenosquamous carcinoma
Guidelines Breast
Version 2020.1 Fibromatosis-like carcinoma Squamous cell carcinoma
Spindle cell carcinoma Metaplastic carcinoma with mesenchymal differentiation
Chondroid differentiation Osseous differentiation
Other types of mesenchymal differentiation Mixed metaplastic carcinoma
Myoepithelial carcinoma

Molecular biology: > 90 % ER-, PR-, HER2-

~. 70 % overexpression of HER1, CK 5/6-expression (stem-cell-like and BRCA-like)(2)
molecular profile mostly basal-like (3)
frequent mutations in PIK3CA and PTEN (mTOR-overactivity)
Clinical features:
 Large tumors at diagnosis ( > 5 cm)
 Frequent hematogenous metastases; nodal involvement in ~ 20 % (no nodal involvement in spindle cell carcinoma
carcinosarcoma)
www.ago-online.de
 Poor clinical course compared to TNBC
 Impaired prognosis in asian women (MRM more frequently, poor grading, more often squamous cell carcinoma, spindle
cell carcinoma less frequent)
 Low response rated to (neoadjuvant) chemotherapy
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Breast Cancer
Follow-Up
 Breast Cancer
Follow-Up
Versionen 2002–2019:
© AGO

e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Bauerfeind / Bischoff / Blohmer / Böhme / Costa / Diel / Friedrich /
Guidelines Breast
Version 2020.1 Gerber / Hanf / Heinrich / Huober / Janni / Kaufmann / Kümmel / Lux
/ Maass / Möbus / Müller-Schimpfle/ Mundhenke / Oberhoff / Rody /
Scharl / Solbach/ Solomayer / Thomssen / Wöckel

 Version 2020:
Kolberg-Liedtke/Möbus

www.ago-online.de
 Breast Cancer Follow-Up
Objectives
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
Early detection of curable events
Version 2020.1
 In-breast recurrence 1a B ++
 Loco-regional recurrence* 1a B ++

Early detection of contralateral cancers 1a B ++

Early detection of metastasis
 Early detection of symptomatic metastases 3b C +
 Early detection of asymptomatic metastases 1a A -

www.ago-online.de

* loco-regional recurrence is associated with a higher risk of mortality in node-positive, PR-negative,

younger patients and in patients with a short time between primary diagnosis and recurrence
 Breast Cancer Follow-Up
Objectives
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Improve quality of life 2b B +
Version 2020.1
 Improve physical performance 2a B +
 Reduction and/or early detection of therapy-related
side effects (such as osteoporosis, cardiac failure, fatigue,
neurotoxicity, lymphedema, sexual disorders, cognitive 2b B +
impairment, sterility, and secondary tumors) and start of
necessary therapies
 Participation in interventional programs during
follow-up for breast cancer survivors in order to
www.ago-online.de 3b B +
maximize therapy adherence, assess life-style
interventions, and improve quality of life
 Breast Cancer Follow-Up
Objectives
Oxford
© AGO e. V. LoE GR AGO
in der DGGG e.V.
sowie
in der DKG e.V.
 Evaluation of current adjuvant therapy 2b B ++
Guidelines Breast
 incl. monitoring of adherence to endocrine therapies
Version 2020.1
 Pro-active improvement of therapy adherence 5 D ++
 Patient information about efficacy data for 5-10 years
endocrine therapy
 Early therapy of side effects (sports, NSAIDs,
vitamin D / calcium)

www.ago-online.de
 Breast Cancer Follow-Up
Objectives
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Psycho-social aspects of support and counseling 4 C +
Version 2020.1
 Pregnancy, contraception, sexuality, quality of life,
menopausal symptoms, fear of recurrence
 Inclusion of related persons (partner, family, friends, caregivers)
 Second opinion regarding primary therapy 2c B ++
 General counseling (e.g. genetics, HRT, prophylactic
2c C +
surgery, breast reconstruction)

www.ago-online.de
 Breast Cancer Follow-Up
Recommended Interventions
© AGO e. V. Interventions regarding lifestyle risks and comorbidity in order to reduce an
in der DGGG e.V.
sowie
in der DKG e.V.
unfavorable impact on disease outcome Oxford
LoE GR AGO
Guidelines Breast
Version 2020.1  Treatment of type II-diabetes
5 D ++
(> 25% undetected DM in postmenopausal BC patients)
 Weight intervention
2a B +
(if BMI < 18.5 and > 30)
 Nightly fastening > 13h 2b B +
 Reduction of dietary intake (at least 15 % calories from fat)
2b B +
in HR-negative BC is associated with improved overall survival
 Stop smoking (smoking causes 2-fold increase in BC-specific and 4-fold
2b B ++
increase in not directly BC-associated mortality)
 Alcohol consumption reduction (below 6g/d) 2b B +
www.ago-online.de
 Moderate sport (in patients with reduced physical activity prior to
1b A ++
diagnosis)
 Distress reduction 3b B +
 Nightly fasting
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. Prolonged nightly fasting improves prognosis in breast cancer patients
Guidelines Breast
Version 2020.1
retrospective cohort study:

2413 BC-pat. (no diabetes), nightly fasting more or less than 13 hrs

Fasting < 13 hrs: HR 1.36, 36% increase of risk for recurrence

HR 1.21, n.s. increase of risk for mortality

every 2-hrs-prolonged fasting was correlated with a 20% increase

www.ago-online.de of sleeping duration
Marinac CR, Nelson SH, Breen CI et al. JAMA Oncol 2016: 2:1049-1055
 Routine Follow-Up Examinations in
Asymptomatic Patients
© AGO
Oxford
e. V.
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V. Tests:
Guidelines Breast
Version 2020.1
 History (specific symptoms) 1a A ++
 Physical examination 1a B ++
 Breast self-examination 5 D +
 Mammography 1a A ++
 Sonography of the breast 2a B ++
 Routine MRI of the breast* 3a B +/-
 Breast MRI if conventional imaging is inconclusive 3b B +
 Pelvic examination 5 D ++
 DXA-scan at baseline and repeat scan according to
www.ago-online.de individual risk in women with premature menopause 5 D +
or women taking an AI
* Consider in case of increased risk (age <50y, HR-neg., diagnostic assessability C/D in mammography + ultrasound)
 Routine Follow-Up Examinations in
Asymptomatic Patients
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast
Version 2020.1
 Routine biochemistry (incl. tumor markers) 1a A -
 Ultrasound of the liver 1a A -
 Bone scan 1a A -
 Chest X-ray 1a A -
 CT of chest, abdomen, and pelvis 2a D -
 Detection of isolated / circulating tumor cells 2a D -
 PET 2b B -
 Whole body MRI 2b B -
www.ago-online.de
 Early Detection of Potentially Curable Events
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast
Version 2020.1 Locoregional recurrence (chest wall, in-breast):
 Incidence 7–20% (depending on time of F/U)
 Breast self-examination 5 D +
 Physical examination, mammography & US 1a A ++
 Magnetic resonance imaging (MRI)* 3a B +/-

www.ago-online.de

* Consider in case of increased risk (age <50y, HR-neg., diagnostic assessability C/D in mammography + ultrasound)
 Early Detection of Potentially Curable Events
© AGO e. V.
Oxford
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.

Guidelines Breast
Contralateral breast cancer:
Version 2020.1
 Relative risk: 2.5–5
 Incidence: 0.5–1.0 % / year

 Breast self-examination 5 D +
 Physical examination, mammography & US 1a A ++
 Routine breast MRI* 3b B +/-

Male breast cancer: analogous to BC in women** 5 D +

www.ago-online.de

* Consider in case of increased risk: age <50y, HR-neg., diagnostic assessability C/D in mammography + ultrasound.
** See chapter “Breast Cancer Specific Situations”
 Early Detection of Potentially Curable Events
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast Unrelated site carcinoma:

Version 2020.1
 MDS (RR 10.9), AML (RR 2.6–5.3), Colon RR 3.0;
endometrium RR 1.6; ovary RR 1.5; lymphoma RR
 Screening for secondary malignancies according to
current guidelines 5 D ++

 Pelvic examination and PAP smear 5 D ++

www.ago-online.de
 Routine endometrial ultrasound / biopsy 1b B -
 Follow-Up Care
for Breast Cancer
Recommendations for asymptomatic pts.
© AGO e. V.
in der DGGG e.V.
(mod. according to ASCO-ACS recommendations 2016, NCCN 3.2017 und S3-guidelines 2017)
sowie
in der DKG e.V.
Screening/
Guidelines Breast Clinical follow-up Follow-up*
Version 2020.1 Follow-up
Years after primary therapy 1 2 3 4 5 >5
History, physical examination,
inv.: every 3 months inv.: every 6 months inv.: every 12 months
counseling
Self-examination monthly
Imaging modalities and
indicated only if complaints, clinical findings, or suspicion of recurrence
biochemistry
Mammo-
BCT** both sides: every 12 months
graphy and
additional
sonography Mastectomy contralateral every 12 months
www.ago-online.de

* Continued follow-up visits if still on adjuvant treatment

** In pts after breast-conserving therapy (BCT): First mammography 1 year after initial mammography or at least 6
months after completion of radiotherapy
 Breast Cancer Follow-up
Duration and Breast Nurses
© AGO e. V.
in der DGGG e.V.
sowie
Oxford
in der DKG e.V.

Guidelines Breast
LoE GR AGO
Version 2020.1

 Duration of follow-up
 up to 5 years 1c A ++
 up to 10 years 1c A +

 Surveillance by specialized breast nurses 2b B +/-*

www.ago-online.de

* Studies recommended
 Luminal-like, HER2-positive and
Triple-negative Breast Cancer Patients
 Intrinsic typing of breast cancer leads to the development of subgroups
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. with different courses of disease
Guidelines Breast
Version 2020.1
 Postoperative surveillance should be tailored to specific breast cancer
type and their associated time periods of recurrence.
 ER-positive patients have a stable risk of recurrence of multiple years.
Long term surveillance is recommended.
 In contrast, patients with HER2-positive disease and TNBC have an
increased risk of recurrence in the early follow up phase. Surveillance
should be adjusted accordingly.

www.ago-online.de

Ribelles et al. BCR 2013

 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.01
Loco-Regional Recurrence
 Loco-regional Recurrence
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  Versions 2002–2019:
Guidelines Breast
Version 2020.01 Audretsch / Bauerfeind / Brunnert / Budach /
Costa / Dall / Fehm / Fersis / Friedrich / Harbeck /
Gerber / Göhring / Hanf / Kühn/ Lisboa / Maass /
Mundhenke / Rezai / Simon / Solomayer /
Souchon / Thomssen / Wenz / Wöckel

 Version 2020:
Lux/Solbach
www.ago-online.de
 Loco-regional Recurrence
Incidence and Prognosis
© AGO e. V. Localization Frequency (%) 5-y. Overall Survival (%)
in der DGGG e.V.
sowie
in der DKG e.V.
Ipsilateral recurrence1 10 (2–20) 65 (45–79)
(post BOT + irradition)
Guidelines Breast
Version 2020.01
Chest wall1 4 (2–20) 50 (24–78)
(post mastectomy)
As above plus supraclavicular fossa2
Axilla: 34% 49% (3-y. OS)
After ALND1 1 (0.1–8) 55 (31–77)
After SLNE4 1 93%
Multiple localizations2 16 (8–19) 21 (18–23)

1 Haffty et al. Int J Radiat Oncol Biol Phys 21(2):293-298, 1991;

www.ago-online.de
2 Reddy JP. Int J Radiat Oncol Biol Phys 80(5):1453-7, 201;
3 Karabali-Dalamaga S et al. Br Med J 2(6139):730-733,1978;
4 Andersson Y, et al. Br J Surg 99(2):226-31,2012
 Loco-regional
Recurrence Staging
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast Examinations before treatment

Version 2020.01
 Tissue biopsy 5 D ++
 Re-assessment of ER, PgR, HER2 3b B ++
 Complete re-staging 5 D ++
 „Liquid biopsy“ 5 D -
 18F-FDG PET-CT 2b B -

www.ago-online.de
 Loco-regional Recurrence
Risk Factors at first diagnosis
Increased risk for loco-regional recurrence Oxford LoE
© AGO e. V. Clinical factors:
in der DGGG e.V.
sowie
 Young age 1a
in der DKG e.V.  First diagnosis with clinical symptoms 2b
 Obesity (Body mass index) 1a
Guidelines Breast
Version 2020.01  Non-alcoholic fatty disease of the liver 2b
 Persistent lymphopenia after systemic therapy 4
Tumor related factors:
 Inflammatory breast cancer 2b
 Multizentricity 3b
 Medial tumor localisation 4
 Axillary lymph node metastasis and number of involved lymph nodes 1a
 pT > 2 cm 1a
* node-negativ 1b*
 HER 2 +++ and tripel-negativ > Luminal B-like > Luminal A-like 1a
 Grade G3 1b*
 Elevated proliferation markers: e.g. Ki-67 2b
 pPR (residual disease) after NACT 2b
 Nipple sparing mastectomy and tumor distance to nipple <1cm 2b
www.ago-online.de Other factors (nomograms/risk-scores):
 Increased risk according to nomogram (f.e. INFLUENCE) 1a
 CPS+EG Score 2c
 Adjuvant Radiotherapy Intensification Classifier (ARTIC) 2b
 Metaanalysis:
TNBC and Local Recurrence
© AGO e. V. Wang et al, Surg Oncol. 2013 Dec;22(4):247-55.
in der DGGG e.V.
sowie
in der DKG e.V.
n = 15312 BC-patients, 22 studies, Hazard-ratios
Guidelines Breast
Version 2020.01
BCT vs. ME
ILRR 0.75 (0.65-0.87)
DM 0.68 (0.60-0.76)

