European Society for Medical Oncology (ESMO) tmc strategic communications

via Ginevra 4, 6900 Lugano, Switzerland www.wearetmc.co.uk

Tel: +41 (0)91 973 19 00
Fax: +41 (0)91 973 19 02
Email: clinicalguidelines@esmo.org www.esmo.org

BREAST CANCER 2019

ESMO POCKET GUIDELINES

BREAST
CANCER 2019
EMEA-HAL-19-00073
DATE OF PREPARATION: SEPTEMBER 2019
Prescribing Information can be found on Page 69
GUIDELINES COMMITTEE
Chair: George Pentheroudakis; Co-Chair: Cristiana Sessa; Steering Committee Members: Dirk Arnold,
Christian Buske, Fatima Cardoso, Paolo Casali, Andrés Cervantes, Elisabeth de Vries, Alan Horwich,
Solange Peters, Rolf Stahel; Subject Editors: Alfredo Berruti, Jean-Yves Blay, Nicoletta Colombo, Silke Gillessen,
Mats Jerkeman, Karin Jordan, Jean-Pascal Machiels, Erika Martinelli, Ulrich Mey, Olivier Michielin,
Matthias Preusser, Martin Reck, Carla Ripamonti, Elzbieta Senkus-Konefka; Deputy Subject Editors:
Jonathan Ledermann, Shani Paluch-Simon, Thomas Powles, Silvia Stacchiotti, Michael Weller; International
Coordinator of Guidelines Adaptation in Asia Pacific: Takayuki Yoshino; Staff: Keith McGregor, Claire Bramley,
Jennifer Lamarre, Sarah Escuin, Louise Green, Lone Kristoffersen, Jean-Yves Douillard, Svetlana Jezdic.

ESMO CLINICAL PRACTICE GUIDELINES

Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, Zackrisson S and Senkus E, on
behalf of the ESMO Guidelines Committee
Ann Oncol 2019;30:1194–220
https://academic.oup.com/annonc/article-pdf/30/8/1194/29103535/mdz173.pdf
4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)
Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, André F, Harbeck N, Aguilar Lopez B, Barrios CH,
Bergh J, Biganzoli L, Boers-Doets CB, Cardoso MJ, Carey LA, Cortés J, Curigliano G, Diéras V,
El Saghir NS, Eniu A, Fallowfield L, Francis PA, Gelmon K, Johnston SRD, Kaufman B, Koppikar S, Krop IE,
Mayer M, Nakigudde G, Offersen BV, Ohno S, Pagani O, Paluch-Shimon S, Penault-Llorca F, Prat A, Rugo HS,
Sledge GW, Spence D, Thomssen C, Vorobiof DA, Xu B, Norton L and Winer EP
Ann Oncol 2018;29:1634–57
https://academic.oup.com/annonc/article-pdf/29/8/1634/25505041/mdy192.pdf
Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer
syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening
Paluch-Shimon S, Cardoso F, Sessa C, Balmana J, Cardoso MJ, Gilbert F and Senkus E, on behalf of the
ESMO Guidelines Committee
Ann Oncol 2016; 27(Suppl 5):v103–10
https://academic.oup.com/annonc/article-pdf/27/suppl_5/v103/6679012/mdw327.pdf

These guidelines have been sponsored and reviewed by Eisai Europe Ltd.
Eisai has not influenced the recommendations within these guidelines.
 ESMO POCKET GUIDELINES PROVIDE YOU WITH A CONCISE SUMMARY OF THE
FUNDAMENTAL RECOMMENDATIONS MADE IN THE PARENT GUIDELINES IN AN
EASILY ACCESSIBLE FORMAT.

This quick reference booklet provides you with the most important content of the
full ESMO Clinical Practice Guidelines (CPGs) and consensus statements on the
management of breast cancer (early breast cancer and BRCA and other high-risk
mutations in breast cancer and the ESO-ESMO consensus guidelines on advanced
breast cancer). Key content includes diagnostic criteria, staging of disease,
treatment plans and follow-up. The ESMO CPGs and consensus statements are
intended to provide you with a set of recommendations for the best standards of
care for breast cancer, using evidence-based medicine. Implementation of ESMO
CPGs facilitate knowledge uptake and help you to deliver an appropriate quality of
focused care to your patients.

The approval and licensed indication of drugs mentioned in this pocket guideline
may vary in different countries. Please consult your local prescribing information.
This booklet can be used as a quick reference guide to access key content
on evidence-based management of breast cancer.

Please visit http://www.esmo.org or http://oncologypro.esmo.org to view the

full guidelines and consensus statements.

4
7–27

EARLY BREAST CANCER

SCREENING/DIAGNOSIS/PATHOLOGY/MOLECULAR BIOLOGY...............................7
STAGING AND RISK ASSESSMENT..........................................................................9
TREATMENT.............................................................................................................9
Local treatment.......................................................................................................11
(Neo)Adjuvant systemic treatment..........................................................................13
PERSONALISED MEDICINE....................................................................................21
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP..........................21
SUMMARY RECOMMENDATIONS FOR EARLY BREAST CANCER................... 23

28–61

ADVANCED BREAST CANCER

ABC DEFINITIONS...................................................................................................28
GENERAL GUIDELINES...........................................................................................29
ASSESSMENT AND TREATMENT GENERAL GUIDELINES......................................32
ER-POSITIVE/HER2-NEGATIVE (LUMINAL) ABC....................................................35
HER2-POSITIVE ABC..............................................................................................38
ADVANCED TNBC....................................................................................................40
HEREDITARY ABC...................................................................................................41
PRECISION MEDICINE............................................................................................42
SPECIFIC SITES OF METASTASES..........................................................................43
SPECIFIC POPULATIONS........................................................................................45
LABC.......................................................................................................................46
SUPPORTIVE AND PALLIATIVE CARE....................................................................47
INTEGRATIVE MEDICINE........................................................................................50
DIAGNOSTIC AND TREATMENT ALGORITHMS FOR
ADVANCED BREAST CANCER........................................................................... 51-61

62–65

BRCA IN BREAST CANCER

REFERRAL FOR BRCA TESTING.............................................................................62
MUTATION DETECTION..........................................................................................62
RISK REDUCTION: NON-SURGICAL PREVENTIVE OPTIONS..................................62

5
 Surveillance............................................................................................................62
Chemoprevention....................................................................................................62
RISK MODIFIERS....................................................................................................63
RISK REDUCTION: PROPHYLACTIC SURGICAL OPTIONS.....................................63
Prophylactic bilateral mastectomy..........................................................................63
Prophylactic bilateral salpingo-oophorectomy........................................................63
TREATMENT...........................................................................................................64
Surgery...................................................................................................................64
Systemic treatment.................................................................................................64
SUMMARY RECOMMENDATIONS FOR BRCA IN BREAST CANCER................. 65

66–68

GLOSSARY

6
 EARLY BREAST CANCER
SCREENING/DIAGNOSIS/PATHOLOGY/MOLECULAR BIOLOGY
• Regular (annual or every 2 years) mammography is recommended in women
aged 50–69 years and may also be reasonable for women aged 40–49 and 70–74
years, although there is less evidence of benefit
• In women with a strong familial history of breast cancer, with or without
proven BRCA mutations, annual magnetic resonance imaging (MRI) and annual
mammography (concomitant or alternating) are recommended
• Diagnosis is based on clinical examination in combination with imaging and
confirmed by pathological assessment, as shown in the table below
DIAGNOSTIC WORK-UP FOR EARLY BREAST CANCER
History
Menopausal status
Physical examination
Assessment of general health status Full blood count
Liver, renal and cardiac (in patients planned for anthracycline
and/or trastuzumab treatment) function tests, alkaline
phosphatase and calcium
Physical examination
Mammography
Breast US
Assessment of primary tumour
Breast MRI in selected cases
Core biopsy with pathology determination of histology,
grade, ER, PgR, HER2 and Ki67
Physical examination
Assessment of regional lymph nodes US
US-guided biopsy if suspicious
Physical examination
Other tests are not routinely recommended, unless high
Assessment of metastatic disease
tumour burden, aggressive biology or when symptoms
suggestive of metastases are present
ER, oestrogen receptor; HER2, human epidermal growth factor receptor 2; MRI, magnetic resonance imaging; PgR, progesterone
receptor; US, ultrasound

• Bilateral mammogram and ultrasound (US) of breasts and axillae are

recommended in all cases, with additional MRI in case of uncertainty or in special
clinical situations
7
 • Pathological evaluation includes primary tumour histology and axillary node
cytology/histology (if involvement is suspected)
• Pathological diagnosis should be made according to the World Health
Organization (WHO) classification and the eighth edition of the American Joint
Committee on Cancer (AJCC) tumour, node, metastasis (TNM) staging system
and the report should include histological type, grade, immunohistochemistry
(IHC) evaluation of oestrogen receptor (ER), progesterone receptor (PgR, for
invasive cancer), human epidermal growth factor receptor 2 (HER2) (for invasive
cancer) and a proliferation marker (e.g. Ki67 for invasive cancer)
• Tumours should be grouped into surrogate intrinsic subtypes, defined by routine
histology and IHC data, as shown in the table below
SURROGATE DEFINITIONS OF INTRINSIC SUBTYPES OF BREAST CANCER

INTRINSIC SUBTYPE CLINICOPATHOLOGIC SURROGATE DEFINITION

‘Luminal A-like’
ER-positive
HER2-negative
Luminal A
Ki67 low*
PgR high†
Low-risk molecular signature (if available)

‘Luminal B-like (HER2-negative)’

ER-positive
HER2-negative
either Ki67 high or PgR low
High-risk molecular signature (if available)
Luminal B
‘Luminal B-like (HER2-positive)’
ER-positive
HER2-positive
any Ki67
any PgR

‘HER2-positive (non-luminal)’
HER2 HER2-positive
ER and PgR absent

‘Triple-negative’‡
‘Basal-like’ ER and PgR absent‡
HER2-negative‡

8
*Ki-67 scores should be interpreted in light of local laboratory values: as an example, if a laboratory has a median Ki-67 score in
receptor-positive disease of 20%, values of 30% or above could be considered clearly high; those of 10% or less clearly low
Suggested cut-off value is 20%; quality assurance programmes are essential for laboratories reporting these results
†

‡
There is an approximate 80% overlap between ‘triple-negative’ and intrinsic ‘basal’ subtype, but ‘triple-negative’ also includes
some special histological types such as carcinoma with a rich lymphocytic stroma (former medullary), secretory carcinoma,
low-grade metaplastic carcinoma and adenoid cystic
ER, oestrogen receptor; HER2, human epidermal growth factor receptor 2; PgR, progesterone receptor
Adapted from the 2013 St Gallen Consensus Conference recommendations. Goldhirsch A et al. Ann Oncol 2013;24:2206–23

• Tumour-infiltrating lymphocyte scoring may add information on a patient’s

prognosis but should not be used to guide treatment decisions or to escalate/
de-escalate treatment
• Genetic counselling and testing for germline BRCA1 and BRCA2 mutations
should be offered to breast cancer patients in high-risk groups
STAGING AND RISK ASSESSMENT
• Disease stage should be assessed according to the AJCC TNM staging system
• Minimum blood work-up (a full blood count, liver and renal function tests,
alkaline phosphatase and calcium levels) is recommended before surgery and
systemic (neo)adjuvant therapy
• Chest, abdomen and bone imaging is recommended for higher-risk patients (high
tumour burden, aggressive biology or clinical signs, symptoms or laboratory
values suggesting the presence of metastases)
• Fluorodeoxyglucose (FDG)–positron emission tomography (PET)-computed
tomography (CT) scanning may be useful for high-risk patients and when
conventional methods are inconclusive
• Postoperative pathological assessment of surgical specimens should be made
according to the pathological TNM system
• Validated gene expression profiles may complement pathology assessment and
help in adjuvant chemotherapy (ChT) decision-making
TREATMENT
• Treatment options for early breast cancer are shown in the figure on the
next page

9
10
Early Breast Cancer

Tumour ≤ 2 cm and/or optimal
surgery feasible* with the exception
of aggressive phenotypes**
Tumour > 2 cm or optimal surgery not feasible No wish for breast conservation
and wish for breast conservation and breast
or breast conservation not
conservation potentially feasible after downstaging
possible with the exception of
TNBC/HER2-positive tumours > 2 cm aggressive phenotypes**
and/or with positive axilla
regardless of feasibility of optimal surgery

Systemic induction therapy***

**Aggressive phenotypes: TNBC or HER2-positive breast cancer

postoperative therapies, should preferentially receive preoperative ChT
Satisfactory response Unsatisfactory response
EARLY BREAST CANCER TREATMENT ALGORITHM

BCS Mastectomy ± reconstruction

Postoperative ChT ± anti-HER2

if applicable

Postoperative RT**** if Postoperative ET****

*Biology that requires ChT (TNBC, HER2-positive, luminal B-like), to assess response and prognosis and eventually decide on
applicable (mandatory after BCS) if applicable
***If ChT is planned, it should all be given as neoadjuvant
****Concomitant postoperative RT, postoperative ET and anti-HER2 therapy
BCS, breast-conserving surgery; ChT, chemotherapy; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2;
RT, radiotherapy; TNBC, triple-negative breast cancer

• Treatment should be carried out by a specialised breast cancer multidisciplinary

team in specialised breast units/centres that can refer patients to other
specialties, including plastic/reconstructive surgeons, psychologists,
physiotherapists and geneticists, if necessary
• Patients should be actively involved in all management decisions and should have
access to: a breast nurse or specialised healthcare practitioner; comprehensive,
easily understandable, verbal and written information on the diagnosis and
treatment choices; and reliable patient-centred websites or similar information
sources
• Treatment strategy should be based on the tumour burden/location (size
and location of primary tumour, number of lesions, extent of lymph node
involvement) and biology (pathology, including biomarkers and gene expression),
as well as the age, menopausal status, general health status and preferences of
the patient
• Age should not be the sole determinant for treatment selection
• Fertility and fertility-preservation should be discussed with younger
premenopausal patients prior to the initiation of any systemic treatment
Local treatment
Surgery
Breast conserving surgery
• Breast conserving surgery (BCS) is the preferred local treatment option for
most early breast cancer patients, with the use of oncoplastic techniques in
cosmetically technically challenging cases, when needed
• Careful histological assessment of resection margins is essential. No tumour at
the inked resection margin is essential and > 2 mm for in situ disease is preferred
Mastectomy
• Breast reconstruction should be available for all women requiring mastectomy
• Immediate reconstruction is suitable for the vast majority of cases except
inflammatory cancer
• The optimal reconstruction technique for each patient should be discussed
individually taking into account anatomic, treatment- and patient-related factors
and preferences

