Contemporary Management of

Early Breast Cancer

What’s New?
Part 2-Management

Dr Mastura Md Yusof
Consultant Clinical Oncologist
March 2023
 The Importance of Multi-disciplinary Team Approach in Managing Breast Cancer

• Management
of breast
cancer is Pathologist
Oncologist
multidisciplina Surgeon Geneticist
ry; the two
major pillars
of breast
cancer
management Radiologist
are
locoregional
treatment
(surgery and
radiation
therapy) and
Early breast cancer: therapy principles
• Management of breast cancer is multidisciplinary
• Locoregional therapy in early breast cancer regardless of molecular subtype comprises
surgery to remove the tumour with BCS, mastectomy and to have either SLNB or axillary
clearance
• Intraoperative Radiotherapy, Postoperative radiation therapy and/or systemic therapies
(which may comprise endocrine therapy, chemotherapy, anti-HER2 therapy, cell cycle
inhibitor, immunotherapy, poly(ADP-ribose) polymerase inhibitors for BRCA mutation
carriers and bone modifying therapies) are usually given depending on the initial tumour
burden and molecular expression pattern of the tumour.
• This approach has allowed us to reorganize the way we think about breast cancer and to make
treatment recommendations as a team, based upon stage and genomic drivers of tumorigenesis.
 Radiation Therapy
Basics
• Adjuvant radiotherapy aims to eradicate clinically occult
tumour deposits in the breast, chest wall, and regional
lymphatic drainage system to improve disease-free and
overall survival.
• Itis offered to most women after either breast-conserving
surgery or mastectomy in the presence of risk factors. Who requires RT? Who doesn’t
• Postmastectomy RT for patients with involved axillary lymph
nodes reduced the 10 year first recurrence rate by 10·6%, require RT?
leading to an 8·1% reduction in breast cancer mortality after • Large tumours (>5
20 years(EBCTCG metaanalysis) pTis, PT1-
cm)
• Post breast- conserving surgery RT showed reductions in 10 2N0MO who
year recurrences rates of 15·4% in patients with negative • Extensive lymph
nodes and 21·2% in patients with positive nodes, and node involvement has had
reductions in 15-year overall mortality rates of 3·3% (patients (>3 axillary nodes) mastectomy
with negative nodes) and 8·5% (patients with positive nodes
(EBCTCG metaanalysis). • After Breast
• RT interact in a positive way with the benefits of systemic Conserving
therapy to decrease the risk of distant metastases, thereby Surgery
increasing the importance of optimizing locoregional • Margin positive
treatments to obtain definitive cancer cure.
• Historically RT was feared to cause late toxicities such as
brachial plexus injury or lymphedema but nowadays modern
regional lymph node radiation therapy technique improves
Decreasing the burden of
radiation therapy and De-
escalation of radiotherapy in
patients at low risk
 Adjuvant Radiotherapy after Breast Conserving Surgery
For years whole breast RT is the standard of care worldwide
Validated by studies comparing lumpectomy alone to lumpectomy and radiation therapy
3-fold reduction in recurrence with use of radiation therapy
Bartelink H et al; Lancet Oncol. 2015

• Target volume: whole breast

• Medial & lateral tangential field
• 45-50Gy/(5 weeks) – 1.8 to 2Gy/# (conventional fractionation)
• Plus boost to lumpectomy cavity 10-16Gy (5-8#)

Breastcancer.org/pictures
 INTRAOPERATIVE RADIOTHERAPY
High dose radiation (Photons or electrons )directly to the
• WHO? tumour bed at time of surgery
• Patient selection – early stage,
small tumour, age, grade 1-2
• HR+ and HER2- status
• Guidelines available

• WHICH?
• Boost
• Primary RT
 Advantages of IORT
• Direct visualization of the target area -> precision in delivering
treatment, eliminate geographical miss
• Sparing surrounding structures by displacing or shielding
• Better integration of radiotherapy with systemic treatment
• Shortening the whole radiation treatment, with significant impact on
workload of radiotherapy (RT) centers, overall costs, and patient
convenience
• Delivering a single high dose in concomitance with surgery, possibly
preventing repopulation of tumour after surgery
 Various hypofractionated regimen for RT has been compared in large trials against
the 50Gy/(5 weeks) (conventional fractionation).
START Pilot START A START B
1986 - 1998 1998-2002 1999-2001
• 42.9Gy in 13Fr • 41.6Gy in 13Fr • 40Gy in 15Fr
• 39Gy in 13Fr • 50Gy in 25Fr
• 39Gy in 13Fr
• 50Gy in 25Fr • 50Gy in 25Fr

• Overall there was no significant difference in loco-regional relapse at 10 years: approximately 5-8% (for pT1-3 N0-N1)
• Toxicity wise : Moderate or marked breast induration, telangiectasia, breast oedema were significantly less in 39Gy or
40Gy compared to 50Gy
• Randomised Phase 3 trials done in Canada, UK and subsequently in China and Denmark have confirmed the safety and
efficacy of 15 fraction or 16 fraction schedules using 2.7Gy
Four of these trials published 10-year follow up data on a total 7000 patients, and the 3-week schedule of 40 Gy in 15 F
has become the standard regimen in many countries over the past decade.