TNBC-subtype vs. other subtype

ILRR 1.88 (1.58-2.22)
DM 2.12 (1.72-2.62) ILRR: ipsilateral locoregional recurrence
DM: distant metastasis
TNBC-subtype vs. HER2-subtype TNBC: triple negative breast cancer
www.ago-online.de
ILRR 0.69 (0.53-0.91) BCT: breast conserving therapy
DM n.s. ME: mastectomy
 Risk factors for loco-regional recurrence after
mastectomy
© AGO
Karlsson et al. Ann Oncol 23:2852-8, 2012
e. V.
in der DGGG e.V. IBCSG-Studie, 13 randomisierte Studien n = 8106 Patienten
sowie
in der DKG e.V. Risikofaktoren für 10 J. kumulative Inzidenz …:
Guidelines Breast  15% Thoraxwand Alter < 40; ≥ 4 pos. Lymphknoten, 0-7 befallene LK
Version 2020.01
 10% supraclaviculär: ≥ 4 pos. LK
 5% axillares Rezidiv: Alter < 40; Tumorgröße unbekannt,
0-7 nicht befallene Lymphknoten
Peng G et al. Biosci Reports 39 (9), 2019
Metaanalyse, 20 Publikation, n = 11.244 Patientinnen, pT1-2 pN0 nach Mastektomie
Risiko für Lokalrezidiv
 Alter HR 1,77 (p=0,001)
 L1/V1 HR 2,23 (p<0,001)
 Grading HR 1,66 (p<0,001)
www.ago-online.de  Her2-Status HR 1,65 (p<0,027)
 Menopausenstatus HR 1,36 (p=0,015)
 Resektionsränder HR 2,56 (p=0,014)
 Loco-regional Recurrence
Prognostic / Predictive factors
Parameters of the locally recurrent tumor to define the risk for re- Oxford
© AGO e. V. recurrence LoE GR AGO
in der DGGG e.V.
sowie  Tumor size 2a B
 Multifocality
in der DKG e.V.
2a B
Guidelines Breast
Version 2020.01  Localisation 2b B
 Negative progesterone receptor 3b B
 High grade 3b C
 Omitted radiotherapy at first recurrence 3b C
 Omitted chemotherapy at first recurrence 3b C

Parameters of the locally recurrent tumor to define the risk for distant
metastasis/survival
 Early (< 2-3 yrs.) vs. late recurrence 2b B
 LVSI / Grade / ER-neg / positive margins
(if ≥ 2 factors positive) 3b B
www.ago-online.de
Predictive factors for treatment considerations
 HER2 2b B ++
 ER and PgR 2b B ++
 Clinicopathological Factors of the Recurrent Tumor to Predict
Outcome in Patients with Ipsilateral Breast Tumor Recurrence
© AGO e. V.
in der DGGG e.V. Panet-Raymond V et al. Cancer 117:2035, 2011
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.01 n = 6020 pts., retrospective cohort-study
pT1/2, N0 tumors, breast conserving treatment
269 ipsilateral breast tumor recurrences (IBTR)

Multivariate analysis:
TTR < 48 months
LVSI (of the LRR)
ER negative LR-tumor
high grade
www.ago-online.de close margins of recurrent tumor

→ if ≥ 2 factors positive ⇒ worse OS

 Ipsilateral Recurrence
after BCT Surgery
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast
Version 2020.01  Mastectomy (aim: R0) 3b B ++
 Re-BCS with tumor-free margins (R0) 2b B +/-
 Axillary intervention after prior AxDiss if cN0 4 C -
 SLNE after prior SLNE if cN0* 2a B -
 Palliative surgery in M1-situation
5 D +
(e.g. pain, ulceration, psychosocial indication)

www.ago-online.de

* If no sentinel lymph node can be identified, axillary dissection is not recommended;

no operation outside the ipsilateral axilla is recommended
 Chest-Wall Recurrence after Mastectomy /
Axillary Recurrence - Surgery
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Curative situation: R0-resection (including deeper
Version 2020.01
parts of the chest wall in selected cases: HR-positive, 2b A ++
primary N-)
 Palliative situation: Resection of deep parts of the
5 D +/-
chest wall
 Palliative surgery in M1-situation
5 D +
(e.g. pain, ulceration, psychosocial)
 SLNE after prior SLNE if cN0* 3b B -
www.ago-online.de

* If no sentinel lymph node can be identified, axillary dissection is not recommended;

no operation outside the ipsilateral axilla is recommended
 Loco-regional Recurrence after
R0-Resection Systemic Treatment
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
According to pathohistological re-evaluation of the
Version 2020.01
recurrent tumor (ER, PgR, HER2)
 Endocrine therapy in endocrine responsive tumors 2b B ++
 Chemotherapy (consider preoperative) 2b B +
 In case of HER2-positive disease, chemotherapy
5 D +
+ HER2-targeted therapy

www.ago-online.de
 Chemo Therapy by
Loco-regional Recurrence
© AGO e. V.
in der DGGG e.V.
sowie
 CALOR Trial update
in der DKG e.V.

Guidelines Breast
n = 163 (2003-2010), median follow-up of 4.9 years, all R0 resection
Version 2020.01
5-year disease-free survival: 69% (95% CI 56-79) with chemotherapy
vs. 57% (44-67) without chemotherapy (hazard ratio 0.59
[95% CI 0.35-0.99]; p=0.046): 24 (28%) patients vs. 34 (44%).
Adjuvant chemotherapy was significantly more effective in
ER negative disease (pinteraction=0.046).
Multivariate analysis: predictors of survival
chemotherapy for primary cancer (HR 3.55, p=0.03)
www.ago-online.de
interval from primary surgery (HR 0.87, p=0.05)
Wapnir IL et al. Annals of Surgical Oncology, February 2017, Volume 24, Issue 2, pp 398–406| Cite as
 Loco-regional Recurrence
Chemotherapy
 CALOR Trial update
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
ER-positive ER-negative
Version 2020.01
Endpoint CT No-CT HR (95%CI) CT No-CT HR (95%CI)
10-yr DFS 50% 59% 1.07 (0.57 – 2.00) 70% 34% 0.29 (0.13 – 0.67)

Interaction P-Value =0.013

10-yr OS 76% 66% 0.70 (0.32 – 1.55) 73% 53% 0.48 (0.19 – 1.20)

Interaction P-value =0.53

10-yr BCFI 58% 62% 0.94 (0.47 – 0.85) 70% 34% 0.29 (0.13 – 0.67)

Interaction P-value = 0.034

www.ago-online.de

Wapnir IL et al. Annals of Surgical Oncology, February 2017, Volume 24, Issue 2, pp 398–406| Cite as
 Locoregional Recurrence in Case of
R1-Resection/Inoperability – Systemic Treatment
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Version 2020.01
According to pathohistological re-evaluation of the
recurrent tumor (ER, PgR, HER2)

 Endocrine based therapy in endocrine responsive

tumors corresponding to metastatic disease 2b B ++

 Chemotherapy and targeted therapy (pre- or

postoperative) corresponding to metastatic disease 2b B ++
www.ago-online.de
 Ipsilateral Recurrence
after BCT Radiotherapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
After Re-BCS
Version 2020.01
 Whole breast irradiation
3b C ++
(in case of no prior adjuvant radiotherapy)
 Re-breast irradiation (Partial breast radiation,
brachytherapy/external beam RT, in case of prior adjuvant 2b B +
radiotherapy)
After mastectomy
 Radiation of chest wall +/- regional lymph nodes
2b B +/-
(14% involved supraclavicular metastasis)
 Radiation dose escalation (+10%) 3b C -
www.ago-online.de  Repeated irradiation (e.g. as brachytherapy)
3a C +
with hyperthermia
 Chest-Wall Recurrence after Mastectomy /
Axillary Recurrence Radiotherapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast Chest-Wall Recurrence (R0-Resection) after Mastectomy

Version 2020.01

 If no prior postmastectomy, radiotherapy

 Curative situation: 2b B +
irradiation of the chest wall +/- regional lymph nodes

 Re-irradiation (chest wall + hyperthermia) 1b B +/-

Axillary Recurrence
 Irradiation of axilla after R0-surgery
 No prior adjuvant irradiation of the axilla 3b C +
www.ago-online.de  Adjuvant irradiation of the axilla 5 D +/-
 Loco-Regional Recurrence
Treatment Options in Non Curative Cases
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
Version 2020.01
 Concomitant radio-chemotherapy 3b C +
 Hyperthermia (in centers listed on DKG website)
 In combination with radiotherapy 1b B +
 In combination with chemotherapy 4 C +/-
 Intra-arterial chemotherapy 4 C +/-
 Photodynamic therapy 4 C +/-
 Electrochemotherapy 3b C +/-
www.ago-online.de
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Endocrine and targeted Therapy
of Metastatic Breast Cancer
 Endocrine Therapy of
Metastatic Breast Cancer
© AGO

▪ Versions 2002–2019:
e. V.
in der DGGG e.V.
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in der DKG e.V.

Guidelines Breast
Albert / Bischoff / Dall / Fasching / Fersis / Friedrich / Gerber /
Version 2020.1
Huober / Janni / Jonat / Kaufmann / Kolberg-Liedtke / Loibl /
Lüftner / Lück / von Minckwitz / Möbus / Müller / Mundhenke /
Nitz / Schmidt / Schneeweiß / Schütz / Stickeler / Thill

▪ Version 2020:
Thill / Untch

www.ago-online.de
 Endocrine Therapy in
Metastatic Breast Cancer
© AGO e. V.
in der DGGG e.V. Indication
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Oxford LoE: 1a GR: A AGO: ++

Endocrine-based therapy is first line treatment in patients with metastatic

breast cancer and positive (or unknown) hormone receptor (HR) status.

Exception: imminent organ failure

Caveat: HR may change during the course of disease.
Histology of recurrent site should be obtained whenever possible

www.ago-online.de
 Comparison ER/PR and HER2
Metastasis vs. Primary Tumor (N=5.521)
© AGO e. V. Meta-analysis based on 39 (mostly retrospective) analyses, exclusively
in der DGGG e.V.
sowie comparing primary tumor and metastasis (no lymph nodes):
in der DKG e.V.

Guidelines Breast Pooled discordance proportions were:

Version 2020.1
 19,3% (95% CI 1⁄4 15.8% to 23.4%) for ER
 30,9% (95% CI1⁄4 26.6% to 35.6%) for PR
 10,3% (95% CI 1⁄4 7.8% to 13.6%) for HER2
Pooled proportions of tumors shifting from positive to negative
 22.5% (95% CI = 16.4% to 30.0%) for ER
 49.4% (95% CI = 40.5% to 58.2%) for PR
 21.3% (95% CI = 14.3% to 30.5%)) for HER2
Pooled proportions of tumors shifting from negative to positive
www.ago-online.de  21.5% (95% CI = 18.1% to 25.5%) for ER
 15.9% (95% CI = 11.3% to 22.0%) for PR
 9.5% (95% CI = 7.4% to 12.1%) for HER2
 Endocrine Therapy
General Considerations
 Within all lines of treatment, treatment options should consider prior
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. endocrine therapies, age and comorbidities as well as the respective
Guidelines Breast
Version 2020.1
approval status.
 Premenopausal patients treated with GnRH analogues or after
ovarectomy can be treated like postmenopausal patients.