11
 Advances in axillary management
• Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in
early, clinically node-negative breast cancer
• Further axillary surgery following positive SLNB is not required for low axillary
disease burden (micrometastases or one to two sentinel lymph nodes containing
metastases treated with postoperative tangential breast radiotherapy [RT])
• Axillary RT is a valid alternative in patients with positive SLNB, irrespective of the
type of breast surgery
Surgery for in situ malignancy (intraepithelial neoplasia)
• BCS followed by whole-breast RT (WBRT) or total mastectomy are acceptable
treatment options for ductal carcinoma in situ (DCIS)
• In BCS, a 2-mm margin is adequate for DCIS treated with WBRT
• Routine SLNB is not recommended for DCIS, except in patients with large and/or
high-grade tumours, especially when mastectomy is required
Management of occult breast cancer
• The preferred locoregional management of occult breast cancer is axillary lymph
node dissection (ALND) and WBRT
Risk-reducing mastectomy
• Risk-reducing surgery (with prophylactic bilateral mastectomy and
reconstruction) may be offered to women at a very high risk, such as BRCA1 or
BRCA2 mutation carriers or those who have had previous chest RT at young age
Presurgery genetic assessment and psychological counselling are mandatory
and intense surveillance should also be discussed
• Non-high-risk patients opting for bilateral mastectomy rather than BCS should be
counselled that survival outcomes with BCS may be better (and are certainly not
worse) than those with mastectomy
Surgery after primary systemic therapy
• Surgery following primary systemic therapy (PST) should be carried out
according to general rules for early breast cancer and considering the baseline
tumour characteristics as well as the post-treatment outcomes
• If BCS is anticipated, the tumour site should be marked and pre- and post-
treatment breast MRI should be carried out
• In clinically negative axilla, post-PST SLNB is preferred to pre-PST SLNB
• SLNB may be carried out in selected cases of baseline axillary involvement
converting to negative, thereby indicating if further axillary surgery may be avoided
• Identification of tumour deposits in post-PST SLNB prompts ALND
12
RT
• In terms of doses and fractionation, moderate hypofractionation schedules
(15–16 fractions of ≤ 3 Gy/fraction) are recommended for routine postoperative
RT of breast cancer
• After BCS, postoperative WBRT is strongly recommended, with boost RT to
reduce the risk of in-breast relapse in patients at higher risk of local recurrence
Accelerated partial-breast RT is an acceptable treatment option in patients with
a low risk for local recurrence
• Post-mastectomy RT (PMRT) is recommended for high-risk patients, including
those with involved resection margins, more than 3 involved axillary lymph nodes
and T3–T4 tumours; it should also be considered in patients with 1–3 positive
axillary lymph nodes
• Regional comprehensive nodal RT is recommended for patients with involved
lymph nodes, although after ALND routine axillary irradiation should not be
applied to the operated part of the axilla
• After immediate breast reconstruction, postoperative RT can be administered, if
indicated, and a multidisciplinary and interactive patient-involving approach is
required to individualise the best combination of the sequence and type of breast
reconstruction and RT
• In intraepithelial neoplasia (DCIS), WBRT is recommended for most women
undergoing BCS, although omission of radiation is an option for patients with
low-risk disease and tumour bed boost can be considered for patients at higher
risk for local failure
• PMRT is not recommended for DCIS
(Neo)Adjuvant systemic treatment
• The choice of therapies should be based on an individual’s risk of relapse, the
predicted sensitivity to treatment, the benefit and toxicities of treatment, and the
patient’s biological age, general health status, comorbidities and preferences, as
shown in the tables and figure on the next pages

13
 SYSTEMIC TREATMENT RECOMMENDATIONS FOR EARLY BREAST CANCER
SUBTYPES

SUBTYPE RECOMMENDED THERAPY COMMENTS

Consider ChT if high tumour burden (≥ 4

Luminal A-like ET alone in the majority of cases
lymph nodes, T3 or higher)

Luminal B-like ChT followed by ET for the majority

(HER2-negative) of cases

If contraindications for the use of

Luminal B-like ChT + anti-HER2 followed by ChT, one may consider ET + anti-HER2
(HER2-positive) ET for all patients therapy, although no randomised
data exist

HER2-positive
ChT + anti-HER2
(non-luminal)

Triple-negative
ChT
(ductal)

For special histological types, the 2013 St Gallen Consensus Conference recommendations (Goldhirsch A et al. Ann Oncol
2013;24:2206–23) propose ET for endocrine-responsive histologies (cribriform, tubular and mucinous), ChT for high-risk
endocrine-nonresponsive histologies (medullary, metaplastic) and no systemic therapy for low-risk endocrine-nonresponsive
histologies (adenoid cystic and apocrine)
ChT, chemotherapy; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2

SUMMARY OF BIOMARKERS USED IN TREATMENT DECISION-MAKING

BIOMARKER METHOD USE

Essential to the characterisation of the IHC

luminal-like group
IHC
ER Poor prognostic marker if negative
Positive if ≥ 1%
Predictive marker for ET
Mandatory for ET prescription

If negative tumour classified as IHC luminal

B-like
IHC
PgR Strong poor prognostic marker if negative
Positive if ≥ 1%
Predictive marker for ET

14
 IHC
Positive if > 10% complete
Essential to the characterisation of:
membrane staining (3+)
ISH • HER2-enriched (ER-negative)
Single probe • Luminal B-like, HER2-positive
HER2 if HER2 ≥ 6 copies Prognostic marker
Dual probe Predictive marker for anti-HER2 treatment
Positive if HER2/CEP17 ≥ 2 and Mandatory for anti-HER2 therapy regardless
HER2 copies ≥ 4
of treatment line
Or HER2/CEP17 < 2 and HER2
copies ≥ 6
Absence of international consensus for
scoring and threshold
Prognostic value in ER-positive, HER2-
negative tumours (primary tumours and
post-neoadjuvant residual tumour)
IHC Absence of prognostic value in HER2-
No final consensus on cut-off but positive or triple-negative tumours
Ki67 values below 10% are considered Predictive of response to neoadjuvant ET†
low and above 30% are considered Predictive of response to neoadjuvant ChT
high* If elevated, ChT is often prescribed in ER-
positive, HER2-negative tumours
Part of the IHC definition of luminal-like
tumours
• Ki67 low, luminal A-like
• Ki67 high, luminal B-like

Prognostic
Gene expression profile, Predictive: Different responses to
Intrinsic subtypes
N-CounterTM technology neoadjuvant ChT and anti-HER2 therapy
according to the subtype

For ER-positive, HER2-negative tumours

First-generation Prognostic
signatures (Neo)Adjuvant ChT is indicated if high risk
Gene expression profile, RT-PCR
(MammaPrint, or high score
Oncotype DX) Can be carried out in biopsy or surgical
specimen

For ER-positive, HER2-negative tumours,

Second-generation include T size and N status in their final score
signatures Prognostic
(Prosigna®, N-CounterTM technology, RT-PCR (Neo)Adjuvant ChT is indicated if high risk
Endopredict®) or high score
Can be carried out in biopsy or surgical
specimen

*According to the International Ki67 Working Group Guidelines, Dowsett M et al. J Natl Cancer Inst 2011;103:1656–64
†
A decrease in Ki67 expression during neoadjuvant ET is highly predictive of response
ChT, chemotherapy; ER, oestrogen receptor; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; IHC,
immunohistochemistry; ISH, in situ hybridisation; PgR, progesterone receptor; RT-PCR, reverse transcription polymerase chain reaction 15
 (NEO)-ADJUVANT SYSTEMIC TREATMENT CHOICE BY MARKER EXPRESSION
AND INTRINSIC PHENOTYPE

+ anti-HER2**
HER2-positive

Luminal B

ChT*****

+ ET
ER-positive

ET ± ChT****
Luminal B
HER2-negative

ChT only in selected

cases with high-
disease burden
Luminal A

ET
Early Breast Cancer

no other risk factors

Special histological
types***, N0,

Observation
or ChT
TNBC

Ductal
ER-negative

ChT
HER2-positive

ChT* + anti-
HER2**

*With possible exception of selected cases with very low-risk T1abN0

**Anti-HER2: Trastuzumab ± pertuzumab
***Adenoid cystic or apocrine, secretory carcinoma, low-grade metaplastic carcinoma
****Depending on level of ER and PgR expression, proliferation, genomically assessed risk, tumour burden and/or patient
preference
*****Except for very low-risk patients T1abN0 for whom ET/anti-HER2 therapy alone can be considered
ChT, chemotherapy; ER, oestrogen receptor; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2;
N0, node-negative; PgR, progesterone receptor; TNBC, triple-negative breast cancer

16
• Adjuvant systemic treatment should preferably start within 3–6 weeks after
surgery and neoadjuvant systemic therapy should start as soon as diagnosis
and staging are completed (ideally within 2–4 weeks)
• All luminal-like cancers should be treated with endocrine therapy (ET)
• Most luminal A-like tumours do not require ChT, except those with high
disease burden
• ChT use in luminal B-like HER2-negative patients depends on individual risk
of recurrence, presumed responsiveness to ET and patient preference
• In cases of uncertainty, adjuvant ChT can be guided by expression of urokinase
plasminogen activator–plasminogen activator inhibitor 1 (uPA-PAI1) or gene
expression assays
• Luminal B-like HER2-positive tumours should be treated with ChT, ET and anti-
HER2 therapy, although selected low-risk patients (T1abN0) may receive the
combination of anti-HER2 therapy and/or ET alone
• Patients with triple-negative breast cancer (TNBC) should receive ChT, with the
possible exception of low-risk ‘special histological subtypes’ such as secretory or
adenoid cystic carcinomas or very early (T1aN0) tumours
• HER2-positive cancers should be treated with ChT plus anti-HER2 therapy, with
the possible exception of selected cases with very low-risk, such as T1aN0
tumours
• ChT should not be used concomitantly with ET, except for gonadotropin-releasing
hormone analogues used for ovarian protection
• Anti-HER2 therapy may routinely be combined with non-anthracycline-based ChT,
ET and RT
• RT may be delivered safely during anti-HER2 therapy, ET and non-anthracycline,
non-taxane-based ChT
• When used together, ChT should usually precede RT
ET
Premenopausal patients
• For premenopausal women, tamoxifen for 5–10 years is a standard of care
• Patients becoming postmenopausal during the first 5 years of tamoxifen can
be switched to letrozole, depending on the predicted risk of late recurrence
• In patients requiring ChT, who recover menses, addition of ovarian function
suppression (OFS) to ET should be strongly considered
• Replacing tamoxifen with an aromatase inhibitor (AI) can be considered in high-
risk patients
17
 If an AI is used, it mandates effective OFS, with regular biochemical control of
oestrogen levels
• In patients < 35 years not requiring ChT, combination of OFS with the most
effective ET is suggested
• OFS during ChT should not be the sole fertility preservation method used, in case
of desired pregnancy
Postmenopausal patients
• For postmenopausal women, AIs (both non-steroidal and steroidal) and
tamoxifen are standard treatments
• AIs can be used upfront (non-steroidal AI and exemestane), after 2–3 years of
tamoxifen (non-steroidal AI and exemestane) or as extended adjuvant therapy,
after 5 years of tamoxifen (letrozole and anastrozole)
• Extended adjuvant ET should be discussed with all patients with greater than a
very low risk of relapse, although the optimal duration and regimen is unknown
There is only a minimal benefit for the use of AIs for more than 5 years
• Patients undergoing OFS or receiving AIs should be advised to have adequate
calcium and vitamin D3 intake and should undergo periodic dual energy X-ray
absorption scan for assessment of bone mineral density
ChT
• ChT should be administered for 12–24 weeks (4–8 cycles)
• A sequential anthracycline/taxane-based regimen is the standard for the
majority of patients, although 4 cycles of anthracycline- or taxane-based ChT or
cyclophosphamide/methotrexate/5-fluorouracil (CMF) may be used in selected
lower risk patients
• Non-anthracycline regimens may be used in patients at risk of cardiac complications
• Anthracycline-based regimens should not include 5-fluorouracil (epirubicin/
cyclophosphamide [EC] or doxorubicin/cyclophosphamide [AC] is standard)
• Platinum compounds should not be used routinely in the adjuvant setting
• Granulocyte colony-stimulating factor (G-CSF)-supported dose-dense schedules
should be considered, particularly in highly proliferative tumours
Anti-HER2 therapy
• The treatment of HER2-positive breast cancer is shown in the figure on the
next page

18
HER2-POSITIVE BREAST CANCER TREATMENT

HER2-positive Breast Cancer

Preoperative ChT + trastuzumab ± pertuzumab

pCR No pCR

Initially N-positive Other cases

or ER-negative

Complete 1 year of dual Complete 1 year of trastuzumab T-DM1*

blockade
or
Complete 1 year of
trastuzumab

*Not yet EMA-approved.

ChT, chemotherapy; EMA, European Medicines Agency; ER, oestrogen receptor; HER2, human epidermal growth factor receptor
2; N-positive, node positive; pCR, pathological complete response; T-DM1, trastuzumab emtansine

• (Neo)Adjuvant trastuzumab should be given to all HER2-positive early breast

cancer patients without contraindications for its use, with the possible exception
of selected very low-risk cases, such as T1aN0 tumours
• HER2-targeted therapy may also be considered in cases where a HER2 test result
is deemed to be equivocal, even after reflex testing with an alternative assay
• One year of (neo)adjuvant trastuzumab is the standard for most HER2-positive
patients, but a 6-month course can be considered for highly selected, low-risk
patients receiving anthracycline/taxane-based ChT
• Trastuzumab must not be given concomitantly with anthracycline-based ChT
but it can be safely combined with non-anthracycline-based ChT (i.e. taxanes),
concomitant use being more effective than sequential treatment
• Regular cardiac monitoring before starting and during trastuzumab treatment
is mandatory
19
 • One-year of treatment with combined trastuzumab/pertuzumab, starting
before or after surgery, can be considered in high-risk patients (node-positive
or ER-negative)
• In cases of residual invasive disease after completion of combined neoadjuvant
ChT and anti-HER2 therapy, adjuvant trastuzumab should be replaced by
adjuvant trastuzumab emtansine (T-DM1), which is currently not approved by the
European Medicines Agency (EMA)
• Extended anti-HER2 therapy with neratinib may be considered in selected high-
risk patients, not previously treated with dual blockade, and with appropriate
diarrhoea prophylaxis and management
Primary (neoadjuvant) systemic therapy
• PST is recommended to reduce the extent of surgery in locally advanced and
large operable cancers, in particular when mastectomy is required due to tumour
size, and should also be considered in all patients with tumours > 2 cm for which
ChT is deemed necessary (particularly with TNBC and HER2-positive subtypes)
• Drugs and drug regimens for preoperative and postoperative settings should be
selected according to the same rules and sequential anthracyclines and taxanes
are recommended for most patients
• The addition of a platinum compound may be considered in TNBC and/or in
patients with deleterious BRCA1/2 mutations
• Where PST is used, all ChT should be delivered preoperatively
• In high-risk TNBC not achieving pathological complete response after standard
neoadjuvant ChT, the postoperative addition of 6–8 cycles of capecitabine may be
considered
• In postmenopausal patients with ER-positive/HER2-negative cancers requiring
PST and without a clear indication for ChT, preoperative ET (4–8 months or until
maximum response) should be considered and continued postoperatively
Bisphosphonates for early breast cancer
• Bisphosphonates for early breast cancer are recommended in women with
low-oestrogen status, especially if at high risk of relapse, and in patients with
treatment-related bone loss
Other clinical scenarios
• The treatment of elderly early breast cancer patients should be preceded by a
geriatric assessment and then adapted to biological (not chronological) age
Patients suitable for standard ChT should receive a standard multidrug
regimen, with consideration being given to less aggressive regimens for
frail patients
20
• In male breast cancer patients, tamoxifen is the standard adjuvant ET, although
a combination of an AI plus a luteinising hormone-releasing hormone (LHRH)
agonist may be considered in patients with contraindications to tamoxifen, but its
higher toxicity must be discussed with the patient to avoid compliance issues
• Male breast cancer patients should not receive an AI alone as adjuvant ET
• ChT and anti-HER2 therapy indications and regimen recommendations are the
same for males and females
• In DCIS, systemic adjuvant therapy with both tamoxifen and AIs may be used
after conservative local treatment (to prevent local recurrence and to decrease
the risk of development of a second primary breast cancer)
• Following mastectomy for DCIS, tamoxifen or AI might be considered to decrease the
risk of contralateral breast cancer in patients at a high risk of new breast tumours
PERSONALISED MEDICINE
• ER, PgR and HER2 status should guide all systemic treatment decisions
• Surrogate intrinsic tumour phenotypes, based on expression of ER, PgR, HER2
and Ki67, should be used to define subpopulations of breast cancers
• Expression of uPA-PAI1 or multigene panels, such as MammaPrint, Oncotype
DX, EndoPredict, Prosigna or Breast Cancer Index, may be used in conjunction
with all clinicopathological factors to guide challenging systemic treatment
decisions, such as in cases of luminal B-like/HER2-negative and node-negative/
nodes 1–3-positive breast cancer
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP
• Regular follow-up visits are recommended every 3–4 months in the first 2 years
(every 6 months for low-risk and DCIS patients), every 6–8 months from years
3–5 and annually thereafter, with the interval between visits being adapted to the
risk of relapse and patients’ needs
• Annual bilateral (after breast-conserving therapy) and/or a contralateral
mammography (after mastectomy), with US and breast MRI when needed, is
recommended
• In asymptomatic patients, other laboratory or imaging tests are not
recommended
• Regular bone density evaluation is recommended for patients on AIs or
undergoing OFS
• Patients should be encouraged to adopt a healthy lifestyle, including diet
modification and exercise