www.ago-online.de
 Endocrine Therapy in Premenopausal Patients
with HER2-Negative Metastatic Breast Cancer
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 GnRH-A + Fulvestrant + Palbociclib 2b B ++
Version 2020.1
 GnRH-A + AI + Palbociclib* 3ba C ++
 GnRH-A + AI + Ribociclib 1b B ++
 GnRH-A + Fulvestrant + Abemaciclib 2b B ++
 GnRH-A + Tamoxifen (vs. OFS or Tam) 1a A ++
 Ovarial function suppression (OFS) 2b B +
 Tamoxifen 2b B +
 GnRH-A + AI (first + second line) 2b B +
 GnRH-A + Fulvestrant 1b B +
www.ago-online.de  Aromatase inhibitors without OFS 3 D --
* Extrapolated from data of postmenopausal patients (with AI)
 Endocrine Mono-Therapy in Postmenopausal Patients
with HER2-Negative Metastatic Breast Cancer
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Fulvestrant 500 mg 1b B +
Version 2020.1
 Aromatase inhibitor* 1a A +
 Tamoxifen 1a A +
 Fulvestrant 250 mg + Anastrozole 1b B +/-
 Repeat prior treatments 5 D +/-

www.ago-online.de

* There is no evidence for superiority of a single aromatase inhibitor. As everolimus plus

exemestane is indicated after AI treatment, a non-steroidal AI should be used in first line.
 Endocrine-Based Treatment Options for Postmenopausal
Patients with HER2-Negative Metastatic Breast Cancer
© AGO e. V. Oxford
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.
 CDK4/6-Inhibitor (Abemaciclib, Palbociclib, Ribociclib)
Guidelines Breast
Version 2020.1  + non-steroidal AI 1b B ++
 + Fulvestrant 1b B ++
 Abemaciclib Monotherapie 3 C +/-
 Alpelisib + Fulvestrant (PIK3CA mutated) 1b B +
 Everolimus
 + Exemestane 1b A +
 + Tamoxifen 2b B +
 + Letrozole 2b B +/-
 + Fulvestrant 2ba B +
www.ago-online.de
 CDK4/6i beyond progression 5 D -
 CDK4/6i switch based on toxicity 5 D +/-
 Endocrine Therapy in Postmenopausal HER2-Negative
Metastatic Breast Cancer in Combination with Bevacizumab
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Maintenance bevacizumab plus endocrine
Version 2020.1
therapy after remission with chemotherapy and 1b B +/-
bevacizumab
 Bevacizumab plus endocrine treatment as first
line therapy for advanced disease 1b B +/-

www.ago-online.de
 PARP Inhibitors in Patients with HER2-negative,
gBRCA-Mutant, Metastatic Breast Cancer
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast  Olaparib 1b A ++
Version 2020.1

Oxford
LoE GR AGO
 Talazoparib 1b B +

www.ago-online.de
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
HER2-Positive and
HR-Positive Metastatic
Breast Cancer
 Endocrine Therapy in Postmenopausal HER2-
Positive Metastatic Breast Cancer Patients
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO

in der DKG e.V.
Anastrozole plus trastuzumab 1b B +/-
Guidelines Breast
Version 2020.1  Letrozole plus trastuzumab 2b B +/-
 Letrozole plus lapatinib 1b B +/-
 Fulvestrant plus lapatinib 1b B +/-
 Abemaciclib plus fulvestrant plus trastuzumab (after
2ba B +/-
T-DM1)
 Aromatase inhibitors plus trastuzumab /
2b B +/-
pertuzumab*
Poor efficacy of endocrine therapy alone.
www.ago-online.de Consider induction chemotherapy + anti-HER2-therapy (followed by
endocrine + anti-HER2-therapy as maintenance therapy)!
* Study participation recommended
 Concomitant or Sequential
Endocrine-Cytostatic Treatment
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Concomitant endocrine-cytotoxic treatment 1b A -
Version 2020.1  May increase response rate and progression
free interval but not overall survival
 May increase toxicity
 Endocrine maintenance therapy after
chemotherapy +/- anti-HER2 therapy-induced 2b B +
response +/- anti HER2 therapy
 Increases progression free interval

www.ago-online.de
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Chemotherapy With or Without

Guidelines Breast
Version 2020.1

Targeted Drugs* in Metastatic

Breast Cancer

* Substances without published evidence based on at least one phase III/II b trial were omitted
 Chemotherapy ± Targeted Drugs in
Metastatic Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  Versions 2002–2019:
Guidelines Breast
Version 2020.1 Bischoff / Dall / Fehm / Fersis / Friedrichs / Harbeck /
Jackisch / Janni / Kolberg-Liedtke/ Lux / von Minckwitz / Möbus /
Müller / Rody / Schaller / Scharl / Schmutzler / Schneeweiss / Schütz /
Stickeler / Thill / Thomssen / Untch

 Version 2020:
Lüftner / Albert

www.ago-online.de
 Metastatic Breast Cancer
Disease-Free and Overall Survival
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE
in der DKG e.V.

Guidelines Breast
 In MBC, an increase in survival over time has been shown in some
Version 2020.1
retrospective analyses 2a

 Multiple lines of sequential therapy are beneficial

(at least same efficacy, less toxicity) 1b

 Targeted drugs in combination with chemotherapy can induce

1b
substantial survival benefits

www.ago-online.de
 Metastatic Breast Cancer
Endocrine Resistance
© AGO e. V.
in der DGGG e.V.
sowie
Primary endocrine resistance:
in der DKG e.V.  Relapse within 2 years of adjuvant endocrine treatment (ET)
Guidelines Breast
Version 2020.1  Progressive disease within first 6 months of first-line ET for MBC

Secondary endocrine resistance:

 Relapse while on adjuvant ET but after the first 2 years or a relapse within
12 months after completing adjuvant ET
 PD ≥ 6 months after initiation of ET for MBC

www.ago-online.de
 Metastatic Breast Cancer
Predictive Factors
© AGO e. V.
Oxford
in der DGGG e.V.
sowie Therapy Factor LoE GR AGO
in der DKG e.V.

Guidelines Breast
Version 2020.1 Endocrine therapy ER / PR (primary tumor, metastasis) 1a A ++
prior response 2b B ++
Chemotherapy prior response 1b A ++
Anti-HER2-drugs HER2 (primary tumor, better in
metastasis) 1a A ++
Checkpoint-inhibitors
PD-L1 IC# positive in TNBC 1b B +
(Atezolizumab)
PARP inhibitors gBRCA 1/2 mutation 1a A ++
Bone modifying drugs bone metastasis 1a A ++
www.ago-online.de
Any therapy CTC monitoring 1b A +*
* Within clinical trials (for additional potential biological factors see chapter„Predictive factors“)
(# ≥ 1% on immune cells (IC) (for more information see chapter “ pathology”)
 Metastatic Breast Cancer
Treatment Rationale
© AGO e. V.
in der DGGG e.V.
Oxford LoE: 1b GR: A AGO: ++
sowie
in der DKG e.V.
 Mono-Chemotherapy:
Guidelines Breast
Version 2020.1
 Favorable therapeutic index
 Indicated in case of
 Slow, not life-threatening progression
 Insensitivity to or progression during endocrine therapy

 Poly-Chemotherapy:
 Unfavorable therapeutic index
 Indicated to achieve rapid remission in the case of
 Extensive symptoms
 Visceral crisis (ABC-4 definition)
 Survival benefit in comparison to sequential single-agent therapies with the same
www.ago-online.de compounds not proven

Therapeutic index evaluates overall efficacy, toxicity, and impact on quality of life
 Definition of visceral crisis (ABC 4)
© AGO e. V.  Visceral crisis is defined as severe organ dysfunction as assessed by signs
in der DGGG e.V.
sowie and symptoms, laboratory studies and rapid progression of disease.
in der DKG e.V.

Guidelines Breast
Visceral crisis is not the mere presence of visceral metastases but implies
Version 2020.1
important visceral compromise leading to a clinical indica-tion for a more
rapidly efficacious therapy, particularly since another treatment option at
progression will probably not be possible.

www.ago-online.de
 Metastatic Breast Cancer
Cytotoxic and Targeted Therapy
© AGO e. V.
in der DGGG e.V.
GR: A AGO: ++
sowie
in der DKG e.V.
 Evaluate compliance before and during therapy (especially in patients of
Guidelines Breast
Version 2020.1 older age, with reduced performance status, or significant co-morbidities
and secondary primaries)
 Assess subjective and objective toxicities, symptoms, and performance as
well as quality of life (QoL) status repeatedly
 Use dosages according to published protocols
 Assess tumor burden at baseline and approx. every 2 months, i.e. every 2-4
cycles. In slowly growing disease, longer intervals are acceptable.

www.ago-online.de
 Metastatic Breast Cancer
Duration of Cytotoxic Therapy
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. Oxford
Guidelines Breast
Version 2020.1
LoE GR AGO
 As long as therapeutic index remains positive 1a A ++
 Treatment until progression 2b B +
 Treatment until best response 2b B +/-
 Change to alternative regimen before progression 2b B +/-

 Stop therapy in case of 1c A ++

 Progression
 Non tolerable toxicity
www.ago-online.de
 Chemotherapy for MBC – General Considerations:
Drug Selection
© AGO e. V. AGO: ++
in der DGGG e.V.
sowie
in der DKG e.V.
 Participation in clinical trials is highly recommended
Guidelines Breast
Version 2020.1
 The choice of systemic therapy depends on:
 ER / PgR, HER2, PD-L1 status, gBRCA status, , PIK3CA, e.g. MSI, NTRK (clinical
actionability of molecular targets)
 Prior therapies (and their toxicities)
 Disease-free interval after end of adjuvant treatment
 Progression-free interval achieved by the previous line of therapy
 Disease aggressiveness and localization of metastases
 Estimated life expectancy
 Co-morbidities (including organ dysfunction)
www.ago-online.de
 Patient preferences and expectations
 MBC HER2-negative/HR-positive
1st-Line Therapy Chemotherapy*
© AGO e. V. Oxford
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.
 Monotherapy:
Guidelines Breast
Version 2020.1  Paclitaxel (q1w), Docetaxel (q3w) 1a A ++
 Doxorubicin, epirubicin,
Peg-liposomal doxorubicin (Alip) 1b A ++
 Vinorelbine 3b B +
 Capecitabine 2b B +
 Nab-paclitaxel 2b B +
 Polychemotherapy:
 A+T 1b A ++
 Paclitaxel + capecitabine 2b B +
 Docetaxel + capecitabine after adj. A 1b A +
 T + gemcitabine after adj. A 2b B ++
www.ago-online.de
 A + C or Alip + C 1b B ++

* In ER pos. patients only if endocrine therapy is not indicated or should be discontinued

 MBC HER2-negative/HR-pos:
Cytotoxic Therapy after Anthracycline Treatment*
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Paclitaxel q1w 1a A ++
Version 2020.1  Docetaxel q3w 1a A ++
 Capecitabine 2b B ++
 Nab-paclitaxel 2b B ++
 Peg-liposomal doxorubicin 2b B +
 Eribulin 1b B +
 Vinorelbine 2b B +
 Docetaxel + Peg-liposomal doxorubicin 1b B +/-

www.ago-online.de

* Independent whether anthracyclines were used in adjuvant or 1 st line metastatic situation

 MBC HER2-negative/HR-positive: Cytotoxic Therapy after
adjuvant Taxane and Anthracycline Treatment
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
Version 2020.1  Capecitabine 2b B ++
 Eribulin 1b B ++
 Vinorelbine 2b B ++
 (Peg)-liposomal Doxorubicin 2b B +
 Taxane re-challenge* 2b B +
 Anthracycline re-challenge* 3b C +
 Metronomic therapy (e.g. cyclophos. + MTX) 2b B +
 Gemcitabine + Cisplatin / Carboplatin 2b B +/-
www.ago-online.de
 Gemcitabine + Capecitabine 2b B +/-
 Gemcitabine + Vinorelbine 1b B -
* At least one year disese-free after adjuvant treatment
 Triple Negative MBC
Independent of gBRCA 1/2 Mutation
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Version 2020.1

 Atezolizumab plus nab-paclitaxel first-line, if PD-L1 IC

positive# 1b B +
 Carboplatin (vs. Docetaxel) 1ba B +/-
 Gemcitabine/Cisplatin (vs. Gem/Pac) 1b A +
 Nab-Paclitaxel/Carboplatin (vs. Carbo/Gem) 2ba B +
 Bevacizumab added to first line cytotoxic therapy 1b B +

www.ago-online.de

(# ≥ 1% on immune cells (IC) (for more information see chapter “ pathology”)

 MBC with gBRCA 1/2 Mutation
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Standard of care i.e.; gBRCA 1/2-negative disease ++
Version 2020.1  Carboplatin (vs. Docetaxel) (if Platinum-naive) 1b B +

 PARP inhibitors
 HER2-negative
 Olaparib 1b A ++
 Talazoparib 1b B +

www.ago-online.de
 Metastatic Breast Cancer
Bevacizumab Treatment in HER2-neg. Disease
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 1st line in combination with:
Version 2020.1  Paclitaxel (q1w) 1b B +
 Capecitabine 1b B +
 Anthracyclines 2b B +/-
 Nab-Pac 2b B +/-
 Docetaxel (q3w) 1b B +/-
 Cap+Bev as maintenance after Doc+Bev 1ba B +/-
 2nd line in combination with:
 Taxanes 1b B +/-
 Capecitabine 1b B +/-
www.ago-online.de  Gemcitabine or vinorelbine 1b B -
 2nd line as treatment through multiple lines 1b B -
 First Line Therapy in HER2-Positive MBC
© AGO e. V. Oxford
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.
 Docetaxel + trastuzumab + pertuzumab 1b A ++
Guidelines Breast
Version 2020.1
 Paclitaxel (weekly) + trastuzumab + pertuzumab 2b B ++
 Nab-Paclitaxel + trastuzumab + pertuzumab 3ba C +
 Vinorelbine + Trastuzumab + Pertuzumab 3b B +
 T-DM 1 (relapse within 6 months after taxane and
trastuzumab-pretreatment) 2b B +
 1st line chemotherapy* + trastuzumab 1b B +
 Trastuzumab mono 2b B +/-
 Taxanes + lapatinib 1b B +/-
 Taxanes + trastuzumab + everolimus 1b B -
 Trastuzumab + aromatase inhibitors (if ER+) 2b B +/-**
www.ago-online.de  Lapatinib + aromatase inhibitors (if ER+) 2b B +/-**

* Taxanes; vinorelbine; paclitaxel/carboplatin; capecitabine/docetaxel

** see chapter Endocrine +/- targeted
 2nd line Therapy in HER2-positive MBC
(Trastuzumab-Pretreated)
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 T-DM 1 1b A ++
Version 2020.1  TBP: 2nd line chemotherapy + trastuzumab 2b B +
 BP: 2nd line chemotherapy + trastuzumab
5 D +/-
+ pertuzumab
 Any other 2nd line chemotherapy* + trastuzumab
5 D +/-
+ pertuzumab)
 Taxane + trastuzumab + pertuzumab 5 D +
 Capecitabine + trastuzumab + pertuzumab 1ba B +/-
 Capecitabine + lapatinib 1b B +
 Trastuzumab + lapatinib (HR-neg. disease) 2b B +
www.ago-online.de

* e.g. vinorelbine; taxane/carboplatin; capecitabine/docetaxel (toxicity!)