21
 • Hormone replacement therapy should usually not be used
• Patients should have unlimited access to specialised rehabilitation facilities
and services
• Long-term survivorship problems, including psychological needs and issues
related to work, family and sexuality, should be addressed

22
SCREENING/DIAGNOSIS/PATHOLOGY/MOLECULAR BIOLOGY
Regular (annual or every 2 years) mammography in women aged 50–69 years and
annual MRI of women with familial breast cancer are recommended
Diagnosis is based on clinical examination and imaging and confirmed by patho-
logical assessment
Bilateral mammogram and US of breasts and axillae are recommended
Tumours should be grouped into surrogate intrinsic subtypes, defined by routine
histology and IHC data
Genetic counselling and testing for germline BRCA1 and BRCA2 mutations should
be offered to high-risk groups

STAGING AND RISK ASSESSMENT

Disease stage should be assessed according to the AJCC TNM staging system
Minimum blood work-up is recommended before surgery and systemic (neo)
adjuvant therapy, with chest, abdomen and bone imaging for higher-risk patients
Postoperative pathological assessment of surgical specimens should be made
according to the pathological TNM system

TREATMENT
Treatment should be carried out by a specialised breast cancer multidisciplinary
team in specialised breast units/centres and patients should be actively involved in
all management decisions
Treatment should be based on the tumour burden/location and biology, as well as
age, menopausal status, general health status and patient preference
Fertility and fertility-preservation should be discussed with younger premenopausal
patients prior to the initiation of any systemic treatment

LOCAL TREATMENT
Surgery
• BCS is the preferred local treatment option for most early breast cancer patients
when needed

23
 • In all women undergoing mastectomy, breast reconstruction should be available
and immediate reconstruction is suitable for the vast majority of cases except
inflammatory cancer; the optimal reconstruction technique for each patient
should be discussed individually
• SLNB is the standard of care for axillary staging in early, clinically node-negative
breast cancer; in patients with positive SLNB, further axillary surgery is not
required for low axillary disease burden, and axillary RT is a valid alternative
• For DCIS, BCS (with a 2 mm margin) followed by WBRT or total mastectomy are
acceptable treatment options
• For occult breast cancer, the preferred locoregional management is ALND and WBRT
Risk-reducing mastectomy
• Risk-reducing surgery may be offered to women at a very high risk and
presurgery genetic assessment and psychological counselling are mandatory
• Non-high-risk patients opting for bilateral mastectomy should be counselled that
survival outcomes with BCS may be better
Surgery after PST
• If BCS is anticipated, the tumour site should be marked and pre- and post-
treatment breast MRI carried out
• In clinically negative axilla, post-PST SLNB is preferred to pre-PST SLNB
• SLNB may be carried out in selected cases of baseline axillary involvement
converting to negative
• Tumour deposits in post-PST SLNB prompt ALND
RT
• Moderate hypofractionation schedules (15–16 fractions of ≤ 3 Gy/fraction) are
recommended for routine postoperative RT
• After BCS, postoperative WBRT is strongly recommended, with boost RT where
there is a high risk of local recurrence; accelerated partial-breast RT is an option
where the risk of recurrence is low
• PMRT is recommended for high-risk patients and should also be considered in
patients with 1–3 positive axillary lymph nodes
• Regional comprehensive nodal RT is recommended for patients with involved
lymph nodes

24
• After ALND, routine axillary irradiation should not be applied to the operated part
of the axilla
• Postoperative RT can be administered after immediate breast reconstruction, if indicated
• In DCIS, WBRT is recommended for most women undergoing BCS, with tumour
bed boost being a consideration for patients at a high risk of local failure
(Neo)Adjuvant systemic treatment
• Adjuvant treatment should start within 3–6 weeks after surgery and neoadjuvant
treatment should start within 2–4 weeks of diagnosis and staging
• All luminal-like cancers should be treated with ET
• ChT is not required for most luminal A-like tumours
• ChT use in luminal B-like HER2-negative disease should be based on risk of
recurrence and presumed responsiveness to ET and it should be used with ET
and anti-HER2 therapy in luminal B-like HER2-positive tumours
• ChT should not be used concomitantly with ET, except for gonadotropin-releasing
hormone analogues used for ovarian protection
• Patients with TNBC should generally receive ChT
• HER2-positive cancers should generally be treated with ChT plus anti-HER2
therapy
• Anti-HER2 therapy may routinely be combined with non-anthracycline-based ChT,
ET and RT
• RT may be delivered safely during anti-HER2 therapy, ET and non-anthracycline,
non-taxane-based ChT
• When used together, ChT should usually precede RT
ET
Premenopausal patients
• Tamoxifen for 5–10 years is a standard of care, with an AI as an alternative for
high-risk patients
• Patients becoming postmenopausal during the first 5 years of tamoxifen, can be
switched to letrozole
• Patients < 35 years not requiring ChT should receive OFS combined with ET
Postmenopausal patients
• AIs (upfront, after tamoxifen or as extended adjuvant therapy) and tamoxifen are
standard treatments
• There is only a minimal benefit for the use of AIs for more than 5 years

25
 ChT
• ChT should be administered for 12–24 weeks (4–8 cycles)
• Sequential anthracycline (EC or AC)/taxane-based regimen is the standard,
although 4 cycles of anthracycline- or taxane-based ChT or CMF may be used
in lower-risk patients
• Non-anthracycline regimens may be used in patients at risk of cardiac
complications
• G-CSF-supported dose-dense schedules should be considered, particularly in
highly proliferative tumours
Anti-HER2 therapy
• One year of (neo)adjuvant trastuzumab is the standard for HER2-positive patients
without contraindications to its use
• Trastuzumab can be given concomitantly with non-anthracycline-based (but not
anthracycline-based) ChT
• Regular cardiac monitoring before starting and during trastuzumab treatment
is mandatory
• One-year of combined trastuzumab/pertuzumab can be considered in
high-risk patients
• In cases of residual invasive disease after combined neoadjuvant ChT and anti-
HER2 therapy, adjuvant trastuzumab should be replaced by adjuvant T-DM1 (not
EMA-approved)
• Extended anti-HER2 therapy with neratinib may be considered in selected high-
risk patients
Primary (neoadjuvant) systemic therapy
• PST is recommended in locally advanced and large operable cancers and can be
considered for tumours > 2 cm requiring ChT
• Sequential anthracyclines and taxanes are recommended for most patients, with
the addition of platinum for TNBC or BRCA1/2-mutated disease
• In postmenopausal patients with ER-positive/HER2-negative cancers requiring
PST, preoperative ET should be considered and continued postoperatively
• Bisphosphonates are recommended in women with low-oestrogen status and
those with treatment-related bone loss

26
Other clinical scenarios
• For elderly patients, treatment should be adapted to biological age and a standard
multidrug regimen is recommended for suitable patients, with less aggressive
regimens for frail patients
• In male breast cancer patients, the standard adjuvant ET is tamoxifen; an AI alone
should not be used
• ChT and anti-HER2 therapy indications and regimen recommendations are the
same for males and females
• In DCIS, both tamoxifen and AIs may be used after conservative local treatment
and after mastectomy
PERSONALISED MEDICINE
ER, PgR and HER2 status should guide all systemic treatment decisions
Surrogate intrinsic tumour phenotypes, based on expression of ER, PgR, HER2 and
Ki67, should be used to define subpopulations of breast cancers
Expression of uPA-PAI1 or multigene panels may be used in conjunction with
clinicopathological factors to guide challenging systemic treatment decisions

FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP

Regular follow-up visits are recommended every 3–4 months in the first 2 years
(every 6 months for low-risk and DCIS patients), every 6–8 months from years 3–5
and annually thereafter
Annual bilateral (after breast-conserving treatment) and/or a contralateral mam-
mography (after mastectomy) is recommended
Regular bone density evaluation is recommended for patients receiving AIs or
undergoing OFS

27
 ABC DEFINITIONS LoE/GoR CONSENSUS
VISCERAL CRISIS is defined as severe organ dysfunction as assessed
by signs and symptoms, laboratory studies and rapid progression of
Expert
disease. Visceral crisis is not the mere presence of visceral metastases
opinion/ 95%
but implies important visceral compromise leading to a clinical indication
n/a
for a more rapidly efficacious therapy, particularly since another treatment
option at progression will probably not be possible
PRIMARY ENDOCRINE RESISTANCE is defined as relapse while Expert
on the first 2 years of adjuvant ET, or PD within first 6 months of first- opinion/ 67%
line ET for ABC, while on ET n/a
SECONDARY ENDOCRINE RESISTANCE is defined
Expert
as relapse while on adjuvant ET but after the first 2 years, or relapse
within 12 months of completing adjuvant ET, or PD ≥ 6 months after
opinion/ 67%
n/a
initiating ET for ABC, while on ET
OLIGOMETASTATIC DISEASE is defined as low volume metastatic
Expert
disease with limited number and size of metastatic lesions (up to 5 and
opinion/ 78%
not necessarily in the same organ), potentially amenable for local
n/a
treatment, aimed at achieving a complete remission status
PATIENTS WITH MULTIPLE CHRONIC CONDITIONS are defined
as patients with additional comorbidities (e.g. cardiovascular, impaired Expert
renal or liver function, autoimmune disease) making it difficult to opinion/ 100%
account for all of the possible extrapolations to develop specific n/a
recommendations for care
ADEQUATE OFS IN THE CONTEXT OF ABC Adequate OFS for ABC
premenopausal patients can be obtained through bilateral ovariectomy,
I/A 85%
continuous use of LHRH agonists or OFA through pelvic RT (this latter is
not always effective and therefore is the least preferred option)
If a LHRH agonist is used in this age group, it should usually be given on II / B 85%
a q4w basis to guarantee optimal OFS
Efficacy of OFS must be initially confirmed analytically through serial Expert
evaluations of serum oestradiol, even in the presence of amenorrhoea, opinion/B 85%
especially if an AI is administered

As all endocrine interventions for premenopausal patients with endocrine-

responsive ABC require indefinite OFS, choosing one method over the Expert
85%
other requires balance of patient’s wish for potentially preserving fertility, opinion/B
compliance with frequent injections over a long period of time and cost

28
 MAINTENANCE THERAPY In the context of ABC Guidelines, Expert
maintenance therapy refers to the continuation of anti-HER2 therapy opinion/ 100%
and/or ET after discontinuation of ChT n/a
INTEGRATIVE MEDICINE CIM represents the use of complementary Expert
treatments side by side with conventional approaches in a proper opinion/ 100%
therapeutic environment n/a
ABC, advanced breast cancer; AI, aromatase inhibitor; ChT, chemotherapy; CIM, complementary and integrative medicine;
Consensus, percentage of panel members in agreement with the statement; ET, endocrine therapy; GoR, grade of
recommendation; HER2, human epidermal growth factor 2; LHRH, luteinising hormone-releasing hormone; LoE, available level
of evidence; OFA, ovarian function ablation; OFS, ovarian function suppression; PD, disease progression; q4w, every 4 weeks;
RT, radiotherapy

LoE/
GENERAL GUIDELINES CONSENSUS
GoR
The management of ABC is complex and, therefore, involvement of all
appropriate specialties in a multidisciplinary team (including but not
Expert
restricted to medical, radiation, surgical oncologists, imaging experts, 100%
opinion/A
pathologists, gynaecologists, psycho-oncologists, social workers,
nurses and palliative care specialists) is crucial
From the time of diagnosis of ABC, patients should be offered
appropriate psychosocial care, supportive care and symptom-related Expert
100%
interventions as a routine part of their care. The approach must be opinion/A
personalised to meet the needs of the individual patient
Following a thorough assessment and confirmation of ABC, the potential
treatment goals of care should be discussed. Patients should be told that Expert
97%
ABC is incurable but treatable, and that some patients can live with ABC for opinion/A
extended periods of time (many years in some circumstances)
This conversation should be conducted in the accessible language,
Expert
respecting patient privacy and cultural differences, and, whenever 97%
opinion/A
possible, written information should be provided
All ABC patients should be offered comprehensive, culturally sensitive,
up-to-date and easy-to-understand information about their disease and I/A 97%
its management
Patients (and their families, caregivers or support network, if the patient
agrees) should be invited to participate in the decision-making process
Expert
at all times. When possible, patients should be encouraged to be 100%
opinion/A
accompanied by persons who can support them and share treatment
decisions (e.g. family members, caregivers, support network)

29
 Every ABC patient must have access to optimal cancer treatment and
supportive care according to the highest standards of patient-centred
care, as defined by:
• Open communication between patients and their cancer care teams
as a primary goal
• Educating patients about treatment options and supportive care,
through development and dissemination of evidence-based Expert
information in a clear, culturally appropriate form 100%
opinion/A
• Encouraging patients to be proactive in their care and to share
decision-making with their health care providers
• Empowering patients to develop the capability of improving their own
QoL within their cancer experience
• Always taking into account patient preferences, values and needs as
essential to optimal cancer care
Every ABC patient should:
• Have access to the most up-to-date treatments and to innovative Expert
therapies at accessible Breast Units/Centres opinion/A
• Be treated in SBUs by a specialised multidisciplinary team including I/A
specialised side effects management and a nurse experienced in the
treatment of ABC
100%
• Survivorship issues and palliative care should be addressed and Expert
offered at an early stage opinion/A
• A quality assurance programme covering the entire breast cancer Expert
pathway from screening and diagnosis to treatment, rehabilitation, opinion/B
follow-up and palliative care including services and support for ABC
patients and their caregivers, should be implemented by SBUs
General: QoL
Strong consideration should be given to the use of validated PROMs for
patients to record the symptoms of disease and side effects of treatment
experienced as a regular part of clinical care. These PROMs should be
simple and user-friendly to facilitate their use in clinical practice, and
thought needs to be given to the easiest collection platform, e.g. tablets I/C 87%
or smartphones. Systematic monitoring would facilitate communication
between patients and their treatment teams by better characterising the
toxicities of all anticancer therapies. This would permit early intervention
of supportive care services enhancing QoL
Expert
Specific tools for evaluation of QoL in ABC patients should be developed 100%
opinion/A

30
Until then, trials evaluating QoL in this setting should use standardised
PROs (instead of focusing exclusively on CTCAEs) and incorporate Expert
100%
specific site and treatment specific modules or subscales that exist both opinion/A
in the EORTC and FACT systems
Additionally, attention needs to be paid to collection methods, timing of
assessments and handling of missing data. More sophisticated statistics Expert
100%
should also be employed to ensure that clinicians have better, reliable opinion/A
data to help patients when choosing between treatment options
General: CLINICAL TRIALS
There are few proven standards of care in ABC management. After
appropriate informed consent, inclusion of patients in well-designed, Expert
100%
prospective, independent trials must be a priority whenever such trials opinion/A
are available and the patient is willing to participate
The ABC community strongly calls for clinical trials addressing
important unanswered clinical questions in this setting, and not just for
Expert
regulatory purposes. Clinical trials should continue to be carried out, 100%
opinion/A
even after approval of a new treatment, providing real world data on its
performance, efficacy and toxicity
General: AFFORDABILITY/COST-EFFECTIVENESS
The medical community is aware of the problems raised by the cost of ABC
Expert
treatment. Balanced decisions should be made in all instances; patients’ 100%
opinion/A
well-being, length of life and preferences should always guide decisions
We strongly recommend the use of objective scales, such as the ESMO-
MCBS or the ASCO Value Framework, to evaluate the real magnitude of Expert
88%
benefit provided by a new treatment and help prioritise funding, particularly opinion/A
in countries with limited resources
The ABC community strongly supports the use of BIOSIMILARS both
for treatment of breast cancer (i.e. T) and for supportive care (i.e. growth
factors). To be used, the biosimilar must be approved after passing the I/A 90%
stringent development and validation processes required by the EMA or
the FDA or other similarly strict authority
General: SURVIVORSHIP
As survival is improving in many patients with ABC, consideration of
survivorship issues should be part of the routine care of these patients.
Health professionals should therefore be ready to change and adapt
Expert
treatment strategies to disease status, treatment adverse effects and QoL, 95%
opinion/A
patients’ priorities and life plans. Attention to chronic needs for home and
family care, job and social requirements should be incorporated in the
treatment planning and periodically updated

31
 ABC patients who desire to work or need to work for financial reasons should
Expert
have the opportunity to do so, with needed and reasonable flexibility in their 100%
opinion/A
working schedules to accommodate continuous treatment and hospital visits
ABC patients with stable disease, being treated as a ‘chronic condition’,
Expert
should have the option to undergo breast reconstruction if clinically 82%
opinion/B
appropriate
In ABC patients with long-standing stable disease, screening breast Expert Yes: 53%
imaging should be an option opinion/C No: 47%
Breast imaging should also be carried out when there is a suspicion of
I/A 100%
locoregional progression
FERTILITY PRESERVATION The impact of the anticancer therapies on
fertility should be discussed with all women with ABC of childbearing age
Expert
and their partners, before the start of treatment. The discussion must also 100%
opinion/B
include appropriate information about the prognosis of the disease and the
potential consequences of pregnancy (e.g. stopping ongoing treatment)
General: OTHER

SPECIALISED ONCOLOGY NURSES (if possible specialised breast

nurses) should be part of the multidisciplinary team managing ABC Expert
92%
patients. In some countries, this role may be played by a physician opinion/A
assistant or another trained and specialised healthcare practitioner

The use of TELEMEDICINE in oncology to help management of patients

with ABC living in remote places is an important option to consider Expert
93%
when geographic distances are a problem and provided that issues of opinion/B
connectivity are solved

ABC, advanced breast cancer; ASCO, American Society of Clinical Oncology; Consensus, percentage of panel members in
agreement with the statement; CTCAE, Common Terminology Criteria for Adverse Events; EMA, European Medicines Agency;
EORTC, European Organisation for Research and Treatment of Cancer; ESMO-MCBS, European Society for Medical Oncology
Magnitude of Clinical Benefit Scale; FACT, Functional Assessment of Cancer Therapy; FDA, Food and Drug Administration; GoR,
grade of recommendation; LoE, available level of evidence; PRO, patient-reported outcome; PROM, patient-reported outcome
measure; QoL, quality of life; SBU, specialist breast unit/centre/service; T, trastuzumab

LoE/
ASSESSMENT AND TREATMENT GENERAL GUIDELINES CONSENSUS
GoR
IMAGE AND DISEASE ASSESSMENT GUIDELINES
Minimal staging work-up for ABC includes a history and physical
examination, haematology and biochemistry tests, and imaging of chest, II / A 67%
abdomen and bone
Brain imaging should not be routinely carried out in asymptomatic
patients. This approach is applicable to all patients with ABC including II / D 94%
those with HER2-positive and/or metastatic TNBC

32
The clinical value of tumour markers is not well established for diagnosis
or follow-up after adjuvant therapy, but their use (if elevated) as an aid to
evaluate response to treatment, particularly in patients with non-measurable II / C 89%
metastatic disease, is reasonable. A change in tumour markers alone
should not be used to initiate a change in treatment
Evaluation of response to therapy should generally occur every 2–4
months for ET or after 2–4 cycles for ChT, depending on the dynamics of
the disease, the location and extent of metastatic involvement and type of
treatment. Imaging of target lesions may be sufficient in many patients.
Expert
In certain patients, such as those with indolent disease, less frequent 81%
opinion/B
monitoring is acceptable. Additional testing should be carried out in a
timely manner, irrespective of the planned intervals, if PD is suspected or
new symptoms appear.Thorough history and physical examination must
always be carried out
BIOPSY GUIDELINES
A biopsy (preferably providing histology) of a metastatic lesion should
be carried out, if easily accessible, to confirm diagnosis particularly when I/B 98%
metastasis is diagnosed for the first time
Biological markers (especially HR and HER2) should be reassessed at
least once in the metastatic setting, if clinically feasible. Depending on
I/B 98%
the metastatic site (e.g. bone tissue), technical considerations need to be
discussed with the pathologist
If the results of tumour biology in the metastatic lesion differ from the primary
tumour, it is currently unknown which result should be used for treatment
decision making. Since a clinical trial addressing this issue is difficult to Expert
87%
undertake, we recommend considering the use of targeted therapy (ET and/ opinion/B
or anti-HER2 therapy) when receptors are positive in at least one biopsy,
regardless of timing
LOCOREGIONAL TREATMENT GENERAL GUIDELINES
To date, the removal of the primary tumour in patients with de novo
stage IV breast cancer has not been associated with prolongation of
survival, with the possible exception of the subset of patients with bone- I/C 70%
only disease. However, it can be considered in selected patients, particularly
to improve QoL, always taking into account the patient’s preferences
Of note, some studies suggest that surgery is only valuable if performed
with the same attention to detail (e.g. complete removal of the disease) as
in patients with early-stage disease. Additional prospective clinical trials II / B 70%
evaluating the value of this approach, the best candidates and best timing
are currently ongoing.

33
 A small but very important subset of patients with ABC, for example those with
oligometastatic disease or low-volume metastatic disease that is
highly sensitive to systemic therapy, can achieve complete remission and a Expert
91%
long survival. A multimodal approach, including locoregional treatments with opinion/B
curative intent, should be considered for these selected patients. A prospective
clinical trial addressing this specific situation is needed
SYSTEMIC TREATMENT GENERAL GUIDELINES
Treatment choice should take into account at least these factors: HR
and HER2 status, previous therapies and their toxicities, DFI, tumour
burden (defined as number and site of metastases), biological age, PS,
Expert
comorbidities (including organ dysfunctions), menopausal status (for 100%
opinion/A
ET), need for a rapid disease/symptom control, socio-economic and
psychological factors, available therapies in the patient’s country and
patient’s preference
The age of the patient should not be the sole reason to withhold effective
therapy (in elderly patients) nor to overtreat (in young patients). Age alone I/E 100%
should not determine the intensity of treatment
CHT GENERAL GUIDELINES
Both combination and sequential single-agent ChT are reasonable options.
Based on the available data, we recommend sequential monotherapy as the
preferred choice for ABC. Combination ChT should be reserved for patients I/A 96%
with rapid clinical progression, life-threatening visceral metastases or need
for rapid symptom and/or disease control
In the absence of medical contraindications or patient concerns,
anthracycline- or taxane-based regimens, preferably as single agents,
would usually be considered as first-line ChT for HER2-negative ABC,
in those patients who have not received these regimens as (neo)adjuvant I/A 71%
treatment and for whom ChT is appropriate. Other options are, however,
available and effective, such as capecitabine and vinorelbine, particularly if
avoiding alopecia is a priority for the patient
In patients with taxane-naive and anthracycline-resistant ABC or with
anthracycline maximum cumulative dose or toxicity (i.e. cardiac) who are
being considered for further ChT, taxane-based therapy, preferably as single
I/A 59%
agent, would usually be considered as treatment of choice. Other options
are, however, available and effective, such as capecitabine and vinorelbine,
particularly if avoiding alopecia is a priority for the patient
In patients pre-treated (in the adjuvant and/or metastatic setting) with
an anthracycline and a taxane, and who do not need combination ChT,
single-agent capecitabine, vinorelbine or eribulin are the preferred choices.
Additional choices include gemcitabine, platinum agents, taxanes and I/A 77%
liposomal anthracyclines. The decision should be individualised and
take into account different toxicity profiles, previous exposure, patient
preferences and country availability

34
 If given in the adjuvant setting, a taxane can be re-used as first-line therapy,
I/B 92%
particularly if there has been at least one year of DFS
If given in the adjuvant setting, provided that maximum cumulative dose
has not been achieved and that there are no cardiac contraindications,
I/B 93%
anthracyclines can be re-used in ABC, particularly if there has been at least
one year of DFS
Metronomic ChT is a reasonable treatment option for patients not requiring
rapid tumour response. The better studied regimen is CM (low-dose oral
cyclophosphamide and methotrexate); other regimens are being evaluated I/B 88%
(including capecitabine and vinorelbine). Randomised trials are needed to
accurately compare metronomic ChT with standard dosing regimens
Duration of each regimen and the number of regimens should be tailored to Expert
96%
each individual patient opinion/A
Usually each regimen (except anthracyclines) should be given until
PD or unacceptable toxicity. What is considered unacceptable should be I/B 72%
defined together with the patient
OTHER AGENTS
Bevacizumab combined with ChT as first- or second-line therapy for
ABC provides only a moderate benefit in PFS and no benefit in OS. The
absence of known predictive factors for bevacizumab efficacy renders
I/C 74%
recommendations on its use difficult. Bevacizumab can only therefore
be considered as an option in selected cases in these settings and is not
recommended after first/second line
ABC, advanced breast cancer; ChT, chemotherapy; CM, low-dose oral cyclophosphamide and methotrexate; Consensus,
percentage of panel members in agreement with the statement; DFI, disease-free interval; DFS, disease-free survival; ET,
endocrine therapy; GoR, grade of recommendation; HER2, human epidermal growth factor 2; HR, hormone receptor; LoE,
available level of evidence; OS, overall survival; PD, disease progression; PFS, progression-free survival; PS, performance status;
QoL, quality of life; TNBC, triple-negative breast cancer

LoE/
ER-POSITIVE/HER2-NEGATIVE (LUMINAL) ABC CONSENSUS
GoR
ET is the preferred option for HR-positive disease, even in the presence
of visceral disease, unless there is visceral crisis or concern/proof of I/A 93%
endocrine resistance
Many trials in ER-positive ABC have not included PREMENOPAUSAL
women. Despite this, we recommend that young women with ER-positive
Expert
ABC should have adequate OFS/OFA and then be treated in the same 95%
opinion/A
way as postmenopausal women, with endocrine agents and with
or without targeted therapies
Future trials exploring new endocrine-based strategies should be designed Expert
92%
to allow for enrolment of both pre- and postmenopausal women, and men opinion/A

35
 For premenopausal women, for whom ET was decided, OFS/OFA combined
I/A 93%
with additional ET is the preferred choice
OFA by laparoscopic bilateral oophorectomy ensures definitive oestrogen
suppression and contraception, avoids potential initial tumour flare with
Expert
LHRH agonist and may increase eligibility for clinical trials. Patients should 91%
opinion/C
be informed on the options of OFS/OFA and decisions should be made on
a case-by-case basis
Single-agent tamoxifen is the only available endocrine option for
premenopausal women who decline OFS/OFA, but the panel believes it is I/D 92%
a less effective option
The preferred first-line ET depends on the type and duration of adjuvant
ET as well as the time elapsed from the end of adjuvant ET; it can be an AI,
I/A 84%
tamoxifen or fulvestrant, for pre- and perimenopausal women with OFS/
OFA, men (preferably with LHRH agonist) and postmenopausal women
The addition of a CDK 4/6 inhibitor to an AI, in patients naïve or pre-
exposed to ET, provided a significant improvement in median PFS (~10
months), with an acceptable toxicity profile, and is, therefore, one of the
preferred treatment options for pre- and perimenopausal women with
OFS/OFA, men (preferably with LHRH agonist) and postmenopausal I/A 90%
women. Patients relapsing < 12 months from the end of adjuvant AI were
not included in the published studies and may not be suitable for this
combination. OS results are still awaited. QoL was comparable to that with
ET alone
The addition of a CDK 4/6 inhibitor to fulvestrant, in patients previously
exposed to ET, provided significant improvement in median PFS (6–7
months) as well as improvement in QoL, and is one of the preferred
I/A 90%
treatment options, if a CDK 4/6 inhibitor was not previously used, for pre-
and perimenopausal women with OFS/OFA and postmenopausal women
and men. OS results are awaited
The addition of everolimus to an AI is a valid option for some patients [for I/B 88%
pre- and perimenopausal women with OFS/OFA, men (preferably with LHRH
agonist) and postmenopausal women] previously exposed to ET, since
it significantly prolongs PFS, albeit without evidence of OS benefit. The
decision to treat must take into account the toxicities associated with this
combination, lack of statistical significant OS benefit, cost and availability
Tamoxifen or fulvestrant can also be combined with everolimus II / B 80%
Adequate prevention, close monitoring and proactive treatment of adverse
events is needed, particularly in older patients treated with everolimus due I/B 97%
to the increased incidence of toxic deaths reported in the BOLERO-2 trial