 Further Lines of Therapy in
HER2-Positive Metastatic Breast Cancer
Oxford
© AGO e. V.
in der DGGG e.V. LoE GR AGO
sowie
in der DKG e.V.  Pretreatment with Trastuzumab
Guidelines Breast  T-DM 1 1b A ++
Version 2020.1  Capecitabine + lapatinib 1b B +
 Vinorelbine + lapatinib 2b B +/-
 Trastuzumab + lapatinib (HR-neg. disease) 2b B +
 Chemotherapy + trastuzumab („treatment beyond progression“) 2b B +
 Trastuzumab + pertuzumab 2b B +
 Vinorelbine + trastuzumab + everolimus
1b B +/-
(trastuzumab resistant, taxane pretreated)
 Abemaciclib + Trastuzumab + Fulvestrant 2ba B +/-
 Data for patients pretreated with trastuzumab and pertuzumab or for treatment beyond
progression with pertuzumab are not available.
www.ago-online.de  Trastuzumab-Deruxtecan 2b B +/-
 Experimental anti-HER2-regimen 5 D +
 For patients pretreated with trastuzumab and pertuzumab treatment 5 D +
according to the recommendations above.
 Lapatinib in HER2-positive
Metastatic Breast Cancer
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast
Version 2020.1
 In combination with
 Trastuzumab for heavily pre-treated pts (HR-negative) 2b B +
 Paclitaxel in 1st line 1b B +/-
 Capecitabine in > 2nd line 1b B +
 Vinorelbine 2b B +/-
 AI in ER-positive disease 2b B +/-
 In patients with brain metastasis (radioresistance) in
2b B +/-
combination with capecitabine

www.ago-online.de
 Immunodiagnostic Tests
and Immunotherapy
Oxford
© AGO e. V.
in der DGGG e.V.
LoE GR AGO
sowie
in der DKG e.V.  Immunodiagnostic tests:
Guidelines Breast  Tumor tissue: PD-L1 IC status in TNBC 1b B +
Version 2020.1
 Blood: Immunological parameters 5 D --
 Systemic immunotherapy:
 Atezolizumab and nab-paclitaxel in PD-L1 IC positive TNBC first line 1b B +
 Other immuntherapies in clinical trials, only
 HER2-vaccination in high-risk population
 Immunomodulation (e.g. addition of Nov-2 to AC –T)
 Dendritic cell intradermal vaccination
 Active vaccination
 Passive vaccination
www.ago-online.de
 Therapy with oncolytic viruses
 Cytokines
 Local immunotherapy
 Imiquimod topically for skin metastasis 4 C +/-
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Osteooncology and
Bone Health

www.ago-online.de
 Osteooncology and
Bone Health
© AGO e. V.
in der DGGG e.V.
sowie  Versions 2002–2019:
in der DKG e.V.

Guidelines Breast
Bischoff / Böhme / Brunnert / Dall / Diel / Fehm /
Version 2020.1
Fersis / Friedrich/ Friedrichs / Hanf / Huober /
Jackisch / Janni / Kolberg-Liedtke / Lux / Maas / Nitz / Oberhoff /
Schaller / Scharl / Schütz / Seegenschmiedt / Solomayer / Souchon

 Version 2020:
Solbach / Solomayer

www.ago-online.de
 Bisphosphonates in Metastatic Breast Cancer
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Hypercalcemia 1a A ++
Version 2020.1
 Reduction of skeletal events (complications) 1a A ++
 Reduction of bone pain 1a A ++
 Increasing bone pain-free survival 1a A ++
 Treatment beyond osseous progression 5 D ++
 Use of bone resorption marker for therapy
monitoring 5 D -
 Bisphosphonates used alone for pain control 5 D -
www.ago-online.de
 Denosumab in
Metastatic Breast Cancer
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Reduction of hypercalcemia 1a A ++
Version 2020.1
 Reduction of skeletal complications 1a A ++
 Reduction of bone pain 1a A ++
 Increasing bone pain-free survival 1b A ++
 Treatment beyond progression 5 D +
 Progression while on bisphosphonates 4 C +/-
 Use of bone resorption markers for therapy
monitoring 5 D -
 Denosumab alone for pain control 5 D -
www.ago-online.de
 Longer-Interval vs Standard Dosing
of Zoledronic Acid

© AGO e. V. 1 CALGB
in der DGGG e.V.
70604 trial: n=1822 patients with metastatic breast cancer, metastatic prostate cancer,
sowie
in der DKG e.V.
or multiple myeloma, 795 completed the study
Guidelines Breast SRE after 2 yrs: 29.5 % zoledronic acid every 4 weeks
Version 2020.1
28.6 % zoledronic acid every 12 weeks

 2 Optimze-2-trial: n=460 with metastatic breast cancer

SRE after 1 year3: 22.0% zoledronic acid every 4 weeks
23.2% zoledronic acid every 12 weeks

1 Himelstein et al. Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events
www.ago-online.de
in Patients With Bone Metastases: A Randomized Clinical Trial. JAMA 317(1):48-58. 2017
2 Horobagyi GN et al. Continued Treatment Effect of Zoledronic Acid Dosing Every 12 vs 4 Weeks in Women With
Breast Cancer Metastatic to Bone: The OPTIMIZE-2 Randomized Clinical Trial. JAMA Oncol 3(7):906-912, 2017
3 Patients eligible for this trial had prior exposure to zoledronate or pamidronate for approx. 1 year or more
 Bone Modifying Agents for the
Therapy of Bone Metastases
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Clodronate PO 1600 mg daily 1a A ++
Version 2020.1
 Clodronate IV 1500 mg q3w / q4w 1a A ++
 Pamidronate IV 90 mg q3w / q4w 1a A ++
 Ibandronate IV 6 mg q3w / q4w 1a A ++
 Ibandronate PO 50 mg daily 1a A ++
 Zoledronate IV 4 mg
 q4w 1a A +
 q12w 1a A ++
 Denosumab 120 mg s.c. q4w 1a A ++
 Denosumab 120 mg s.c. q12w 4 C -
www.ago-online.de
 Other dosing or schedules, e.g. derived from
adjuvant studies or therapy of osteoporosis 5 D --
 Skeletal Metastases
Treatment with Radionuclids
© AGO e. V.
Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast  Tumor progression after standard treatment of

Version 2020.1
multiple / disseminated metastases and intolerable 1b B +
bone pain
 186Rhenium-hydroxyethyliden-diphosphonat 2b B +
 153Samarium 1b B +
 89Strontium 1b B +
 223Radium 2b C +
 177Lu-EDTMP 2b C +
 188 Rhenium-HEDP 1b B +

www.ago-online.de
Cave: the potential benefits should be weighed against the risk of
myelosuppression with pancytopenia
 Metastatic Bone Disease of the Spine
© AGO e. V. Indications for surgery
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Oxford LoE: 2b GR: C AGO: ++
Version 2020.1

 Spinal cord compression

 With progressive neurological symptoms
 With pathological fractures

 Instability of the spine

 Lesions in pre-irradiated parts of the spine

www.ago-online.de
 Bone Metastases Acute Spinal
Cord Compression / Paraplegia
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Decompression surgery, reduction of tumor volume,
Version 2020.1
stabilization surgery (< 24 h) and irradiation of the 2b C ++
spine (RT)
 Irradiation of the spine (< 24 h) +/- steroids 3b C ++
 Immediate start of treatment 1c D ++

Clinical trials have included patients with different tumor entities!

www.ago-online.de
 Surgery for Bone Metastases
Technical Aspects
© AGO e. V. Spine and limbs
in der DGGG e.V.
sowie
in der DKG e.V.
Oxford LoE: 3b GR: C AGO: +
Guidelines Breast
Version 2020.1
 Marrow splints
 Plate osteosynthesis
 Compound osteosynthesis (replacement by PMMA and osteosynthesis)
 Vertebral replacement by titanspacer
 Tumor-Endoprothesis
 Vertebroplasty / Kyphoplasty +/- thermoablation of the tumor
 Kypho-IORT (in studies only)*
www.ago-online.de
 Resection of involved bone in oligometastatic disease
(sternum, ribs, vertebrectomy and replacement with spondylodesis)
* Study participation recommended
 Metastatic Bone Disease:
Radiotherapy (RT)
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
Bone metastases
Version 2020.1
 With fracture risk 1a B ++
 With functional impairment 1a B ++
 With bone pain 1a B ++
Single dose RT = fractionated RT 2a B ++
 With neuropathic bone pain 1b B ++
 Asymptomatic isolated bone metastasis 5 D +/-
 Reduction of radiation induced pain flare by
dexamethasone 1b B +
 Radiotherapy in combination with hyperthermia 2b B +/-
www.ago-online.de

Limited studies included breast cancer patients!

 Metastatic Bone Disease
Recurrent Bone Pain after RT
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
Version 2020.1
Recurrent bone pain in pre-irradiated parts of skeleton
 Single dose RT * 3b C ++
 Fractionated RT * 3b C ++
 Radionuclide therapy 3b C +
 Magnetic resonance-guided focused ultrasound 1b B +
 Radiofrequency ablation 4 C +
 Cryoablation 4 C +

www.ago-online.de

* Dose and fractionation depending on location, interval from first RT,

and dose and fractionation of first radiotherapy.
 Side-Effects and Toxicity –
Bisphosphonates (BP) and Denosumab (Db)
© AGO e. V. LoE
 Renal function deterioration due to IV-aminobisphosphonates
in der DGGG e.V.
sowie 1b
in der DKG e.V.
 Osteonecrosis of the jaw (ONJ) mostly under IV-BP and
Guidelines Breast 1b
Version 2020.1
denosumab therapy (1.3 % / 1.8 %)
 Association with (simultaneous) anti-angiogenetic therapies 3b
 Severe hypocalcemia (Dmab > BPs) 1b
 Acute Phase Reaction (IV Amino-BPs, Dmab) 10–30 % 1b
 Gastrointestinal side effects (oral BPs) 2–10 % 1b
 Atypical femur fractures
2b
(absolute risk of 11 per 10,000 person years of BP use)
 Extremely rare: Uveitis / Scleritis under BP treatment 4
www.ago-online.de
 Frequent side effects under treatment with
BPs / Denosumab
© AGO e. V. Osteo
in der DGGG e.V. Acute
sowie Kidney Upper necrosis
in der DKG e.V. Drug phase- Diarrhea
Tox. GI of the
reaction
Guidelines Breast
Version 2020.1
jaw
Clodronate 1500 i.v. 0 + 0 0 0 Non-Amino.
Clodronate 1600 p.o. 0 0 + + 0 Non-Amino.
Ibandronate 50 mg p.o. 0 0 + 0 0 Aminobisp.
Ibandronate 6 mg i.v. + 0 0 0 + Aminobisp.
Zoledronate 4 mg i.v. Aminobisp.
q4w oder q12w + + 0 0 +
Pamidronate 90 mg i.v. + + 0 0 + Aminobisp.
Zoledronate 4 mg i.v. q6m + 0 0 0 0 Aminobisp.
www.ago-online.de
Denosumab 120 mg sc q4w 0 0 0 + +
Cave: Hypocalcemia under antiresorptive therapy in pts with bone metastases!
 Recommendations for Prevention of
Osteonecrosis of the Jaw (ONJ)
© AGO e. V. Oxford LoE: 2a GR: A AGO: ++
in der DGGG e.V.
sowie
in der DKG e.V.
 During bisphosphonate or denosumab treatment, avoid any elective dental
Guidelines Breast
Version 2020.1 procedures involving jaw bone manipulations during treatment with
bisphosphonates or denosumab (LoE 2a, recommendation grade A)
 Optimize dental status before start of bisphosphonate or denosumab treatment
(LoE 2a, recommendation grade A)
 Inform patients about ONJ risk and educate about early symptom reporting
 In case of high risk for ONJ, use oral bisphosphonate
 Good oral hygiene, limiting of alcohol intake and stopping smoking should be
recommended
 In adjuvant bisphosphonate therapy, ONJ was rare (<1%)
www.ago-online.de

ASORS Evaluation
https://www.onkosupport.de/asors/content/e4126/e1743/e1861/e1862/e4628/LaufzettelAGSMOFarbefinal.pdf
 Adjuvant Bone Targeted Therapy for
Improvement of Prognosis
© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V. LoE GR AGO
Guidelines Breast
Version 2020.1
 Clodronate (oral)
 Postmenopausal patients 1a A +
 Premenopausal patients 1a B +/-
 Aminobisphosphonate (iv or oral)
 Postmenopausal patients 1a A +
 Premenopausal patients 1a B +/-
 Denosumab (6 x 120 mg/3–4w + 14 x 120 mg/3m)
 Postmenopausal patients Stage II and III 1b B -

www.ago-online.de
 Denosumab (60 mg s.c. q6m)
 Postmenopausal patients undergoing AI therapy 1b B +/-
 Dosage of Adjuvant Bisphosphonates
for Improvement of Survival
© AGO e. V.  Non-Aminobisphosphonates:
in der DGGG e.V.
sowie  Clodronat po 1600 mg/d (Bonefos / Clodronic acid)
in der DKG e.V.