36
 The optimal sequence of endocrine-based therapy is uncertain. It depends
on which agents were previously used [in the (neo)adjuvant or advanced
settings], the burden of the disease, patients’ preference, costs and availability.
Available options [for pre- and perimenopausal women with OFS/OFA,
I/A 95%
men (preferably with LHRH agonist) and postmenopausal women] include
AI, tamoxifen, fulvestrant, AI/fulvestrant + CDK 4/6 inhibitor, AI/tamoxifen/
fulvestrant + everolimus. In later lines, also megestrol acetate and oestradiol,
as well as repetition of previously used agents, may be used
It is currently unknown how the different combinations of endocrine +
targeted agents compare with each other, and with single-agent ChT. Trials
are ongoing
Everolimus and CDK 4/6 inhibitors should not be used after PD on that n/a
74%
specific agent (i.e. beyond progression) /E
At present, no validated predictive biomarkers other than HR status exist
to identify patients who will/will not benefit from the addition of a targeted
I/E 95%
agent (i.e. CDK 4/6 inhibitor, mTOR inhibitor) to ET and none of the studied
biomarkers is ready for use in clinical practice. Research efforts must continue
The combination of a non-steroidal AI and fulvestrant as first-line therapy
for postmenopausal patients resulted in significant improvement in both
PFS and OS compared to AI alone in one phase III trial and no benefit Yes: 33%
in a second trial with a similar design. Subset analysis suggested that II / C No: 53%
the benefit was limited to patients without prior exposure to adjuvant ET Abstain: 14%
(tamoxifen). Based on these data, combination ET may be offered to some
patients with ABC without prior exposure to adjuvant ET
Concomitant ChT and ET has not shown a survival benefit and should not
II / D 100%
be carried out outside a clinical trial
Endocrine treatment after ChT (maintenance ET) to maintain benefit is a
III / B 88%
reasonable option, though it has not been assessed in randomised trials
ABC, advanced breast cancer; AI, aromatase inhibitor; CDK, cyclin-dependent kinase; ChT, chemotherapy; Consensus, percentage
of panel members in agreement with the statement; ER, oestrogen receptor; ET, endocrine therapy; GoR, grade of recommendation;
HER2, human epidermal growth factor 2; HR, hormone receptor; LHRH, luteinising hormone-releasing hormone; LoE, available level
of evidence; mTOR, mammalian target of rapamycin; OFA , ovarian function ablation; OFS, ovarian function suppression; OS, overall
survival; PD, progressive disease; PFS, progression-free survival; QoL, quality of life

37
 LoE/
HER2-POSITIVE ABC CONSENSUS
GoR
Anti-HER2 therapy should be offered early (as first line) to all patients
with HER2-positive ABC, except in the presence of contraindications to I/A 98%
the use of such therapy
Patients progressing on an anti-HER2 therapy combined with a cytotoxic
or endocrine agent should be offered additional anti-HER2 therapy with
subsequent treatment, except in the presence of contraindications, since
it is beneficial to continue suppression of the HER2 pathway. The choice
of the anti-HER2 agent will depend on country-specific availability, the I/A 91%
specific anti-HER2 therapy previously administered and the relapse-free
interval. The optimal sequence of all available anti-HER2 therapies is
currently unknown. The optimal duration of anti-HER2 therapy for ABC
(i.e. when to stop these agents) is currently unknown
In patients achieving a complete remission, the optimal duration of
maintenance anti-HER2 therapy is unknown and needs to be balanced
against treatment toxicity, logistical burden and cost. Stopping anti-HER2 Expert
93%
therapy after several years of sustained complete remission may be opinion/C
considered in some patients, particularly if treatment rechallenge is
available in case of progression
Patients who have received any type of (neo)adjuvant anti-HER2 therapy
should not be excluded from clinical trials for HER2-positive ABC. These I/B 100%
patients remain candidates for anti-HER2 therapies
For the highly selected patients* with ER-positive/HER2-positive ABC, for
whom ET + anti-HER2 therapy was chosen as first-line therapy, dual anti-
HER2 blockade (with either pertuzumab + T or lapatinib + T) can be used
I/B 80%
since it provides a benefit in PFS. This decision must be balanced against
the higher side effects, higher costs and lack of OS benefit so far, when
compared with ET + anti-HER2 monotherapy
For patients with ER-positive/HER2-positive ABC, for whom ChT + anti-HER2
therapy was chosen as first-line therapy and provided a benefit, it is reasonable
to use ET + anti-HER2 therapy as maintenance therapy, after stopping ChT,
although this strategy has not been studied in randomised trials. Duration
n/a
of maintenance therapy should be until progression, unacceptable toxicity 80%
/B
or patient request and needs to be evaluated in clinical trials. There are
no data to decide between single-agent anti-HER2 or dual blockade, to
combine with maintenance ET after stopping ChT, in ER-positive/HER2-
positive ABC
In the first-line setting, for HER2-positive ABC previously treated (in the
adjuvant setting with DFI >12 months) or untreated with T, combinations
I/A 95%
of ChT + T are superior to combinations of ChT + lapatinib in terms of
PFS and OS

38
 The standard first-line therapy for patients previously untreated with anti-
HER2 therapy is the combination of ChT + T and pertuzumab, because it I/A 86%
has proven to be superior to ChT + T in terms of OS in this population
For patients previously treated [in the (neo)adjuvant setting] with
anti-HER2 therapy, the combination of ChT + T and pertuzumab is an
I/A 76%
important option for first-line therapy. Few (88) of these patients were
treated in the CLEOPATRA trial and all with T-free interval > 12 months
There are currently no data supporting the use of dual blockade with T +
pertuzumab and ChT beyond progression (i.e. continuing dual blockade Expert
86%
beyond progression) and therefore this three-drug regimen should not be opinion/E
given beyond progression outside clinical trials
In a HER2-positive ABC patient, previously untreated with the combination
II / B 76%
of ChT + T + pertuzumab, it is acceptable to use this treatment after first line
After first-line T-based therapy, T-DM1 provides superior efficacy relative
to other HER2-based therapies in the second line (versus lapatinib +
capecitabine) and beyond (versus treatment of physician’s choice). T-DM1
I/A 88%
should be preferred in patients who have progressed through at least one line
of T-based therapy, because it provides an OS benefit. However, there are no
data on the use of T-DM1 after dual blockade with T + pertuzumab
In case of progression on T-based therapy, the combination T + lapatinib is
a reasonable treatment option for some patients. There are however, no data I / B 84%
on the use of this combination after progression on pertuzumab or T-DM1
Regarding the ChT component of HER2-positive ABC treatment:
When pertuzumab is not given, first-line regimens for HER2 ABC
can include T combined with vinorelbine or a taxane. Differences in
toxicity between these regimens should be considered I/A 88%
and discussed with the patient in making a final decision. Other ChT
agents can be administered with T but are not as well studied and are
not preferred
For later lines of therapy, T can be administered with several ChT agents,
including but not limited to, vinorelbine (if not given in first line), taxanes
(if not given in first line), capecitabine, eribulin, liposomal anthracyclines,
II / A 91%
platinum, gemcitabine or metronomic CM. The decision should be
individualised and take into account different toxicity profiles, previous
exposure, patient preferences and country availability
ChT agents to combine with a dual blockade of T + pertuzumab are
See in
docetaxel [I , A] or paclitaxel [I , B]. Also possible are vinorelbine 86%
statement
[II , A], nab-paclitaxel [II, B] and capecitabine [II , A]
*Highly selected patients include those with contraindications to ChT, patients with a strong preference against ChT or those
with a long DFI, minimal disease burden (in particular in terms of visceral involvement) and/or strong ER/PgR expression
ABC, advanced breast cancer; ChT, chemotherapy; CM, low-dose oral cyclophosphamide and methotrexate; Consensus,
percentage of panel members in agreement with the statement; DFI, disease-free interval; ER, oestrogen receptor; ET, endocrine
therapy; GoR, grade of recommendation; HER2, human epidermal growth factor 2; LoE, available level of evidence; OS, overall
survival; PFS, progression-free survival; PgR, progesterone receptor; T, trastuzumab; T-DM1, trastuzumab emtansine

39
 LoE/
ADVANCED TNBC CONSENSUS
GoR
For non-BRCA-associated advanced TNBC, there are no data supporting
different or specific ChT recommendations. Therefore, all ChT I/A 98%
recommendations for HER2-negative disease also apply for advanced TNBC
In advanced TNBC patients (regardless of BRCA status) previously treated
with anthracyclines with or without taxanes in the (neo)adjuvant setting,
carboplatin demonstrated comparable efficacy and a more favourable I/A 91%
toxicity profile compared with docetaxel, and is, therefore, an important
treatment option
The AR is a potential target in advanced TNBC. There are however no
standardised methods to assay AR. Limited data suggest a low level of
efficacy for AR antagonist agents such as bicalutamide and enzalutamide.
II / D 85%
At this time, these agents should not be used in routine clinical practice.
More definitive trials are needed, and research efforts must continue to
optimise and standardise the determination of AR
AR, androgen receptor; ChT, chemotherapy; Consensus, percentage of panel members in agreement with the statement; GoR,
grade of recommendation; HER2, human epidermal growth factor 2; LoE, available level of evidence; TNBC, triple-negative
breast cancer

40
 LoE/
HEREDITARY ABC CONSENSUS
GoR
GENETIC TESTING
In the ABC setting, results from genetic testing may have therapeutic Expert
100%
implications and should therefore be considered as early as possible opinion/B
Genes to be tested for depend on personal and family history; however, at
present, only germline mutations in BRCA1/2 have proven clinical utility I/A 100%
and therapeutic impact
Testing for other additional moderate- to high-penetrance genes may be
considered, if deemed appropriate by the geneticist/genetic counsellor.
Expert
However, it must be clarified to the patient that at present, a mutation 100%
opinion/C
in another moderate- to high-penetrance gene has no direct clinical
implications, for the patients themselves, in the setting of ABC
The therapeutic implications of somatic BRCA1/2 mutations in breast
n/a
tumours need to be further explored within a research setting and 83%
/E
should not be used for decision making in routine clinical practice
BRCA-ASSOCIATED ABC
In patients with BRCA-associated advanced TNBC or endocrine-resistant
ABC previously treated with an anthracycline with or without a taxane (in
the adjuvant and/or metastatic setting), a platinum regimen is the preferred II / A 86%
option, if not previously administered and no suitable clinical trial is available.
All other treatment recommendations are similar to sporadic ABC
A PARPi (olaparib or talazaparib) is a reasonable treatment option for
patients with BRCA-associated advanced TNBC or luminal (after progression
on ET) ABC, previously treated with an anthracycline with/without a taxane (in
the adjuvant and/or metastatic setting), since its use is associated with a PFS I/B 80%
benefit, improvement in QoL and a favourable toxicity profile. OS results are
awaited. It is unknown how PARPis compare with platinum compounds in this
setting and their efficacy in truly platinum-resistant tumours
ABC, advanced breast cancer; Consensus, percentage of panel members in agreement with the statement; ET, endocrine
therapy; GoR, grade of recommendation; LoE, available level of evidence; OS, overall survival; PARPi, poly adenosine diphosphate
ribose polymerase inhibitor; PFS, progression-free survival; QoL, quality of life; TNBC, triple-negative breast cancer

41
 LoE/
PRECISION MEDICINE CONSENSUS
GoR
Multigene panels, such as those obtained using NGS or other
technology on tumour DNA have not yet proven beneficial in clinical
trials for ABC, their impact on outcome remains undefined and should
not be used in routine clinical practice. For patients who are suitable
to participate in clinical trials of novel therapies and are readily able/
I/D 83%
motivated to attend a centre with relevant clinical trials, NGS testing may
be used in the context of prospective molecular triage programmes to
select patients for therapeutic trials. Specific tests (as distinguished from
broad mutation profiles) may play a role in the future as the medicines they
are linked with achieve regulatory approval
ctDNA assessment is not ready for routine clinical practice use and is not
I/D 74%
recommended, either for demonstration of PD or selection of targeted therapies
In case an ABC patient was tested in the context of a clinical trial and the
information is available

• If an ABC patient presents with a tumour with Expert Yes: 41%
MSI-H/MMR deficiency, treatment with an anti-PD-1 agent opinion/C Abstain: 10%
is a possible consideration
Insufficient
data: 49%

• If an ABC patient presents with a tumour with a NTRK fusion, Expert Yes: 29%
treatment with a TRKi is a possible consideration opinion/C Abstain: 24%
Insufficient
Patients must be informed about the amount of data available for ABC data: 47%
specifically. Research on the best companion diagnosis tools and techniques
is needed. Prospective registries should be created to collect data from all
patients treated with these innovative approaches, after proper consent
Immunotherapy, with a checkpoint inhibitor, for any biological
subtype of ABC should not be used in routine clinical practice, outside
III / D 85%
clinical trials. Several ongoing trials are evaluating the role of this type of
treatment in all ABC subtypes
ABC, advanced breast cancer; Consensus, percentage of panel members in agreement with the statement; ctDNA, circulating
tumour DNA; GoR, grade of recommendation; LoE, available level of evidence; MMR, mismatch repair; MSI-H, microsatellite
instability-high; NGS, next-generation sequencing; NTRK, neurotrophic tyrosine receptor kinase; PD, disease progression; PD-1,
programmed cell death protein 1; TRKi, tropomyosin receptor kinase inhibitor

42
 LoE/
SPECIFIC SITES OF METASTASES CONSENSUS
GoR
BONE METASTASES
Radiological assessments are required in patients with persistent and
localised pain due to bone metastases to determine whether there are
impending or actual pathological fractures. If a fracture of a long bone is likely
I/A 96%
or has occurred, an orthopaedic assessment is required as the treatment of
choice may be surgical stabilisation, which is generally followed by RT. In the
absence of a clear fracture risk, RT is the treatment of choice
Neurological symptoms and signs which suggest the possibility of spinal
cord compression must be investigated as a matter of urgency. This requires
a full radiological assessment of the potentially affected area as well as
adjacent areas of the spine. MRI is the method of choice. An emergency I/B 100%
surgical opinion (neurosurgical or orthopaedic) may be required for surgical
decompression. If no decompression/stabilisation is feasible, emergency RT
is the treatment of choice and vertebroplasty is also an option
A bone-modifying agent (bisphosphonate, denosumab) should be
routinely used in combination with other systemic therapy in patients with I/A 95%
ABC and bone metastases
Three-monthly zolendronic acid seems to be not inferior to standard
I/B 95%
monthly schedule
Supplementation of calcium and vitamin D3 is mandatory, unless
I/A 95%
contraindications exist
BRAIN METASTASES
Patients with a single or a small number of potentially resectable brain
metastases should be treated with surgery or radiosurgery. Radiosurgery I/B 92%
is also an option for some unresectable brain metastases
If surgery/radiosurgery is performed it may be followed by WBRT, but this
should be discussed in detail with the patient, balancing the longer duration I/C 72%
of intracranial disease control and the risk of neurocognitive effects
HER2-positive ABC and BRAIN METASTASES
Because patients with HER2-positive ABC and brain metastases can live
for several years, consideration of long-term toxicity is important and
less toxic local therapy options (e.g. stereotactic RT) should be preferred I/A 89%
to WBRT, when available and appropriate (e.g. in the setting of a limited
number of brain metastases)

43
 In patients with HER2-positive ABC who develop brain metastases with
I/D 95%
stable extracranial disease, systemic therapy should not be changed
For patients with HER2-positive ABC where brain metastases are the only
site of recurrence, the addition of ChT to local therapy is not known to I/D 83%
alter the course of the disease and is not recommended
It is recommended to re-start the anti-HER2 therapy (T) if this had been
I/B 83%
stopped
For patients with HER2-positive ABC with progressive brain metastases
as the predominant cause of disease burden, if no further relevant local
III / A 85%
therapy options are available, a change in systemic therapy is a reasonable
option, preferably in clinical trials
Radionecrosis after stereotactic RT for brain metastases is an
uncommon complication that may occur especially with longer survival
and follow-up, and in particular in cases of re-irradiation. Differential
diagnosis with tumour progression is often difficult. Treatment of
symptomatic patients with a course of high-dose steroids is the first III / B 61%
treatment of choice. If no response, bevacizumab may be used, as an
option to decrease the surrounding oedema, usually at a dose of 7.5 mg/
kg every 2 weeks, for a median of four cycles. Prospective randomised
trials are needed to validate further this option
LIVER METASTASES
Prospective RCTs of local therapy for breast cancer liver metastases are
urgently needed, since available evidence comes only from series in
highly selected patients. Since there are no randomised data supporting
the effect of local therapy on survival, every patient must be informed of
this when discussing a potential local therapy technique. Local therapy Expert
83%
should only be proposed in very selected cases of good PS, with limited opinion/C
liver involvement, no extrahepatic lesions, after adequate systemic therapy
has demonstrated control of the disease. Currently, there are no data to
select the best technique for the individual patient (surgery, stereotactic RT,
intrahepatic ChT etc.)
MALIGNANT PLEURAL EFFUSIONS
Malignant pleural effusions require systemic treatment with/without local
III / A 86%
management
Thoracentesis for diagnosis should be performed if it is likely that this will
III / B 86%
change clinical management. False negative results are common
Drainage is recommended in patients with symptomatic, clinically
III / A 86%
significant pleural effusion
Use of an intrapleural catheter or intrapleural administration of talc or drugs
III / B 86%
(e.g. bleomycin, biological response modifiers) can be helpful
Clinical trials evaluating the best technique are needed

44
 CHEST WALL AND REGIONAL (NODAL) RECURRENCES
Due to the high risk of concomitant distant metastases, patients with chest
Expert
wall or regional (nodal) recurrence should undergo full restaging, including 100%
opinion/A
assessment of chest, abdomen and bone
Chest wall and regional recurrences should be treated with surgical
II / A 97%
excision when feasible with limited risk of morbidity
Locoregional RT is indicated for patients not previously irradiated II / A 97%
For patients previously irradiated, re-irradiation of all or part of the chest Expert
97%
wall may be considered in selected cases opinion/C
In addition to local therapy (surgery and/or RT), in the absence of distant
metastases, the use of systemic therapy (ChT, ET and/or anti-HER2 therapy) I / B 95%
should be considered
ChT after first local or regional recurrence improves long-term outcomes
I/B 95%
primarily in ER-negative disease and can be used
ET in this setting improves long-term outcomes for ER-positive disease
I/B 95%
and should be used
The choice of systemic treatment depends on tumour biology, previous
Expert
treatments, length of DFI and patient-related factors (comorbidities, 95%
opinion/A
preferences etc.)
In patients with disease not amenable to radical local treatment, the choice
of palliative systemic therapy should be made according to principles Expert
97%
previously defined for ABC. These patients may still be considered for opinion/B
palliative local therapy
ABC, advanced breast cancer; ChT, chemotherapy; Consensus, percentage of panel members in agreement with the statement;
DFI, disease-free interval; ER, oestrogen receptor; ET, endocrine therapy; GoR, grade of recommendation; HER2, human
epidermal growth factor 2; LoE, available level of evidence; MRI, magnetic resonance imaging; PS, performance status; RCT,
randomised controlled trial; RT, radiotherapy; T, trastuzumab; WBRT, whole brain radiotherapy

LoE/
SPECIFIC POPULATIONS CONSENSUS
GoR
ADVANCED MALE BREAST CANCER
For ER-positive male ABC, which represents the majority of the cases, ET is
the preferred option, unless there is concern or proof of endocrine resistance III / A 100%
or rapidly progressive disease needing a fast response
For ER-positive male ABC tamoxifen is the preferred option IV / B 83%
For male patients with ABC who need to receive an AI, a concomitant LHRH
agonist or orchidectomy is the preferred option. AI monotherapy may also IV / B 86%
be considered, with close monitoring of response
Clinical trials are needed in this patient population
ABC, advanced breast cancer; AI, aromatase inhibitor; Consensus, percentage of panel members in agreement with the statement;
ER, oestrogen receptor; ET, endocrine therapy; GoR, grade of recommendation; LHRH, luteinising hormone-releasing hormone; LoE,
available level of evidence 45
 LoE/
LABC* CONSENSUS
GoR
Before starting any therapy, a core biopsy providing histology and biomarker
(ER, PgR, HER2, proliferation/grade) expression is indispensable to guide I/A 97%
treatment decisions
Since LABC patients have a significant risk of metastatic disease, a full staging
work-up, including a complete history, physical examination, laboratory tests
I/A 100%
and imaging of chest and abdomen (preferably with CT scan) and bone, before
initiation of systemic therapy is highly recommended
PET-CT, if available, may be used (instead of and not in addition to CT
II / B 100%
scans and bone scan)
Systemic therapy (not surgery or RT) should be the initial treatment III / A 100%
If LABC remains inoperable after systemic therapy and eventual RT,
Expert
‘palliative’ mastectomy should not be done, unless the surgery is likely to 100%
opinion/D
result in an overall improvement in QoL
A combined treatment modality based on a multidisciplinary approach
(systemic therapy, surgery and RT) is strongly indicated in the majority I /A 100%
of cases
Options for HR-positive LABC include an anthracycline- and taxane-based I/A 85%
ChT regimen, or ET
The choice of ChT versus ET, as initial treatment, will depend on tumour Expert 85%
(grade, biomarker expression) and patient (menopausal status, PS, Opinion/A
comorbidities, preference) considerations
For triple-negative LABC, anthracycline- and-taxane-based ChT is I /A 85%
recommended as initial treatment
For HER2-positive LABC, concurrent taxane and anti-HER2 therapy is I/A 92%
recommended since it increases the rate of pCR
For HER2-positive LABC, anthracycline-based ChT should be I/A 72%
incorporated in the treatment regimen
When an anthracycline is given, it should be administered sequentially with I/A 87%
the anti-HER2 therapy
For patients with HER2-positive LABC (inflammatory or non-
inflammatory), without distant metastases, who are in complete
remission after appropriate neoadjuvant systemic therapy and appropriate I/A 85%
locoregional therapy, and being treated with a potential curative intent, the
approved adjuvant duration of 1 year of anti-HER2 therapy should be used
Following effective neoadjuvant systemic therapy with or without RT,
surgery will be possible in many patients. This will consist of mastectomy
II / A 98%
with axillary dissection in the majority of cases, but in selected patients with
a good response, BCS may be possible

46
 In patients with axillary low burden of disease at presentation (previously cN0-
cN1) with complete response after systemic treatment (ycN0), SLNB can be
an option, provided all the recommendations for sentinel node after primary III / B 62%
systemic treatment are followed (i.e. dual tracer, clipping/marking positive
nodes, minimum of three sentinel nodes)
INFLAMMATORY LABC
For inflammatory LABC, overall treatment recommendations are similar to
I/A 93%
those for non-inflammatory LABC, with systemic therapy as first treatment
Mastectomy with axillary dissection is recommended in almost all cases,
I/A 95%
even when there is good response to primary systemic therapy
Immediate reconstruction is generally not recommended in patients with
IV / E 95%
inflammatory LABC
Locoregional RT (chest wall and lymph nodes) is required, even when a
I/A 98%
pCR is achieved with systemic therapy
*For the purposes of these recommendations, LABC means inoperable non-metastatic locally advanced breast cancer
BCS, breast-conserving surgery; ChT, chemotherapy; Consensus, percentage of panel members in agreement with the statement;
CT, computed tomography; ER, oestrogen receptor; ET, endocrine therapy; GoR, grade of recommendation; HER2, human epidermal
growth factor 2; HR, hormone receptor; LABC, locally advanced breast cancer; LoE, available level of evidence; pCR, pathological
complete response; PET, positron emission tomography; PgR, progesterone receptor; PS, performance status; QoL, quality of life; RT,
radiotherapy; SLNB, sentinel lymph node biopsy

LoE/
SUPPORTIVE AND PALLIATIVE CARE CONSENSUS
GoR
Supportive care allowing safer and more tolerable delivery of appropriate
I/A 100%
treatments should always be part of the treatment plan
Early introduction of expert palliative care, including effective control of
I/A 100%
pain and other symptoms, should be a priority
Access to effective pain treatment (including morphine, which is
I/A 100%
inexpensive) is necessary for all patients in need of pain relief
Optimally, discussions about patient preferences at the end of life should
begin early in the course of metastatic disease. However, when active treatment
no longer is able to control widespread and life-threatening disease, and Expert
96%
the toxicities of remaining options outweigh benefits, physicians and other opinion/A
members of the healthcare team should initiate discussions with the patient (and
family members/friends, if the patient agrees) about end-of-life care
MANAGEMENT OF CANCER-RELATED FATIGUE
Cancer-related fatigue is frequently experienced by patients with ABC,
exerts a deleterious impact on QoL and limits physical, functional,
100%
psychological and social well-being. The aetiology of this fatigue is -
complex; therefore, effective management needs to be multidimensional
It is important to assess cancer-related fatigue using appropriate PROMs
See in
before implementing various non-pharmacological approaches, such as 100%
statement
exercise [I, A], and, if needed, pharmacological interventions [II, B]
47
 MANAGEMENT OF CDK INHIBITOR-INDUCED NEUTROPAENIA
Neutropaenia is the most common toxicity associated with CDK 4/6
inhibition and is not generally associated with febrile neutropaenia,
although an increase in infections has been reported. Treatment should II / A 100%
be delayed until neutrophils have recovered to at least 1000/μL; dose
reduction can also be considered
MANAGEMENT OF NIP
NIP is an uncommon complication of mTOR inhibition. Patient
education is critical to ensure early reporting of respiratory symptoms.
Treatment interruption and dose reduction are generally effective for II / A 100%
grade 2 symptomatic NIP with use of systemic steroids and treatment
discontinuation for grade 3 or greater toxicity
MANAGEMENT OF DYSPNOEA
Treatable causes like pleural effusion, pulmonary emboli, cardiac
insufficiency, anaemia or drug toxicity must be ruled out. Patient support 100%
-
is essential. Oxygen is of no use in non-hypoxic patients
Opioids are the drugs of choice in the palliation of dyspnoea I/A 100%

Benzodiazepines can be used in patients experiencing anxiety II / A 100%

Steroids can be effective in dyspnoea caused by lymphangitis
carcinomatosis, RT or drug-induced pneumonitis, superior vena cava Expert
100%
syndrome, an inflammatory component or in (cancer-induced) obstruction opinion/B
of the airways (in which case laser/stent is to be considered)
MANAGEMENT OF NAUSEA AND VOMITING
ESMO/MASCC guidelines are available for management of ChT-induced n/a 100%
and morphine-induced nausea and vomiting, and these are endorsed by
the ABC community
There is a need to study nausea and vomiting related to chronic use of Expert
100%
anticancer drugs opinion/A
MANAGEMENT OF ENDOCRINE TOXICITIES OF MTOR INHIBITION
Hyperglycaemia and hyperlipidaemia are common sub-acute complications
of mTOR inhibition. Evaluation of pre-existing diabetes or hyperglycaemia
at baseline is essential. Regular careful monitoring of glycaemia and lipid
panel is needed to identify these toxicities. Management of grade 1 and 2
hyperglycaemia includes treatment with oral antidiabetics and basal insulin,
in accordance with international recommendation for diabetes mellitus II / A 100%
treatment. Statins are indicated to treat grade 2 and 3 hypercholesterolaemia,
and fibrates should be introduced if triglyceride level > 500 mg/dL (with
attention to possible drug–drug interaction between everolimus and fibrates).
Treatment interruption and dose reduction are generally effective for grade 2
and 3 toxicity. Treatment should be discontinued for grade 4 toxicity
48
 MANAGEMENT OF MUCOSITIS/STOMATITIS
Steroid mouthwash should be used for prevention of stomatitis induced by
mTOR inhibitors (suggested schedule: 0.5 mg/5 mL dexamethasone, 10 I/B 100%
mL to swish x 2 minutes, then spit out; qid)
Expert
Early intervention is recommended 100%
opinion/A
For > grade 2 stomatitis, delaying treatment until the toxicity resolves and Expert
100%
considering lowering the dose of the targeted agent are also recommended opinion/A
Mild toothpaste and gentle hygiene are recommended for the treatment Expert
100%
of stomatitis opinion/B
Expert
Consider adding steroid dental paste to treat developing ulcerations 100%
opinion/B
MANAGEMENT OF CIPN
CIPN is frequent and potentially dose-limiting. Risk factors for neuropathy
- 100%
and pre-existing neuropathy need to be identified
No medical prevention can currently be recommended II / C 100%

Drug-related factors (dosing, timing, route) can lower the risk of CIPN - 100%
The use of tight gloves and socks during ChT may help reduce the Expert
100%
incidence and severity of CIPN opinion/C
There are limited evidence-based treatments for CIPN, with tricyclic
antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin II/B 100%
and gabapentin being most often used
High-quality studies are needed to evaluate strategies for prevention and
- 100%
management of CIPN
MANAGEMENT OF HFS
HFS is also described as palmar–plantar erythrodysesthaesia syndrome.
Most frequent causes are capecitabine; pegylated liposomal doxorubicin; - 100%
multikinase inhibitors
Patients should be instructed about early recognition of HFS - 100%

Drug-related factors (dosing, timing, route) can lower the risk of HFS - 100%
Treatment of hyperkeratosis / fungal infections, comfortable shoes, Expert
100%
avoidance of friction and heat are recommended opinion/A
Intensive skin care of hands and feet (urea cream/ointment) is recommended II / A 100%
High-quality studies are needed to evaluate strategies for prevention and
- 100%
management of HFS
ABC, advanced breast cancer; CDK, cyclin-dependent kinase; ChT, chemotherapy; CIPN, chemotherapy-induced peripheral
neuropathy; Consensus, percentage of panel members in agreement with the statement; GoR, grade of recommendation; HFS,
hand and foot syndrome; LoE, available level of evidence; MASCC, Multinational Association of Supportive Care in Cancer; mTOR,
mammalian target of rapamycin; NIP, non-infectious pneumonitis; PROM, patient-reported outcome measure; qid, four times a
day; QoL, quality of life; RT, radiotherapy 49
 LoE/
INTEGRATIVE MEDICINE CONSENSUS
GoR
Alternative therapies (i.e. therapies used instead of scientifically-based n/a
100%
medicines) are not recommended in any phase or stage of cancer treatment /E
Breast Cancer Centres/Units/Departments should be aware that the majority
Expert
of their patients would like to be informed about complementary and 100%
opinion/C
integrative medicine and that many of them are using it
Physicians should actively ask for information about its use, in view of the
potential deleterious interactions with specific anticancer therapies

If complementary therapies are not available at the centre, certified contacts

should be available to promote referral to practitioners qualified in the
therapies people are interested in receiving

Some complementary therapies have the potential to reduce disease

Expert
symptom burden and/or side effects of anticancer therapies, and, therefore, 100%
opinion/C
improve the QoL of ABC patients
Evidence suggests beneficial effects of the following methods, which can
therefore be used:
• Physical exercise/sport (equivalent to 3–5 hours of moderate
walking per week) improves QoL, cardiorespiratory fitness, physical
performance and fatigue, and it may also improve DFS and OS I/B 100%
• MBSR programmes, hypnosis and yoga may improve QoL and fatigue, and
help reduce anxiety, distress and some side effects of anticancer therapies
• Acupuncture may help against ChT-induced nausea and vomiting,
fatigue and hot flashes
Methods with no or unfavourable effects
The following methods of alternative medicine are not recommended in
ABC since available evidence shows no effect at best, or even association
with worse outcome:
• Antioxidant supplements
• Drugs outside the approved indication (e.g. methadone)
• Herbs including Chinese herbal medicine II / E 100%
• Orthomolecular substances (selenium, zinc...)
• Oxygen and ozone therapy
• Proteolytic enzymes, thymic peptides
• Phytoestrogens (soy food, isoflavones)
• High-dose vitamins (vitamin C, D, E, carotenoids, etc.)
• L-carnitine, laetrile
ABC, advanced breast cancer; ChT, chemotherapy; Consensus, percentage of panel members in agreement with the statement;
DFS, disease-free survival; GoR, grade of recommendation; LoE, available level of evidence; MBSR, mindfulness-based stress
reduction; OS, overall survival; QoL, quality of life.