Guidelines Breast
 Clodronat po 1040 mg/d (Ostac / Clodronic acid)
Version 2020.1

 Aminobisphosphonates:
 Zoledronat iv 4 mg/6 m (Zometa / Zoledronic acid)
 Ibandronat po 50 mg/d (Bondronat / Ibandronic acid)
 Pamidronat po (orally not available in most countries)
 Risedronat po 35 mg/w*(Actonel / Risedronic acid)
 Alendronat po 70 mg/w (Fosamax / Alendronic acid)
 Optimal duration yet to be defined; in adjuvant studies duration of BP treatment varied
from 2–5 years
www.ago-online.de

Aminobisphosphonates include:
Zoledronic acid (65 %), oral ibandronate (24 %), oral pamidronate (8 %),
oral risedronate (2 %), oral alendronate (1 %) (data from EBCTCG-metaanalysis)
 Reduction in bone density of individual agents
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V. Ovarian ablation after Chemo 7,6
Guidelines Breast
Version 2020.1
AI + GnRH in premenopausal 7

AI in postmenopausal 3

Postmenopausal women 1

Normal 0,5
0 1 2 3 4 5 6 7 8

www.ago-online.de
BMD (%) reduction within 1 yr

(1) Kanis JA Osteoporosis 22, 1997, (2) Gnant M SABCS 2004, (3) Shapiro CL,
JCO 19:3305, 2001
 Risk of osteoporosis and tamoxifen
(fracture risk)
© AGO e. V.
in der DGGG e.V.
sowie
premenopausal postmenopausal
in der DKG e.V.

Guidelines Breast
Version 2020.1

www.ago-online.de

Kyvernitakis et al Osteoporosis Int 2018

 Therapy and Prevention of Tumor
Therapy-Induced Bone Loss / Osteoporosis
Oxford
© AGO e. V.
in der DGGG e.V.
LoE GR AGO
sowie
in der DKG e.V.  Bisphosphonates
Guidelines Breast  Therapy 1b B ++
Version 2020.1
 Prevention (2–5 yrs) 1b A +
 after discontinuation of Denosumab (time-limited) 3c C +
 Denosumab
 Therapy 1b B ++
 Prevention (up to max. 3yrs) 1b A +
 Hormone replacement therapy 5 D -
 Clinical risk assessment for osteoporosis at baseline
according to DVO S3 - guidelines ++
 DXA-Scan at baseline in pts with endocrine therapy and/or
5 D +
premature menopause
www.ago-online.de
 Antiresorptive therapy according to according to DVO S3 - ++
guidelines
 Repeat DXA-scan based on risk 5 D +
 Therapy and Prevention of Tumor Therapy-
Induced Bone Loss / Osteoporosis
© AGO e. V.
in der DGGG e.V.
Further recommendations (based on DVO-guidelines for
sowie
in der DKG e.V. treatment, diagnosis and prevention of osteoporosis)* Oxford
Guidelines Breast
Version 2020.1
LoE GR AGO
 Physical activity 4 C ++
 Avoiding immobilisation 4 C ++
 Calcium (1000–1500 mg/d)** 4 C ++
 Vitamine D3 suppl. (800–2000 U/d or 20,000 U/w) 4 C ++
 Stop smoking, reduction of alcohol 2b B ++
 Avoiding BMI < 20 mg/m2 3b C ++
 Bisphosphonates after discontinuation of Denosumab
(time-limited) 3c C +
www.ago-online.de
 Drugs approved for osteoporosis treatment
in adults (see next slide)
* http://www.dv-osteologie.org/dvo_leitlinien/dvo-leitlinie-2014; revised version expected in 2018
** if nutritional supply is insufficient, (in combination with Vit D3 only)
 Effect of Denosumab Discontinuation
© AGO e. V.
in der DGGG e.V. FREEDOM / FREEDOM Extension Trial
sowie
in der DKG e.V.

Guidelines Breast
N=1001, ≥ 2 dose of Denosumab or placebo, follow up ≤ 7 months after
Version 2020.1 discontinuation treatment
Vertebral fracture rate per 100 participant year :
1.2 during denosumab therapy
7.1 after denosumab therapy
8.5 placebo
Non vertebral fracture rate per 100 participant year:
2.8 after denosumab vs. 3.8 placebo (n.s.)
www.ago-online.de Multiple vertebral fracture (% of all vertebral fractures):
60.7% after denosumab therapy vs. 38.7% placebo; p=0.049
Cummings SR et al. J Bone Miner Res 2017
 Medical Treatment of Osteoporosis
© AGO e. V.
Oxford
in der DGGG e.V.
sowie LoE GR AGO

in der DKG e.V.
Alendronate 70 mg po/w* 1b B ++
Guidelines Breast
Version 2020.1  Denosumab 60 mg sc/6m* 1b B ++
 Ibandronate 150 mg po/m* 1b B ++
 Ibandronat e 3 mg iv/3 m 1b B ++
 Parathyroid hormone (1-84) 100 µg sc/d 1b B +
 Raloxifene 60 mg po/d (improves spine only) 1b B +/-
 Risedronate 35 mg po/w* 1b B ++
 Strontium ranelate 2 g po/d** 1b B +
 Teriparatide (1-34) 20 µg sc/d 1b B +
www.ago-online.de
 Zoledronate 5 mg iv/12 m* 1b B ++
* Drugs tested in clinical studies with breast cancer patients and tumor therapy-induced osteoporosis
** Elevated risk of myocardial infarction. Substance restricted to postmenopausal pats. with severe osteoporosis
and high fracture risk.
 https://www.dv-
osteologie.org/uploads/Leitlinie%202017/DVO%20Leitlinie_
Kitteltaschenversion_16012020.pdf
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

www.ago-online.de

Photo Courtesy of the DVO

 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Specific Sites of Metastases

www.ago-online.de
 Specific Sites Of Metastases
Local Approaches to Metastatic Disease
 Versions 2002–2019:
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
Albert / Bauerfeind / Bischoff / Böhme / Brunnert / Dall / Diel / Fehm /
Guidelines Breast
Version 2020.1 Fersis / Friedrich / Friedrichs / Gerber / Hanf / Janni / Kolberg-Liedtke /
Kreipe / Lück / Lux / Maass / Oberhoff / Rezai / Schaller / Schütz /
Seegenschmiedt / Solomayer / Souchon / Thommssen

 Version 2020:
Loibl / Rody

www.ago-online.de
 Specific Sites of Metastases

 Liver and lung metastases

© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
 Malignant pleural and pericardial effusions
Guidelines Breast
Version 2020.1  Ascites
 Bone marrow involvement
 Soft tissue metastases
 Any other organs

www.ago-online.de

See also chapters „CNS Metastases “ and „Locoregional Recurrence

(Loco-Regional Recurrence Treatment Options in Non Curative Cases)“
 General Treatment Aspects of Metastases
Oxford
© AGO e. V.
in der DGGG e.V. LoE GR AGO
 Histological / cytological verification
sowie
in der DKG e.V. 3 B +
Guidelines Breast
Version 2020.1
 Systemic therapy preferred 2a B ++*
 Consider surgery only in case of good response to
2b C +
palliative treatment
 Radiation for patients in good physical condition with
3a B +
late onset of oligometastases
 Local treatment in the case of pain,
exulceration, persistence after systemic
5 D +/-
treatment, bowel obstruction, hydrocephalus
occlusus, spinal cord compression
www.ago-online.de
 Systemic treatment after surgery 5 D ++

* See chapters with systemic treatment recommendations

 Local Therapy
in Primary Metastatic Disease
© AGO e. V.
Oxford
in der DGGG e.V.
sowie
LoE GR AGO
 Surgery (R0) of the primary tumor
in der DKG e.V.

Guidelines Breast
Version 2020.1  In case of bone metastases only 2ba B +/-
 In case of visceral metastases 2ba B -
 Axillary surgery for cN1 5 D +/-
 Sentinel if cN0 5 D -
 Radiotherapy of the primary tumor
 Alone (without surgery) 3a C +/-
 After local surgical treatment with BCS or mastectomy
3a C +
(according to adjuvant indication)
www.ago-online.de
 Liver Metastases
Local Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Resection of liver metastases (R0) 3a B +/-
Version 2020.1
HR-positive: chemotherapy-sensitive, long disease-free
interval, absence of extrahepatic disease, ≤ 3 metastases
HER2-positive: age < 50y, metastasis < 5 cm, no further
metastasis
 Regional chemotherapy 3b C +/-
 Regional radiotherapy 3b C +/-
[SIRT, stereotactic body radiosurgery with volumetric
intensity modulated arc therapy (SRS-VMAT),
www.ago-online.de radiochemo-embolization, other modalities]
 Thermoablation
3b C +/-
(RFA, LITT, cryotherapy)
 Pulmonary Metastases
Local Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Before any surgery: staging and biopsy
Guidelines Breast 3a B +
Version 2020.1
(CT-guided FNA / CNB or transbronchial FNA)
 Resection of pulmonary metastases by VATS or
conventional resection
 In case of multi-locular metastatic disease 3a B -
 In case of single / few unilateral metastasis
3a B +/-
with curative intent
 Thermoablation (CT-guided RFA, LITT) 3b C +/-
 Regional radiotherapy 3a B +/-
(e.g. stereotactic body radiosurgery with volumetric
www.ago-online.de
intensity modulated arc therapy (SRS-VMAT))
* VATS = video-assisted thoracic surgery
 Malignant Pleural Effusions (MPE)
© AGO e. V. Incidence:
  10 % of all breast cancer patients
in der DGGG e.V.
sowie
in der DKG e.V.
  50 % of pat. with advanced breast cancer
Guidelines Breast
Version 2020.1
  30 % of all MPE are caused by breast cancer
Clinical presentation:
 Extensive MPE are mostly due to malignancy
 The majority of MPE are symptomatic [dyspnea (80%), dull chest pain (30%),
nonproductive cough (10%)]
 Survival is related to the presence of additional metastases,
age, ECOG PS and extent of involving the pleural surface
Diagnostic procedures:
www.ago-online.de  Clinical examination
 Imaging techniques (chest X-Ray, US, CT-Scan)
 Proven malignant effusion [cytology (→ 50% false negative), histology by thoracoscopy)
 Malignant Pleural Effusion (MPE)
Local Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast  If short life expectancy, less invasive procedures

Version 2020.1 4 C ++
should be considered
 VATS and Talcum-pleurodesis* 1b B ++
 Chemical pleurodesis*
 Talcum powder 1a B +
 Bleomycin, Doxycycline, Mitoxantrone 2b C +/-
 Povidone-iodine (20 ml of 10% solution) 1b B +
 Continous pleural drainage 2a B ++
 Systemic treatment after pleurodesis 3b C +/-
www.ago-online.de  Serial thoracocentesis 4 C +/-
* Adequate pain-relief
VATS: video-assisted thoracoscopic surgery
 Malignant Ascites
Local Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
Ascites: LoE GR AGO
Guidelines Breast  Puncture, drainage in symptomatic patients 4 D ++
 Systemic therapy
Version 2020.1
3b D ++
 Local chemotherapy 3b D +/-

www.ago-online.de
 Malignant Pericardial Effusion
Local Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
Symptomatic pericardial effusion: LoE GR AGO
Guidelines Breast  Drainage, fenestration 3b B ++
Version 2020.1
 Combination with optimized systemic therapy 4 C ++
 VATS (video-assisted thoracic surgery) 4 C +
 Ultrasound-guided puncture and instillation of
cytotoxic compounds
 Bleomycin, cisplatinum, mitomycin C, mitoxantrone etc. 4 C +/-
 Bevacizumab 4 C +/-

www.ago-online.de
 Bone Marrow Infiltration
Associated with Pancytopenia
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Version 2020.1
 Weekly chemotherapy with*:
 Epirubicin, Doxorubicin, Paclitaxel 4 D ++
 Capecitabine 4 D ++
 HER2-pos.:
5 D ++
add anti-HER2-treatment

www.ago-online.de

* Consider pre-treatment
 Soft Tissue Metastasis
Local Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast  Surgery of limited locoregional metastasis
Version 2020.1
(skin, muscular, nodal) with complete resection 4 C +
(R0) after exclusion of further metastasis
 Radiotherapy (after surgery or, if immediate
surgery is not indicated):
 Soft tissue metastasis 3b C +
 Paresis, spinal cord compression 2b C ++
 Plexus infiltration 3b C ++

www.ago-online.de
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
CNS Metastases
in Breast Cancer

www.ago-online.de
 CNS Metastases in Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
 Versions 2003–2019:
Guidelines Breast
Version 2020.1 Bischoff / Diel / Fehm / Friedrich / Gerber / Huober / Loibl / Lück / Maass /
Müller / Nitz / Jackisch / Jonat / Junkermann / Rody / Schütz / Solbach /
Stickeler / Witzel

 Version 2020:
Bauerfeind / Ditsch

www.ago-online.de
 CNS Metastases
in Breast Cancer
© AGO e. V.
 Breast cancer is the 2nd most common cause of CNS metastases
in der DGGG e.V.
sowie
in der DKG e.V.  At autopsy:
Guidelines Breast  Parenchymal CNS metastases: ~ 30–40%
Version 2020.1
 Leptomeningeal CNS metastases: ~ 5–16%

 Increasing incidence (10 % ⇨ 40 % )

 Increasing incidence due to
 More effective treatment of extra-cerebral sites with improved prognosis
 Increasing use of MRI for diagnostic evaluation

 Lack of specific knowledge about treatment of brain metastases in breast

cancer since most studies are not breast cancer specific. Therefore,
www.ago-online.de
participation in the German registry study is recommended
(www.gbg.de)
 CNS Metastases in Breast Cancer
Tumour biology
 Primary Tumor:
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.
 Negative hormonereceptor status (basal-like cell type / triple-negative)
Guidelines Breast
 High grade, high Ki-67 index
Version 2020.1  HER2 and/or EGFR (HER1) overexpression
 Molecular subtype (Luminal B, HER2 positive, triple-negative)

 Brain metastases are more likely estrogen receptor negative

and overexpress HER2 and/or EGFR
 Discordance of molecular subtype between primary tumor and
brain metastases: for ER= 16,7%, for PR = 25,2% and Her2 neu
= 10,4%
www.ago-online.de  There is no evidence for BM-screening in asymptomatic BC-patients
 Diagnosis-specific Graded Prognostic Assessment (DS-GPA)
Worksheet to Estimate Survival from Brain Metastases (BM)
by Diagnosis
© AGO e. V. 0 0.5 1 1.5 2 Score
in der DGGG e.V.
sowie Prognostic Factor
in der DKG e.V.
KPS ≤ 50 60 70-80 90-100 n/a ____
Guidelines Breast
Version 2020.1 Subtype Basal n/a LumA HER2 LumB ____
Age, years > 60 < 60 n/a n/a n/a ____
Sum total ____
Median survival by GPA:
DS-GPA 0-1.0 = 3.4 months
DS-GPA 1.5-2.0 = 7.7 months
DS-GPA 2.5-3.0 = 15.1 months
DS-GPA 3.5-4.0 = 25.3 months;

DS-GPA confirmed as prognostic factor

www.ago-online.de Subtype: Basal: triple negative; LumA: ER/PR positive, HER2 negative; LumB: triple positive; HER2:
ER/PR negative, HER2 positive

Sperduto PW et al, JCO 2012; Nagtegaal SHJ et al, Radiother Oncol 2019
 WBRT-30-BC – zur Abschätzung des Risikos
von Hirnmetastasen
© AGO e. V. Characteristic 6-month OS Scoring points - Based on 170 patients
in der DGGG e.V. rate (%) - WBRT: whole brain radiotherapy alone
sowie
in der DKG e.V. Karnofsky performance - (30 Gy in 30 sessions)
Guidelines Breast
score
Version 2020.1
<70% 8 1 Prognostic OS at 6
group months (%)
70% 32 3
>70% 72 7 6-9 points 8

Time between 1.diagnosis 10-12 points 41

of breast cancer and WBRT
≤33 months 29 3 13-15 points 68

≥34 months 38 4
16 points 100
Extra-cerebral metastatic
disease
No 53 5
www.ago-online.de
Yes 28 3
Regarding the PPV to identify patients who will live 6 months or longer after WBRT,
the WBRT-30-BC (100%) was superior to both DS-GPA (74%) and Rades-Score (68%). Janssen S et al, Radiol Oncol, 2019
 Single / Solitary Brain Metastasis
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Version 2020.1
Local therapy alone: SRS (≤ 4 cm) o. FSRT or resection 2b B ++
Resection + irradiation of the tumor bed (without WBRT) 1b B ++
WBRT + Boost (SRS, FSRT) or resection + WBRT 2a B +

WBRT alone
Patients with reduced general condition and limited life expectancy 2b B +

Hippocampal-sparing 2b C +/-
 WBRT in addition to SRS/FSRT or tumor resection improves local control
and symptoms, but has no survival benefit. WBRT impairs
neurocognitive function.
www.ago-online.de

SRS = stereotactic radiosurgery (single session), FSRT = fractionated stereotactic RT; WBRT = whole brain radiotherapy,
 Oligo-Brain Metastases
© AGO e. V. Oxford
in der DGGG e.V.
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast
Local therapy alone: SRS (≤ 4 cm) or FSRT 2b B ++
Version 2020.1
WBRT + Boost (SRS, FSRT) 2a B ++
WBRT alone
2b B +
Patients with reduced general condition and limited life expectancy
Hippocampal-sparing 2b C +/-
 Maximal number of metastases treated by SRS depends on localization, size, and additional,
factors e.g. number of metastases, pre-treatment, Karnofsky.Index
 WBRT in addition to SRS/FSRT improves local control and symptoms, but has no survival benefit.
Additional WBRT seems to impair neurocognitive function
www.ago-online.de  In case of limited number of brain metastases, SRS/FSRT are preferred

SRS = stereotactic radiosurgery (single session), FSRT = fractionated stereotactic RT; WBRT = whole brain radiotherapy,
 NCCTG N0574 (Alliance): A Phase III Randomized Trial of
Whole Brain Radiation Therapy (WBRT) in Addition to
Radiosurgery (SRS) in Patients with 1 to 3 Brain Metastases
© AGO e. V.
in der DGGG e.V.
Study design:
sowie
in der DKG e.V.
Patients with 1-3 brain metastases, each < 3 cm by contrast MRI, were randomized to
Guidelines Breast
SRS alone or SRS + WBRT and underwent cognitive testing before and after treatment.
Version 2020.1
The primary endpoint was cognitive progression (CP) defined as decline > 1 SD from
baseline in any of the 6 cognitive tests at 3 months. Time to CP was estimated using
cumulative incidence adjusting for survival as a competing risk.*
Conclusion:
Decline in cognitive function, specifically immediate recall, memory and verbal fluency,
was more frequent with the addition of WBRT to SRS. Adjuvant WBRT did not improve
OS despite better brain control. Initial treatment with SRS and close monitoring is
recommended to better preserve cognitive function in patients with newly diagnosed
brain metastases that are amenable to SRS.
www.ago-online.de
* Remark: No hippocampus-sparing was applied

Brown A, Asher AL, Ballman K, Farace E, Cerhan J, Anderson K,

et al. JAMA. 2016 Jul 26;316(4):401-9. doi: 10.1001/jama.2016.9839
 Adjuvant Whole-brain Radiotherapy Versus Observation After
Radiosurgery or Surgical Resection of One to Three Cerebral
Metastases: Results of the EORTC 22952- 26001 Study
© AGO e. V. 2-year relapse rate after whole-brain radiotherapy (WBRT) versus
in der DGGG e.V.
sowie
observation after surgical resection or radiosurgery
in der DKG e.V.
after surgical resection after radiosurgery
Guidelines Breast
Version 2020.1
(n=160) (n=199)
WBRT observation WBRT observation
Local recurrence 27% 59% 19% 31%
(p<0.001) (p=0.040)
New lesions 23% 42% 33% 48%
(p=0.008) (p=0.023)

 Only 12% of the patients had brain metastases from breast cancer.
 Overall survival was similar in the WBRT and observation arms
(median, 10.9 vs. 10.7 months, respectively; P = .89).
 Intracranial progression caused death in 44% patients in the OBS
www.ago-online.de
arm and in 28% patients in the WBRT arm.

Kocher M. J Clin Oncol 2011, 29:134-141

 Possible Factors for Decision Making Neurosurgery
versus Stereotactic Radiosurgery
© AGO e. V.
in der DGGG e.V. Factors in favor of neurosurgery:
sowie

 Histological verification e.g. after a long recurrence-free interval

in der DKG e.V.

Guidelines Breast
Version 2020.1
 Need for immediate decompression, life-threatening symptoms
 Tumor size not allowing stereotactic radiotherapy

Factors in favor of primary radiotherapy:

 Tumor location poorly amenable to surgery

www.ago-online.de
 More than four lesions
 Multiple Brain Metastases
if Stereotactic Radiotherapy is not indicated
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 WBRT (supportive steroids*) 1a A ++
Version 2020.1
 Hippocampal-sparing radiotherapy 2b C +/-
 Corticosteroids alone* 3a B +/-
 Radiochemotherapy for intracerebral control 3b C -
 WBRT in case of recurrence** 4 C +/-

SRS = stereotactic radiosurgery

FSRT = fractionated stereotactic radiotherapy
WBRT = whole brain radiotherapy

www.ago-online.de * adapted to symptoms

** can be discussed depending on time-interval from first radiation, prior dose, and localization if local therapy
(surgery, SRS, FSRT) is not indicated and / or possible
WBRT = whole brain radiotherapy
 Systemic and Symptomatic Therapy
of Brain Metastases*
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Continuation of the current systemic therapy if first
Version 2020.1
diagnosis of brain metastasis and stable extracranial 2c C +
disease
 Lapatinib + Capecitabine as initial treatment
2b B +/-
(HER2 pos. disease)
 Chemotherapy alone as primary treatment 3a D -
 Anticonvulsants only if symptoms of seizures 3a C +
 Glucocorticoids only if symptoms and /
3a C ++
or mass effect (Dexamethasone with best evidence)
www.ago-online.de  For patients with bad prognosis and reduced physical
5 D +
common conditions best supportive care is an option
 Leptomeningeal Carcinomatosis:
Local Therapy
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
Intrathecal or ventricular therapy
Version 2020.1  MTX 10–15 mg 2–3x/ week (+/- folinic acid rescue) 2b B +
 Liposomal cytarabine 50 mg, q 2w* 3b C +
 Thiothepa 3b C +/-
 Steroids 4 D +/-
 Trastuzumab (HER2 pos. disease) 4 C +/-
Systemic therapy 3b B +
Radiotherapy
 Focal (bulky disease) 4 D +
 WBRT 4 D +
 Neuroaxis (disseminated spinal lesions ) 4 D +/-
www.ago-online.de
Due to poor prognosis, consider best supportive care, especially in
patients with poor performance status
* Currently not available
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1
Complementary Therapy
Survivorship

www.ago-online.de
 Complementary Therapy – Hormonal Treatment and
Alternatives in Breast Cancer Survivors – Survivorship
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  Versions 2002–2019:
Guidelines Breast
Version 2020.1
Albert / Bauerfeind / Blohmer / Fersis / Friedrich / Gerber / Göhring /
Hanf / Janni / Kümmel / Lück / von Minckwitz / Nitz / Oberhoff /
Rhiem / Scharl / Schmidt / Schütz / Thomssen

 Version 2020:
Kümmel / Schütz

www.ago-online.de
 CAM
© AGO e. V.
in der DGGG e.V. „Integrative Oncology“ „Unconventional
sowie
in der DKG e.V. methods“
Guidelines Breast
Version 2020.1
CAM UCT
Complementary + alternative medicine Unconventional Tx