50
 DIAGNOSTIC AND TREATMENT ALGORITHMS
FOR ADVANCED BREAST CANCER

Diagnostic and treatment algorithms for advanced breast cancer (ABC) are shown
in the following pages:
• ABC diagnostic work-up and staging
• Treatment of locally advanced breast cancer (LABC)
• Treatment of eostrogen receptor (ER)-negative/human epidermal growth factor
receptor 2 (HER2)-positive ABC
• Treatment of ER-positive/HER2-positive ABC
• Treatment of ER-positive/HER2-negative ABC
• Treatment of advanced triple-negative breast cancer (TNBC)
• ABC follow-up and supportive care
• ABC symptom control

51
 ABC DIAGNOSTIC WORK-UP AND STAGING ALGORITHM

LABC ABC
Diagnosis

Core biopsy to evaluate Biopsy of metastatic lesion

histology and biomarker to confirm ABC diagnosis,
expression (ER, PgR, particularly if first incidence
HER2, proliferation/grade) of metastatic disease

Reassess biomarkers
(ER, PgR and HER2)
at least once in the
metastatic setting
Staging

Minimal staging work-up: history and physical examination,

haematology, biochemistry and imaging of chest, abdomen
and bone with CT, bone scan or PET-CT *

*Discuss indications. Brain MRI not indicated unless there are symptoms
ABC, advanced breast cancer; CT, computed tomography; ER, oestrogen receptor; HER2, human epidermal growth factor 2; LABC,
locally advanced breast cancer; MRI, magnetic resonance imaging; PET, positron emission tomography; PgR, progesterone receptor

52
TREATMENT OF LABC
LABC
ALGORITHM

Multimodality treatment strongly

indicated in almost all cases

Initial therapy should

be systemic

Initial therapy depends on

tumour and patient type

HR+ HER2- Triple-negative HER2+ LABC

LABC LABC

Non-inflammatory Inflammatory ChT + anti-

HER2 therapy

ET ChT
Tumour remains
inoperable

Further systemic treatment

(if appropriate) RT

Operable tumour

Tumour remains inoperable

Non-inflammatory Inflammatory

Palliative care
BCS if appropriate Mastectomy
Adjuvant ET continuation of
anti-HER2
RT (if not given previously) (if appropriate)

BCS, breast conserving surgery; ChT, chemotherapy; ET, endocrine therapy; HER2, human epidermal growth factor
receptor 2; HR, hormone receptor; LABC, locally advanced breast cancer; RT, radiotherapy
53
 TREATMENT OF ER-NEGATIVE/HER2-POSITIVE ABC ALGORITHM

Previously untreated Previously treated Patients unsuitable for

with anti-HER2 (neo)adjuvantly with ChT or with long DFI,
therapy anti-HER2 therapy minimal disease burden

ChT + T T alone
+ pertuzumab ChT + pertuzumab or dual blockade alone
(ChT + T only if +T
(T + pertuzumab or T +
pertuzumab or ChT + T lapatinib)
not available)

No progression
First line

Progression
Anti-HER2 as

Second lines
maintenance therapy

T-DM1 if available
(no data available on
If complete remission,
use after dual blockade)
optimal duration of
maintenance anti-HER2
therapy is unknown

T in
Later lines

combination T + lapatinib
Stopping therapy after with an unused
several years ChT agent
of complete remission
may be an option

Additional anti-HER2
therapy and ChT

Note: Include in clinical trials when available

ABC, advanced breast cancer; ChT, chemotherapy; DFI, disease-free interval; ER, oestrogen receptor; HER2, human
epidermal growth factor receptor 2; T, trastuzumab; T-DM1, trastuzumab-emtansine

54
 TREATMENT OF ER-POSITIVE/HER2-POSITIVE ABC ALGORITHM

Patients unsuitable for

Previously untreated Previously treated ChT or with long DFI,
with anti-HER2 (neo)adjuvantly with minimal disease
therapy anti-HER2 therapy burden and/or strong
ER/PgR expression

ChT + T
+ pertuzumab ChT + pertuzumab
+T ET + anti-HER2 (T or
(ChT + T only if lapatinib)
pertuzumab or ChT + T
not available) or ET + dual HER2
blockade
(T + lapatinib or
T + pertuzumab)
First line

No progression

ET + Progression
anti-HER2 as

Second lines
maintenance therapy
T-DM1 if available
(no data available on use after
If complete remission, dual blockade)
optimal duration of
maintenance anti-HER2
therapy is unknown
T in combination T + lapatinib
with an unused ChT + ET, if not
agent or with ET previously used
(if appropriate)
Stopping anti-HER2
Later lines

therapy after several

years of complete
remission may be Maintenance ET + anti-HER2
an option therapy

Note: Include in clinical trials when available

ABC, advanced breast cancer; ChT, chemotherapy; DFI, disease- Additional anti-HER2 therapy
free interval; ER, oestrogen receptor; ET, endocrine therapy; HER2, and ChT or ET
human epidermal growth factor receptor 2; PgR, progesterone
receptor; T, trastuzumab; T-DM1, trastuzumab-emtansine
55
 TREATMENT OF ER-POSITIVE/HER2-NEGATIVE ABC ALGORITHM

Diagnosis of ER+/HER2- disease

ET
(preferred treatment option)

Premenopausal Perimenopausal Postmenopausal

First line

Ovarian ablation/
suppression

Prior ET No prior ET

AI + Al + Tamoxifen Fulvestrant
everolimus Al Fulvestrant
CDK 4/6 + CDK 4/6
inhibitor inhibitor
Second line

Fulvestrant Al + AI + Tamoxifen +
+ CDK 4/6 CDK 4/6 everolimus everolimus
inhibitor inhibitor
Later
lines

Megestrol acetate, estradiol, repetition of previously used agent

56
 Genetic counselling and BRCA mutation status testing to be discussed
with selected patients (see text for details)

ChT (patients with visceral crisis, Combination ChT

proven endocrine resistance) (patients with rapid
progression, visceral crisis,
need for rapid symptom/
disease control, to be used
rarely)
Sequential single-agent ChT

Previously untreated Previously treated wtih

anthracycline or taxanes

Anthracycline Capecitabine Eribulin Vinorelbine

or taxanes

ChT to maximum response or toxicity

Combination
ET (AI and Maintenance ET
fulvestrant) after ChT to maintain benefit

Fulvestrant +
everolimus AI Fulvestrant Tamoxifen

ABC, advanced breast cancer; AI, aromatase inhibitor;

CDK, cyclin-dependent kinase; ChT, chemotherapy; ER, oestrogen receptor; ET,
endocrine therapy; HER2, human epidermal growth factor receptor 2

57
 TREATMENT OF ADVANCED TNBC ALGORITHM

Diagnosis of advanced TNBC

Genetic counselling
and BRCA mutation
status testing should be
discussed with patient

Combination ChT Preferred regimens:

(patients with rapid Carboplatin +
gemcitabine
progression, visceral OR
crisis, need for rapid Cisplatin + 5-FU
symptom/disease control) or capecitabine
Sequential
single-agent ChT

Previously Previously treated

untreated with with anthracycline
anthracycline and/or taxanes
or taxanes

Anthracycline
or taxanes

BRCA mutation BRCA wild-type

PARPi Carboplatin Capecitabine Eribulin Vinorelbine

Note: Include in clinical trials when available

5-FU, 5 fluorouracil; ChT, chemotherapy; PARPi, poly adenosine diphosphate ribose polymerase inhibitor;
TNBC, triple-negative breast cancer
58
 ABC FOLLOW-UP AND SUPPORTIVE CARE ALGORITHM

Supportive care

Diagnosis and treatment Survivorship issues End-of-life care

Discussed with
Access to personalised supportive and psychological patients early
care and symptom-related intervention from time in course of
of diagnosis, allowing for safer/more tolerable metastatic disease
delivery of treatment, taking into account patient
preferences, values and needs Facilitate
return/continue
to work

Encouraging patients Suspicion of

Open Educating patients Empowering locoregional progression
communication to be proactive in patients to
on treatment and their care and share
between patients supportive care improve their
and care team decision making with own QoL
cancer care teams
Breast imaging

Systematic monitoring of patients to permit early

intervention of supportive care to enhance QoL

Note: Throughout the cancer path, adequate information should be provided to the patient
ABC, advanced breast cancer; QoL, quality of life

59
 ABC SYMPTOM CONTROL ALGORITHM

Management of symptoms

Assess using PROMs

Cancer-related CDK inhibitor- Non-infectious

Pain fatigue induced neutropaenia* pneumonitis

Early information Multidimensional Continue at current dose

on pain relief and approach to complete cycle or
supportive care interrupt the drug until
recovery to grade < 3
Repeat complete blood
count on Day 21 Patient education
Consider dose reduction critical for
in cases of prolonged early symptom
Access to pain reporting
relief including (> 1 week) recovery from
early access Grade 3 neutropaenia
to morphine or recurrent Grade
3 neutropaenia in
subsequent cycles

Pharmacological
interventions

Non-pharmacological
interventions
(e.g. exercise)

Treatment interruption/ Grade 2

dose reduction

Systemic steroids
Treatment discontinuation ≥ Grade 3

*PROMs not relevant

ABC, advanced breast cancer; CDK, cyclin-dependent kinase; MASCC, Multinational Association of Supportive Care in Cancer;
mTOR, mammalian target of rapamycin; PROM, patient-reported outcome measure
60
 Mucositis/ Dyspnoea Nausea and Endocrine toxicities
stomatitis vomiting of mTOR inhibition

Prevention from Patient support Refer to

start with steriod essential as well as ESMO/MASCC
mouthwash treatment of causes guidelines
(e.g. if pleural effusion,
pleurodesis)
Mild toothpaste
and dental
hygiene Opioids, Regular monitoring
Palliation steroids

≥ Grade 2 Anxiety Benzodiazepines

Oral antidiabetics Grade 1/2

Lower dose of and basal insulin hyperglycaemia
targeted agent/
delay treatment
Treatment Grade 3/4
discontinuation hyperglycaemia

Statins, fibrates
Treatment interruption Grade 2/3
Dose reduction hypercholesterolaemia

Treatment Grade 4
discontinuation hypercholesterolaemia

61
 • Mutations in the high-penetrance breast cancer predisposition genes BRCA1
and BRCA2 explain ~ 20% of the familial clustering of breast cancer
REFERRAL FOR BRCA TESTING
• Widely accepted clinical criteria for referral include: ≥ 3 breast and/or ovarian
cancer cases with at least one patient aged < 50 years, two breast cancer cases
in patients aged < 40 years, women of Ashkenazi Jewish descent aged < 60 years
with breast cancer, male breast cancer and ovarian cancer or early onset female
breast cancer, early onset bilateral breast cancer, and breast and ovarian cancer
in the same patient
• Genetic testing should be performed in adults who have received genetic
counselling and provided informed consent
• Those carrying mutations should be encouraged to advise close family members
to get genetic counselling
MUTATION DETECTION
• Direct DNA sequencing is the gold standard for mutation detection, although
several techniques are available
• Specific techniques to detect duplications or deletions of ≥ 1 exons, such as
multiplex ligation-dependent probe amplification (MLPA), are required as
2–12% of high-risk families harbour a large genomic alteration
RISK REDUCTION: NON-SURGICAL PREVENTATIVE OPTIONS
Surveillance
• Surveillance of breast cancer in women carrying BRCA mutations includes
monthly self-examinations, clinical breast examinations twice a year, yearly
mammograms and yearly magnetic resonance imaging scans of the breasts,
starting at age 25–30 years
Chemoprevention
• The benefit of tamoxifen for primary prevention of breast cancer in women
carrying BRCA mutations has not been demonstrated
• Adjuvant tamoxifen reduces the risk of contralateral breast cancer in women
with BRCA mutations and breast cancer

62
RISK MODIFIERS
• Parity appears to confer protection from breast cancer in women carrying BRCA
mutations, as in the general population
RISK REDUCTION: PROPHYLACTIC SURGICAL OPTIONS
• There are no randomised controlled trials to support recommendations on
prophylactic surgery; prospective cohort studies have shown a consistent
risk reduction
• Risk reduction options include prophylactic bilateral mastectomy (PBM),
prophylactic bilateral salpingo-oophorectomy (PBSO) or both
PBM
• PBM is the most effective strategy for risk reduction in women carrying
BRCA mutations (risk reduction ≥ 90%)
 Survival benefits have not been demonstrated
• In addition to total mastectomy, other surgical techniques are available, but no
randomised trials have compared them
 Skin-sparing mastectomy (SSM)
– Several large series have reported the oncological safety of SSM with a similar
rate of local failures to total mastectomy
– SSM has a cosmetic advantage, but total loss of all nipple sensation makes it
less satisfactory
 Nipple-sparing mastectomy (NSM)
– Preliminary reports indicate similar failure rates with superior cosmetic results
compared with the other mastectomy techniques
• Types of prophylactic mastectomy and immediate breast reconstruction should
be discussed with the patient, addressing the potential risks and benefits
• Routine sentinel lymph node biopsy is not recommended
• Contralateral prophylactic mastectomy (CPM) is an option for women
carrying BRCA mutations with early breast cancer who have undergone
unilateral mastectomy
 CPM decreases the risk of contralateral breast cancer; however, there are
limited data to suggest that it is associated with decreased mortality
PBSO
• Recommended in women aged > 35 years who have completed childbearing
 PBSO is associated with a risk reduction for breast cancer and ovarian
cancer and there is evidence of a reduction in overall mortality in
premenopausal women
63
 – The significantly reduced risk of breast cancer with PBSO appears to be higher in
women carrying BRCA2 mutations than those carrying BRCA1 mutations
• Short-term hormonal replacement therapy after PBSO appears not to decrease the
overall benefit of PBSO in terms of breast cancer risk reduction
TREATMENT
Surgery
• Surgical treatment of breast cancer in women carrying BRCA mutations should be
based on the same parameters as sporadic cancer, while considering the higher risk
of contralateral breast cancer
 Women carrying BRCA1/2 mutations treated with breast-conservation surgery
(BCS) or mastectomy have similar breast cancer-specific and overall survival
– Chemotherapy (ChT) was the only independent predictor of local failure in those
treated with BCS
• It is not known whether PBSO is associated with a significantly decreased risk
of breast cancer in women carrying BRCA1 mutations who have previously had
breast cancer
Systemic treatment
• BRCA deficiency seems to be predictive of chemosensitivity, particularly to DNA-
damaging agents
• There is no definitive ChT regimen for women carrying BRCA mutations with breast
cancer; standard prognostic features should be used to decide treatment

64
REFERRAL FOR BRCA TESTING
Widely accepted clinical criteria for referral include: ≥ 3 breast and/or ovarian cancer
cases with at least one patient aged < 50 years, two breast cancer cases in patients
aged < 40 years, women of Ashkenazi Jewish descent aged < 60 years with breast
cancer, male breast cancer and ovarian cancer or early onset female breast cancer,
early onset bilateral breast cancer, and breast and ovarian cancer in the same patient
Women should receive genetic counselling and provide informed consent
MUTATION DETECTION
Direct DNA sequencing is the gold standard
RISK REDUCTION
Non-surgical options
Surveillance: Includes monthly self-examinations, clinical breast examinations
twice a year, yearly mammograms and yearly magnetic resonance imaging scans of
the breasts, starting at age 25–30 years
Chemoprevention: The benefit of tamoxifen for primary prevention has not been
demonstrated; adjuvant tamoxifen reduces the risk of contralateral breast cancer
in women with BRCA mutations and breast cancer
Surgical options
PBM: The most effective strategy for risk reduction (no effect on survival); surgical
techniques (total mastectomy, SSM, NSM) and reconstruction should be discussed
with the patient
CPM: An option for women carrying BRCA mutations with early breast cancer who
have undergone unilateral mastectomy
PBSO: Recommended in women aged > 35 years who have completed childbearing
BREAST CANCER TREATMENT IN WOMEN WITH BRCA MUTATIONS
Surgery
• Should be based on the same parameters as for sporadic cancer, while
considering the higher risk of contralateral breast cancer
Systemic treatment
• No definitive ChT regimen for these patients; standard prognostic features
should be used to decide treatment; BRCA deficiency seems to be predictive of
chemosensitivity
65
 5-FU, 5 fluorouracil
ABC, advanced breast cancer
AC, doxorubicin/cyclophosphamide
AI, aromatase inhibitor
AJJC, American Joint Committee on Cancer
ALND, axillary lymph node dissection
AR, androgen receptor
ASCO, American Society of Clinical Oncology
BCS, breast-conserving surgery
CDK, cyclin-dependent kinase
ChT, chemotherapy
CIM, complementary and integrative medicine
CIPN, chemotherapy-induced peripheral neuropathy
CM, low-dose oral cyclophosphamide and methotrexate
CMF, cyclophosphamide/methotrexate/5 fluorouracil
cN0, no regional lymph node
cN1, metastasis to movable ipsilateral level I, II axillary node
Consensus, percentage of panel members in agreement with the statement
CPG, Clinical Practice Guideline
CPM, contralateral prophylactic mastectomy
CT, computed tomography
CTCAE, Common Terminology Criteria for Adverse Events
ctDNA, circulating tumour DNA
DCIS, ductal carcinoma in situ
DFI, disease-free interval
DFS, disease-free survival
EC, epirubicin/cyclophosphamide
EMA, European Medicines Agency
EORTC, European Organisation for Research and Treatment of Cancer
ER, oestrogen receptor
ESMO, European Society for Medical Oncology
ESMO-MCBS, European Society for Medical Oncology Magnitude of Clinical Benefit Scale
ESO, European School of Oncology
ET, endocrine therapy
FACT, Functional Assessment of Cancer Therapy
FDA, Food and Drug Administration
FDG, fluorodeoxyglucose
G-CSF, granulocyte colony-stimulating factor
GoR, grade of recommendation
HER2, human epidermal growth factor receptor 2
HFS, hand and foot syndrome
HR, hormone receptor

66
IHC, immunohistochemistry
ISH, in situ hybridisation
LABC, locally advanced breast cancer
LHRH, luteinising hormone-releasing hormone
LoE, available level of evidence
MASCC, Multinational Association of Supportive Care in Cancer
MBSR, mindfulness-based stress reduction
MMR, mismatch repair
MLPA, multiplex ligation-dependent probe amplification
MRI, magnetic resonance imaging
MSI-H, microsatellite instability-high
mTOR, mammalian target of rapamycin
N0, node-negative
NGS, next-generation sequencing
NIP, non-infectious pneumonitis
N-positive, node-positive
NSM, nipple-sparing mastectomy
NTRK, neurotrophic tyrosine receptor kinase
OFA, ovarian function ablation
OFS, ovarian function suppression
OS, overall survival
PARPi, poly adenosine diphosphate ribose polymerase inhibitor
PBM, prophylactic bilateral mastectomy
PBSO, prophylactic bilateral salpingo-oophorectomy
pCR, pathological complete response
PD, disease progression
PD-1, programmed cell death protein 1
PET, positron emission tomography
PET-CT, positron emission tomography-computed tomography
PFS, progression-free survival
PgR, progesterone receptor
PMRT, post-mastectomy radiotherapy
PRO, patient-reported outcome
PROM, patient-reported outcome measure
PS, performance status
PST, primary systemic therapy
qid, four times a day
qXw, every X weeks
QoL, quality of life
RCT, randomised controlled trial
RT, radiotherapy
RT-PCR, reverse transcription polymerase chain reaction
SBU, specialist breast unit/centre/service
SLNB, sentinel lymph node biopsy
SSM, skin-sparing mastectomy
T, trastuzumab

67
 T-DM1, trastuzumab-emtansine
TNBC, triple-negative breast cancer
TNM, tumour node metastasis
TRKi, tropomyosin receptor kinase inhibitor
uPA-PAI1, urokinase plasminogen activator-plasminogen activator inhibitor 1
US, ultrasound
WBRT, whole breast radiotherapy
WHO, World Health Organization
ycN0, clinically lymph node negative after neoadjuvant chemotherapy

68
HALAVEN® (ERIBULIN) PRESCRIBING INFORMATION
Please refer to the Summary of Product Characteristics (SmPC) before prescribing.
Presentation: 2 ml vial containing eribulin mesilate equivalent to 0.88 mg eribulin.
Indication: The treatment of adult patients with locally advanced or metastatic breast cancer who have
progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have
included an anthracycline and a taxane in either the adjuvant or metastatic setting unless not suitable. The
treatment of adult patients with unresectable liposarcoma who have received prior anthracycline containing
therapy (unless unsuitable) for advanced or metastatic disease.
Dose and administration: For intravenous use. Should only be administered under the supervision of a
qualified physician.
Recommended dose in adults and elderly: 1.23 mg/m2 eribulin as the ready to use solution
administered intravenously over 2-5 minutes on Days 1 and 8 of a 21-day cycle. The dose may be diluted
in up to 100 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. See SmPC for full information
regarding dilution. Patients may experience nausea or vomiting. Antiemetic prophylaxis including
corticosteroids should be considered. See SmPC for guidelines on dose delay and reduction due to toxicity.
Renal impairment: Some patients with moderately or severely impaired renal function (creatinine clearance
<50 ml/min) may have increased eribulin exposure and may need a reduction of the dose. For all patients
with renal impairment, caution and close safety monitoring is advised.
Hepatic impairment due to metastases: Reduce dose for mild or moderate impairment – see SmPC for
guidelines; severe impairment not studied.
Hepatic impairment due to cirrhosis: Not studied; close monitoring recommended.
Paediatrics: There is no relevant use in children and adolescents for the indication of breast cancer. The
safety and efficacy in children from birth to 18 years of age have not yet been established in soft tissue
sarcoma. No data are available.
Contra-Indications: Hypersensitivity to eribulin or any excipients. Breast-feeding.
Special warnings and precautions: Myelosuppression is dose dependent and primarily manifested
as neutropenia. Monitoring of complete blood counts should be performed prior to each dose of eribulin.
Treatment should only be initiated in patients with ANC values ≥1.5 x 109/l and platelets >100 x 109/l. Febrile
neutropenia reported in <5% of patients. Febrile neutropenia, severe neutropenia or thrombocytopenia
requires dose delay or reduction. Patients with ALT or AST >3 x ULN or bilirubin >1.5 x ULN have a
higher incidence of Grade 4 neutropenia and febrile neutropenia. Fatal cases of febrile neutropenia,
neutropenic sepsis, sepsis and septic shock have been reported. Severe neutropenia may be managed with
granulocyte colony-stimulating factor (G-CSF) or equivalent at the physician’s discretion in accordance
with relevant guidelines. Monitor closely for signs of peripheral motor and sensory neuropathy. Severe
peripheral neurotoxicity requires dose delay or reduction. QT prolongation on Day 8 has been observed.
ECG monitoring recommended in patients with congestive heart failure, bradyarrhythmias, if also receiving
medicinal products known to prolong the QT interval, including Class Ia and III antiarrhythmics, and
electrolyte abnormalities. Correct hypokalaemia, hypocalcaemia or hypomagnesaemia prior to initiating
eribulin and monitor during therapy. Eribulin should be avoided in patients with congenital long QT
syndrome. Medicinal product contains small amounts of ethanol (<100 mg per dose).
Drug Interactions: Eribulin is mainly (up to 70%) eliminated through biliary excretion. No drug-drug
interactions are expected with CYP3A4 inhibitors and inducers. Eribulin exposure (AUC and Cmax) was

69
 unaffected by ketoconazole, a CYP3A4 and P glycoprotein (Pgp) inhibitor, and rifampicin, a CYP3A4 inducer.
In vitro data indicate that eribulin is a mild inhibitor of CYP3A4. Exercise caution and monitor for adverse
events when using concomitantly with substances that are eliminated mainly via CYP3A4 and have a narrow
therapeutic window.
Pregnancy and lactation: Do not use during pregnancy unless clearly necessary. Contraception advised
during and up to 3 months after treatment (either for women of childbearing potential or their male partners
when receiving Halaven). Do not use during breast-feeding.
Effects on ability to drive and use machines: Do not drive or use machines if experiencing tiredness
or dizziness.
Undesirable effects: Refer to SmPC for information on all side effects. The incidence rates of
adverse reactions observed in breast cancer and soft tissue sarcoma patients who received the recommended
eribulin dose in Phase 2 and Phase 3 studies: Very common (≥1/10 ): Neutropenia, leukopenia, anaemia;
Decreased appetite; Peripheral neuropathy, headache; Dyspnoea, cough; Nausea, constipation, diarrhoea,
vomiting; Alopecia; Arthralgia and myalgia, back pain, pain in extremity; Fatigue/ asthenia, pyrexia;
Weight decreased. Common (≥1/100 to <1/10): Urinary tract infection, pneumonia, oral candidiasis,
oral herpes, upper respiratory tract infection, nasopharyngitis, rhinitis; herpes zoster; Lymphopenia,
febrile neutropenia, thrombocytopenia; Hypokalaemia, hypomagnesaemia, dehydration, hyperglycaemia,
hypophosphataemia, hypocalcaemia; Insomnia, depression; Dysgeusia, dizziness, hypoaesthesia, lethargy,
neurotoxicity; Lacrimation increased, conjunctivitis; Vertigo, tinnitus; Tachycardia; Hot flush, pulmonary
embolism; Oropharyngeal pain, epistaxis, rhinorrhoea; Abdominal pain, stomatitis, dry mouth, dyspepsia,
gastrooesophageal reflux disease, abdominal distention; Alanine aminotransferase increased, aspartate
aminotransferase increased, gamma glutamyl transferase increased, hyperbilirubinaemia; Rash, pruritus, nail
disorder, night sweats, dry skin, erythema, hyperhidrosis, palmar plantar erythrodysaesthesia; Bone pain,
muscle spasms, musculoskeletal pain, musculoskeletal chest pain, muscular weakness; Dysuria; Mucosal
inflammation, peripheral oedema, pain, chills, chest pain, influenza like illness. Serious but uncommon
( ≥1/1,000 to <1/100): Sepsis, neutropenic sepsis, septic shock; Deep vein thrombosis; Interstitial lung
disease; Mouth ulceration, pancreatitis; Hepatotoxicity; Angioedema; Haematuria, proteinuria, renal failure.
Serious but rare ( ≥ 1/10,000 to < 1/1,000): Disseminated intravascular coagulation. Serious but
frequency not known: Stevens-Johnson syndrome / Toxic epidermal necrolysis.
Overdose: No known antidote. Closely monitor and manage with supportive medical interventions.
Legal Category: POM
Basic UK NHS Cost: Eribulin 0.44mg/ml 2ml vial: £361 per vial
Marketing authorisation number: Eribulin 0.44mg/ml 2ml vial x 1: EU/1/11/678/001
Marketing authorisation holder: Eisai GmbH.
Further information from: Eisai Ltd., Mosquito Way, Hatfield, Hertfordshire, AL10 9SN, United Kingdom
Date of preparation: March 2019.

Adverse events should be reported. Reporting forms and information can be found by either visiting
www.mhra.gov.uk/yellowcard or searching for ‘MHRA Yellow Card’ in Google Play or the Apple
App Store.
Reporting forms and information for Ireland can be found at www.hpra.ie
Adverse events should also be reported to Eisai Ltd.
Tel: +44 (0) 208 600 1400/+44 (0) 845 676 1400; email: eumedinfo@eisai.net
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Access the full ESMO Clinical Practice Guidelines

© 2019 European Society for Medical Oncology

All rights reserved. No part of this booklet may be reprinted, reproduced, transmitted or utilised in any form by any electronic, mechanical or
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This booklet contains information obtained from authentic and highly regarded sources (http://www.esmo.org). Although every effort
has been made to ensure that treatment and other information are presented accurately in this publication, the ultimate responsibility
rests with the prescribing physician. Neither the publisher or the Guidelines Working Groups can be held responsible for errors or for any
consequences arising from the use of information contained herein. For detailed prescribing information on the use of any product or
procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer.

75
European Society for Medical Oncology (ESMO) tmc strategic communications
via Ginevra 4, 6900 Lugano, Switzerland www.wearetmc.co.uk
Tel: +41 (0)91 973 19 00
Fax: +41 (0)91 973 19 02
Email: clinicalguidelines@esmo.org www.esmo.org

BREAST CANCER 2019

ESMO POCKET GUIDELINES

BREAST
CANCER 2019
EMEA-HAL-19-00073
DATE OF PREPARATION: SEPTEMBER 2019
Prescribing Information can be found on Page 69