Complementary Alternative Unconventional

In addition to Instead of Unproven outsider
scientifically scientifically methods
based medicine based medicine

www.ago-online.de
 General Considerations
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 CAM instead of loco-regional interventions 2b B --
Version 2020.1
 CAM instead of systemic treatment 2b B --
 Patients should be asked and advised about their use
of CAM modalities
 Diagnostic procedures in connection with
complementary and alternative therapy concepts
without evidence (e.g. iris diagnostics, bioresonance)
should not be recommended.
www.ago-online.de
 During anti-cancer treatment: Beware of drug
interactions
 Complementary Therapy
Pre- and Postoperative
Oxford
© AGO e. V.
in der DGGG e.V. LoE GR AGO
sowie
in der DKG e.V. Preoperative:
Guidelines Breast  Hypnosis (reduces anxiety, pain, nausea) 1b B +
Version 2020.1
Postoperative:
 Acupuncture (pain relief, anxiety) 1b B +/-
 Acupuncture (nausea, vomiting) 2b B +
 Massage therapy (pain relief) 2b C +/-
 Early postoperative exercise reduces upper-limb dysfunction
(beware: increased wound drainage) 1a A +
 Physical exercise
to reduce breast cancer related secondary lymphedema 1a A +
as a prophylaxis of lymp edema 1b B +/-
www.ago-online.de
 Prophylactic lymphatic drainage 1b B -
 Yoga (arm and shoulder pain) 2b C +
 Music therapy (reduces pain after mastectomy) 2b C +/-
 Complementary Treatment
While on Cancer Treatment – Impact on Toxicity I
Oxford
© AGO e. V. During anti-cancer treatment: Beware of drug interactions
in der DGGG e.V. LoE GR AGO
sowie  Mistletoe (Viscum album)
in der DKG e.V. 1a B +/-
in order to reduce side effects
Guidelines Breast
 Thymic peptides
Version 2020.1 2a B +/-
lower risk of severe infections
 Ginseng
in order to reduce cancer related fatigue; note: interacts with cytochrome P 2b C -
enzymes e.g. CYP 3A4
 Ganoderma Lucidum
may improve fatigue, note: inhibits cytochrome P 2b C -
enzymes (e.g. CYP 3A4)
 L-Carnitine
 given for prevention of toxicity; however, increased chemotherapy-induced
1b B --
peripheral neuropathy
 Improvement of cancer related fatigue
1b B -
 Curcumin
1b B +/-
www.ago-online.de adjunct to reduce radiation-induced dermatitis
 Ginger
adjunct to guideline-oriented medication to treat chemotherapy induced nausea & 1b C +/-
vomiting – beware of drug interactions
 Complementary Treatment
While on Cancer Treatment – Impact on Toxicity II
Oxford
© AGO e. V.
in der DGGG e.V. LoE GR AGO
sowie
in der DKG e.V.  Antioxidant supplements 1b B -
Guidelines Breast  various antioxidative extracts to reduce anthracyclin-
Version 2020.1 2b B +/-
induced cardiotoxicity
 High dose vitamin C 1b C -
 Vitamine E 2b D -
 Selenium for alleviating therapy side effects 1b B -
 Co-Enzyme Q 10 (fatique, QoL) 1b B -
 Proteolytic enzymes for reduction of chemotherapy-induced
3b B -
toxicity
 Chinese herbal medicine improves wound healing 1b B -*inf
www.ago-online.de  Oxygen and ozone therapy 5 D --
 Short-term fasting (Qol, Fatigue) 3b C +/-*
inf: i.v.-infusion (in Germany not approved)
* treatment in clinical trials recommended
 Additional Complementary Therapy
of Side Effects Related to Cancer Treatments
Oxford
© AGO e. V.
in der DGGG e.V. LoE GR AGO
sowie
in der DKG e.V.  Chinese medicinal herbs to treat the side effects
1b B -
Guidelines Breast
Version 2020.1
of chemotherapy in breast cancer patients

 Homoeopathic medicine against therapy side effects 1b B +/-

 Topical calendula (>= 20% Calendula amount) for prophylaxis of
acute dermatitis during radiotherapy
 Traumeel S® mouthwash to treat chemotherapy-induced
stomatitis
 Topical Silymarin for prophylaxis of acute dermatitis during
3a B +/-
radiotherapy
 Massage to improve on fatigue, pain, anxiety, nausea 1b C +/-
www.ago-online.de
 Transcutaneous Electrical Nerve stimulation (TENS) against 2b D +/-
cancer pain
 Hydrotherapy 3b C +/-
 Additional Complementary Therapy
of Side Effects Related to Cancer Treatments
Oxford
© AGO e. V. LoE GR AGO
in der DGGG e.V.
sowie Acupuncture in order to improve on
in der DKG e.V.
 Chemotherapy-induced nausea and vomiting
Guidelines Breast  (Electro)-Acupuncture as adjunct to entiemetic treatment 1b B +
Version 2020.1
 Acupressure as adjunct to entiemetic treatment 1b B +
 Pain
 Cancer pain 1b B +
 Aromatase-inhibitor – induced athralgia 1a B +
 TENS – Transcutaneous Electrical Nerve Stimulations to relieve cancer pain 2b D +/-
 Fatigue 1a B +
 Acupressure 1b B +
 Anxiety and depression 2b B +
 Cognitive dysfunction 5 D +/-
 Menopause syndrome in Breast Cancer Patients 1b B +
 to improve on frequency and severity of hot flashes 1b B +/-
 Electro-Acupuncture to improve on sleep and hot flashes 2a B +
 Leucopenia (Moxibustion) 2b B +/-
www.ago-online.de  Treatment of chemotherapy induced polyneuropathy
 prophylactically 1b B -
 therapeutically 2b B +/-
 Chronic lymph edema after Breast Cancer Treatment 2b B +/-
 Complementary Treatment
Mind-Body Medicine I
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
MBSR (Mindfulness-Based Stress Reduction) 1a A +
Version 2020.1
Program improves quality of life, coping strategies,
attentiveness, and lowers stress, anxiety, depression,
fatigue, and sleep disturbances

Physical exercise / sport

min. 3x/week moderate endurance training in
combination with workout exercises (2x per week) 1a A ++
improve quality of life, cardio-respiratory fitness, physical
www.ago-online.de performance, sleep, pain, depression, lymphedema, and
fatigue
 Complementary Treatment
Mind-Body Medicine II
Oxford
© AGO e. V.
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.
Relaxation technieques
Guidelines Breast 2b C +/-
Version 2020.1
Reduction of anxiety and nausea, improvement of quality of life,
reduction of psychological stress
Yoga
Improves sleep, quality of life, stress, anxiety,
1b A +
depression, fatigue, and sleep
Qi Gong
2a B +/-
May improve quality of life, fatigue, and mood
Tai Chi
2a B +/-
Improves quality of life, muscular strength, sleep
www.ago-online.de
Hypnosis (in combination with cognitive training)
1b A +
Improves fatigue and muscle weakness under radiotherapy; also
reduces distress
 CAM
Prevention of Recurrence/Improvement of Overall Survival I
Modifiable Lifestyle Factors

© AGO e. V.
in der DGGG e.V.
Oxford
sowie
in der DKG e.V.
LoE GR AGO
Guidelines Breast  Physical exercise 2a A ++
Version 2020.1
(equivalent to 3–5 hrs moderate walking per week)
improves DFS and OS, cardio-respiratory fitness,
physical functioning
 Reduce Smoking 2b A +
 Reduce Alcohol consumption (< 6 g/day) 2b A +

www.ago-online.de
 Modifiable Lifestyle Factors
Nutrition after Breast Cancer Diagnosis
Prevention of Recurrence / Improvement of Overall Survival II
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Adherence to normal BMI / weight loss
Guidelines Breast 1a A ++
Version 2020.1 if overweight, irrespective of HR-status
 Low fat diet
1a B +
dietary counseling recommended
 Increased fiber intake (e.g. Flaxseed) 2a B +
 Adherence to general nutrition guidelines
2a B ++
(e.g. DGE, WCRF) similar to a Mediterranean Diet
 Dietary extremes 2a B --

www.ago-online.de
 Complementary Treatment
Prevention of Recurrence / Improvement of Overall Survival III
Dietary Supplements – Herbal Therapies
Oxford
© AGO e. V. LoE GR AGO
in der DGGG e.V.
Post treatment vitamin/antioxidant supplements does not appear to be associated with increased risk
sowie 2b B
in der DKG e.V. of recurrence (beware of drug/treatment interactions)

Guidelines Breast
Smokers on antioxidant supplements are at higher risk for lung cancer 1b A
Version 2020.1 For Prevention of BC Recurrence:
 Antioxidants 2a B +/-
 Orthomolecular substances (Selenium, Zinc...) 5 D -
 Vitamine supplementation in patients on a balanced diet (esp. Vit C, E, D) 2a B +/-
 Artificial carotenoids appear to be associated with worse outcome 2b B -
 Proteolytic enzymes (Papain, Trypsin, Chymotrypsin) 3b B -
 Soy-food (natural source of phytoestrogenes) 2a B +/-
 food or concentrates containing ≥ 100 mg) isoflavones per day 2a B -
 Black Cohosh (Cimicifuga racemosa) 3b C +/-
 Mistletoe (Viscum album) 1b C -
 Thymic peptides (impact on OS) 2a B -
 Oxygen- and ozone therapy 5 D --
 Antioxidant supplements (after completion of radiotherapy) 2b B +/-
 Laetrile 1c D --
 Green tea 3a C +/-
www.ago-online.de  Methadone 5 D --
 Cancer bush (Sutherlandia frutescens),
Devil's claw (Harpagophytum procumbens),
5 D -
Rooibos tea (Aspalathus linearis),
Bambara groundnut (Vignea subterranean)
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.

Guidelines Breast
Version 2020.1

Gynecological Issues in
Breast Cancer Patients

www.ago-online.de
 Gynecologic Issues in
Breast Cancer Patients
© AGO e. V.
in der DGGG e.V.
sowie
in der DKG e.V.  Versions 2015–2019:
Guidelines Breast
Version 2020.1 Albert / Bauerfeind / Blohmer/ Fersis / Gerber / Hanf / Huober/
Loibl / Maas / Scharl / Thill / Witzel

 Version 2020:
Rody/Witzel

www.ago-online.de
 Hormone (Replacement) Therapy (HT) of Estrogen
Deficiency after Diagnosis of Breast Cancer
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Endocrine responsive disease (ER pos.) 1b B -
Version 2020.1

 Endocrine non-responsive disease (ER neg.) 2b D +/-

 Endocrine responsive disease (ER pos.):
2b B +/-
combined treatment TAM plus low-dose-HT
 Tibolone 1b A --

 Topical vaginal application of

 Estriol (E3 0.03 mg as treatment course*) 4 D +/-
 Estradiol (E2) during AI therapy 4 C -
www.ago-online.de

* 4 weeks daily 1 x 1, followed by 8 weeks 3 x 1 per week

 Further Medical Approaches to Reduce
Menopausal Symptoms I
© AGO e. V.
Oxford
Medical approaches:
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.
 Selective serotonin reuptake inhibitors and
Guidelines Breast serotonin-(noradrenalin) reuptake inhibitors
Version 2020.1
(SSRI-SNRI): reduce hot flashes in BC patients
 Venlafaxine 1a A +
 Desvenlafaxine 1b A +/-
 sertraline, escitalopram 1b A +/-
 Gabapentin (patients using TAM) 1a A +
 Pregabalin 1b A +/-
 Clonidine (patients using TAM) 1a A +
 Oxybutynin (2,5mg/5 mg) 1aa A +/-
 MPA (i.m. 500 mg single shot) 1b A +/-
(most potent, but endocrine agent!)
 Vitamin E 1b A -
www.ago-online.de  Omega 3 fatty acids 1b A +/-
 Melatonin (improvement in sleep quality) 2b C +
 Duloxetine (treating arthralgias while on AI) 1b B +
 CAM* - Approaches to
Reduce Menopausal Symptoms II
* Complementary and Alternative Medicine
Oxford
© AGO e. V. During anti-cancer treatment: Beware of drug interactions!
LoE GR AGO
in der DGGG e.V.
sowie
in der DKG e.V.
 Soy-derived phytoestrogens – isoflavonoids*
Hot flush 1b B -
Guidelines Breast
Version 2020.1
Sleep disturbance 1b B +/-
Topical vaginal application 1b B +/-
 Red Clover isoflavonoids*
Hot flush, sleep disturbance 1b B +/-
 Flaxseed-supplementation (40 g/d) (in HR+ ≤ 10 g/d)
2b B +/-
(reduces relapses, no effect on hot flashes)
 Black Cohosh for hot flushes 1b B +/-
 Black cohosh + St. John's Wort‫‏‬ 1b B +/-
 St. John‘s Wort
(pharmacokinetic interference with endocrine therapy, 1b B +/-
cyctotoxic drugs and tyrosin kinase inhibitors)
 Ginseng root (Panax ginseng or P. quinquefolius) 1b B -
www.ago-online.de  Bromelain + Papain + Selenium + Lektin (for AI induced joint symptoms) 3b B +
 Homeopathic medicine to reduce hot flushes 1b B -
* might stimulate BC, especially in endocrine responsive disease
 General Approaches to Reduce Menopausal
Symptoms III - Integrative Oncology Aspects
© AGO e. V. Oxford
in der DGGG e.V. General approaches:
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Physical exercise 1A A ++
Version 2020.1
 Mind body-medicine
(yoga, hypnosis, education, counseling, mindfulness 1b B +
training)
 Cognitive behavioral therapy (CBT) 1a A ++
 (Electro) Acupuncture
Aromatase-inhibitor treatment induced arthralgia 1b B +
Hot flushes 1a B +/-
Depression 2b B +/-
www.ago-online.de Anxiety, Sleep 3b C +/-
 Ovarian Protection and Fertility Preservation in Premenopausal Patients
Receiving (Neo)-Adjuvant Chemotherapy (CT)

© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Fertility preservation counselling including
Version 2020.1
referral of all potential patients to appropriate
++
reproductive specialists (further information
www.fertiprotekt.com)
 CT + GnRHa
(preservation of ovarian function)
1a A +
(GnRHa application > 2 weeks prior to chemo-
therapy, independent of hormone receptor status )
 CHT + GnRHa
1b A +/-
www.ago-online.de (preservation of fertility)
 Ovarieller Funktionserhalt –
Synopse der randomisierten Studien
ZORO PROMISE Munster et al. - US POEMS Option
© AGO e. V.
in der DGGG e.V. Patient number 60 (60 HR-) 281 (50 HR-) 49 (13 HR-) of 124 218 (218 HR-) 227 (126 HR-)
sowie Age median 38 years 39 years 39 years Premenop. < 50 years premenopausal
in der DKG e.V.
Treatment goserelin triptorelin triptorelin goserelin goserelin
Guidelines Breast
Version 2020.1 Start of treatment >2 weeks prior to cht >1 week prior to cht > 1 week prior to cht > 1 week prior to cht > 1 week prior to cht

Primary Endpoint menstruation at rate of early menopause at menstruation Ovarian failure at Amenorrhea with elevated
month 6 month 12 after cht rate within 2 years 2 yrs after cht FSH levels between 12 and
after chemotherapy after cht 24 months

Primary objective to detect 30% to detect at least 20% to detect 20% difference in To detect 20%-25% absolute
absolute increase absolute reduction in amenorrhea rate – from 10% reduction in early
of menstruation early menopause to 30% menopause
rate
Multivar. analysis age as only treatment as only n.d. Treatment as only Age, total
independent independent predictive Independent cyclophosphamide dose and
predictive factor factor predictive factor baseline AMH

Resumption of 83% with LHRH vs. 93% with LHRHa vs. 74% with LHRH vs. 78% with LHRH vs. 78% with LHRHa vs. 62%
menses at month 80% w/o 74% w/o 68% w/o 75% w/o; at 2 years; amnorrhea rate between
12 22% with LHRH vs. 8% month 12 and 24
www.ago-online.de
Median time to 6.1 with LHRHa vs. not reached with LHRH 5.8 with LHRH vs. n.d. n.d.
restoration of 6.8 w/o; p=0.30 vs. 6.7 w/o; p=0.07 5.0 w/o; p=0.58
menses (months)
Cyclophosph. dose 4600 vs. 4700mg 4080 vs. 4008 mg n.r. n.a. 5940 vs. 5940mg
 Assessment of Ovarian Reserve
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
Tests for fertility assessment
Version 2020.1
 Anti-Müllerian Hormone 1b B +
 Antral follicle count 3b B +
 FSH 2ba B +
 Combined test procedures for assessment of ovarian
5 C +
reserve*

www.ago-online.de
* Tests are suggested for women > 35y and infertility for 6-12 months; the tests do not predict failure to conceive.
They should be used in counselling patients and to provide a ‫‏‬rough estimate of the fertility window. Results may
decrease patient referral time to infertility ‫‏‬centers.‫‏‬
 Contraceptive Options for Women
after Diagnosis of Breast Cancer
© AGO e. V.
Oxford
in der DGGG e.V.
sowie
LoE GR AGO
in der DKG e.V.
 Barrier methods 5 D +
Guidelines Breast
Version 2020.1  Sterilization (tubal ligation/salpingectomy/vasectomy) 5 D +
 Non-hormonal intrauterine devices (IUDs) 3b D +
 Levonorgestrel-releasing IUDs 2b C -
 Removal in newly diagnosed patients 4 D +/-
 Timing methods 5 D -
 Injectable progestin-only contraceptives 5 D -
 Progestin-only oral contraceptives 5 D -
 Combined oral contraceptives 5 D -
 Emergency Contraception Options
www.ago-online.de
 Copper intrauterine device (Cu-IUD) 5 D +
 Levonorgestrel, Ulipristal orally 5 D +
 Sexual Health
© AGO e. V. Oxford
in der DGGG e.V.
sowie LoE GR AGO
in der DKG e.V.

Guidelines Breast
 Use of patient-reported questionnaires 4 C +
Version 2020.1
 Assessment of sexual dysfunction 5 D +
 Vaginal dryness:
1b B +
Non-hormonal lubricants / moisturizers
 Fractionated microablative CO2-Laser/Vaginal
2a B +/-
Erbium:YAG-Laser
 DHEA local application 2b B +/-
 Topical vaginal application of
 Estriol (E3 0.03 mg as treatment course*) 4 D +/-
 Estradiol (E2) during AI therapy 4 C -
www.ago-online.de
 Psychoeducational support, group therapy, sexual
1b B +
counseling, marital counseling, psychotherapy
* 4 weeks daily 1 x 1, followed by 8 weeks 3 x 1 per week
 Assessment of Sexual Health
© AGO e. V.  Sexual Complaints Screener (SCS) for women*
in der DGGG e.V.
sowie German Translation
in der DKG e.V.
Screening-Check-Fragebogen: Overall Sexual Function
Guidelines Breast
Version 2020.1 1. Are you satisfied with your sexual life? yes, no; if no
2. How long have you been dissatisfied with your sexual life?
3. The problems with your sexual life are:‎(mark one or more):
1. Problem with little or no interest in sex
2. Problem with decreased genital sensation (feeling)
3. Problem with decreased vaginal lubrication (dryness)
4. Problem reaching orgasm
5. Problem with pain during sex
6. Other
4. Which problem is most bothersome? (circle) 1, 2, 3, 4, 5, 6.
5. Would you like to talk about it with your doctor?
www.ago-online.de

* Hatzichristou D, Rosen RC, Denogatis LR, Low WY, Sadovsky R, Symonds T. Recommendations for the clinical
evaluation of men and women with sexual dysfunction. J Sex Med 2010:7:337-348
 Diagnosis and Treatment of Patients
with early and advanced Breast Cancer
© AGO e. V.
in the DGGG e.V.
and
in the DKG e.V.

Guidelines Breast
Version 2020.1
Health literacy and communication

www.ago-online.de
 Health literacy
© AGO e. V.
in the DGGG e.V.
and
in the DKG e.V.
 Version 2020:
Guidelines Breast
Version 2020.1 Rhiem / Schmidt

www.ago-online.de
 Health literacy
Definition
© AGO e. V.
in the DGGG e.V. e.g.*
and
in the DKG e.V.

Guidelines Breast
Version 2020.1
“Health literacy is linked to literacy and entails
people’s knowledge, motivation and competences
to access, understand, appraise, and apply health
information
in order to make judgments and take decisions in
everyday life concerning healthcare, disease
prevention and health promotion to maintain or
improve quality of life during the life course.”
www.ago-online.de
SØrensen et al., (2012)
* further definition, e.g..: The Secretary's Advisory Committee on National Health Promotion and Disease Prevention
Objectives used this working definition of health literacy for 2030: “Health literacy occurs when a society provides accurate
health information and services that people can easily find, understand, and use to inform their decisions and actions.”
 Health literacy model
(according to Sörensen)

© AGO e. V. Competencies
in the DGGG e.V.
and Access: seek, find, obtain
in the DKG e.V. health information.
Guidelines Breast Understand:
Version 2020.1 Understanding the health
information received
Appraise: Interpret, select,
assess, review health
information
Apply: Use health
information to make
decisions that support and
improve health

www.ago-online.de
Sørensen K, Van den Broucke S, Fullam J, Doyle G, Pelikan J, Slonska Z, Brand H. Health
literacy and public health: A systematic review and integration of definitions and models.
BMC Public Health. 2012, 12:80
 Health literacy

© AGO e. V.
in the DGGG e.V.
and  The more developed health literacy is, the better a person can inform himself or
in the DKG e.V.
herself about health (e.g. prevention, therapy) in everyday life, form an opinion
Guidelines Breast
Version 2020.1 and make self-determined decisions that maintain or improve the quality of life
and health throughout the course of life.

 However, the extent of health literacy of a person depends not only on his or her
individual prerequisites and acquired competencies, but especially on the
professional quality, appropriateness, comprehensibility, form of
communication and availability of the information provided.

www.ago-online.de
 Health literacy
User participation

© AGO e. V.
in the DGGG e.V. Reasons cited for overuse, underuse and misuse in the health care system
and
in the DKG e.V. include the weak position of patients (SVR 2001).
Guidelines Breast
Version 2020.1

In the context of health literacy, the individual is

 more actor and co-designer and less passive carrier of risk factors
 autonomous actor who takes responsibility and an active role in medical
decision-making processes
 the person who extracts the individually relevant meaning from
professionally offered information and behaves in accordance with
individual ideas about certain health situations
www.ago-online.de

SVR - Council of Experts for the Assessment of Developments in the Health Care System
 Health literacy
Communication

© AGO e. V.
in the DGGG e.V. Doctor-patient communication is a central means of acquiring health
and
in the DKG e.V. competence. It is the basis for successful oncological treatment and support.
Guidelines Breast
Version 2020.1
Core elements are, for example:
 Non-directive communication - i.e. those seeking advice have the right to
choose their own goals in life, even if they contradict generally accepted,
even evidence-based, recommendations after well-founded consideration.
 Comprehensible communication - i.e. geared to the level of knowledge,
reception habits, competence requirements and preferences of the
different patients.
Goal: Enabling a "self-responsible" decision based on sufficient health literacy.
www.ago-online.de
 Health literacy
Basic principles of communication

© AGO e. V.  Communicate information truthfully and empathetically

in the DGGG e.V.
and
in the DKG e.V.
 actively listening and expressing empathy
Guidelines Breast
Version 2020.1
 Find out if and how the patient wants to be informed about his/her situation
 use understandable language avoiding or explaining technical terms
 Continuously improve understanding through e.g. repetitions, breaks,
summary, comprehensible information material
 Encourage asking questions and expressing feelings
 Identifying individual stresses, problems and needs
 Motivating self-determination and personal activities ("empowerment")
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 Giving hope for healing and relief
 Offer further assistance (e.g. psycho-oncology, self-help)
 Health literacy
evidence-based information

© AGO e. V. Evidence-based information in health care should be used to answer patients' questions in an
in the DGGG e.V.
and
understandable way. They are based on the current state of knowledge and are free from
in the DKG e.V.
influence:
Guidelines Breast
Version 2020.1 requirement for evidence-based health information:
• The information on services or products may not be used directly or indirectly for marketing purposes.
• The systematic search corresponds to the questions relevant to the target group.
• The selection of evidence suitable for the research question is justified.
• An undistorted presentation of the results relevant to the patients (e.g. mortality, complaints, complications, health-
related QoL) is available.
• The presentation of uncertainties is appropriate in terms of content and language.
• The presentation of results is clearly separated from the derivation of recommendations.
• Consideration of current evidence to communicate figures, risk information and probabilities.
• there must be sufficient time for the decision.
www.ago-online.de • The possibility that the measure may be refused must not be a reason for withholding information.
 Health literacy
Communication

© AGO e. V. Non-directive and evidence-based doctor-patient communication that is

in the DGGG e.V.
and geared to the current needs, values, problems, resources and preferences of
in the DKG e.V.

Guidelines Breast
patients has beneficial effects.
Version 2020.1
Oxford
LoE
 Patients feel less anxious 2b
 Trust in treating oncologists is increased 2b
 Treatment satisfaction is increased 2a
 Therapy adherence is increased 2a
 Decision making is improved 2a
 Mental complaints are improved 2a
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 Health literacy
Communication

© AGO e. V. Qualified training measures can help to

in the DGGG e.V.
and
in the DKG e.V.
promote communicative skills.
Guidelines Breast
Version 2020.1 Oxford
LoE GR AGO
communication training for doctors can e.g.
 Enhance empathy 2a
 Extend and enrich communication skills 2a
 Increase patient satisfaction (information, 2b
support, consideration of concerns)

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 Health literacy
shared decision making - participatory decision

© AGO e. V.
in the DGGG e.V.
and
in the DKG e.V.

Guidelines Breast
Version 2020.1
The vast majority of patients want to be actively involved in decisions about
their care.
Oxford
LoE GR AGO
 Patients want open discussions about prognosis, 1b A
treatment options and quality of life
 Doctors should motivate patients to ask questions, 3b C +
demand clarification, express emotions, opinions
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 Health literacy
Patient decision aids

© AGO e. V. Patient decision support tools are tools that help people to participate in decision making by
in the DGGG e.V.
and
making the decision to be made explicit, providing information on options and outcomes, and
in the DKG e.V. clarifying personal values. They are intended to complement, not replace, the advice of a doctor.
Guidelines Breast  Patient Rights Act (2013) stipulates that information must be understandable for patients
Version 2020.1
 National Cancer Plan (2015) "Roadmap - informed and participatory decision-making by 2020
Decision support
 clarify the decision on
 describe the available options
 help patients to view these from a personal point of view
 should be evidence-based = evidence-based health information (EBGI)
 bring patients: more knowledge about options, more accurate risk perception, more satisfaction
and that decisions are more in line with their values

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 Participatory decision making
(PEF, English Shared decision-making, SDM)

© AGO e. V.
in the DGGG e.V.
and Oxford
in the DKG e.V.
The use of decision aids (EH)
Guidelines Breast
Version 2020.1
LoE
 improves knowledge about treatment options 1a
 reduces the decision conflict 1a
 improves the level of information 1a
 increases the feeling about the clarity of personal 1a
values
 encourages a more active role in decision-making 2b
 improves risk perception 2b
www.ago-online.de  improves the match between the chosen option 3a
and the patient's values