Then 47 Radiotherapy centres in UK treated 1368 patients with 28.5Gy in 5Fr once weekly
Vs 30Gy in 5Fr once weekly vs 50Gy in 25Fr in the FAST 2004-2007 study. It showed Very low LR at 5 years <2 % (non
inferior) with Moderate or marked normal tissue effects in (11.9%) vs (9.9%) 40Gy arm . That led to the FAST FORWARD
trial between 2011-2014 which has published its results recently.
FAST-FORWARD is a multicentre, phase 3, randomised, non-inferiority trial done at 97
hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK.

Patients aged atleast 18 years with invasive carcinoma of the breast (pT1-3, pN0-1, M0) after
breast conservation surgery or mastectomy

Aim : to identify a 5 fraction schedule of adjuvant radiotherapy delivered in 1 week that is

non-inferior in terms of local control and is as safe as an international standard 15 fraction
regimen after primary surgery for early breast cancer.

Whole breast or chest wall treatment, randomly allocated to :

40Gy in 15 fractions over 3 weeks (2.67 Gy per fraction)
27Gy in 5 fractions over 1 week (5.4Gy per fraction)
26Gy in 5 fractions over 1 week (5.2Gy per fraction)
 Results and Interpretation of FAST FORWARD
26 Gy in five fractions is non inferior to the standard of 40Gy in 15 fractions over 3 weeks for local tumor
control, and is safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local
radiotherapy after primary surgery for early-stage breast cancer.

• Can this now be new standard for all breast radiotherapy?

Still not yet Level 1 evidence supporting 26Gy in 5Fr as a

treatment option in breast/chest wall alone RT for pT1-3 N0-1
breast cancer as the 10 year follow up to see the trend of late
effects have not been realised however
many have implemented it ( since Covid 19 happened) with
consideration of its potential benefits namely the late side
effects are not worse compared to 40Gy

• At a consensus meeting held in October 2020 under

the auspices of The Royal College of Radiologists, the
UK breast cancer radiotherapy community voted for
five-fraction breast radiotherapy as its new national
standard for breast radiotherapy
(https://www.rcr.ac.uk/publication/postoperativeradiothe
rapy-breast-cancer-hypofractionation-rcr-
consensusstatements).
 Hormone Therapy
Hormone therapy for 5–10 years is the standard treatment for women with
ER-positive eBC.
Premenopausal patients
• Tamoxifen is the standard endocrine therapy.
Reducing breast cancer mortality about a third
throughout the first 15 years of follow-up in the
EBCTCG MA.
• In premenopausal patients at a high risk for
relapse (ie, after chemotherapy or age ≤35 years),
the addition of ovarian suppression drugs
(gonadotropin-releasing hormone agonist [GnRH])
to tamoxifen or administering GnRH together with
an aromatase inhibitor improved disease-free
survival but not overall survival advantage ( SOFT
and TEXT studies)
• Use of this approach need to be discussed
carefully with the patient considering the treatment
toxicity and QoL
Post menopausal patients
• Postmenopausal women, options include
tamoxifen or a steroidal (exemestane) or non-
steroidal (letrozole or anastrozole) aromatase
inhibitor. However starting upfront with with an
aromatase inhibitor I postmenopausal women
results in a significant absolute risk reduction of
recurrence at 10 years of 3·6% and in an increase
in overall survival of 2·1% compared with
tamoxifen. Aromatase inhibitor therapy has been
shown to provide greater benefit in patients with
advanced stage (II–III), high-grade, HER2-
positive, or highly proliferative disease.
• The sequential approach of aromatase inhibitor
after 2–5 years of tamoxifen results in a smaller
benefit than the aromatase inhibitor upfront
therapy but it still results in significant risk
reduction for breast cancer recurrence of 2·0%
and death of 1·5% compared with tamoxifen
alone.
www.thelancet.com Vol 389 March 18, 2017
What is new in locally advanced or high
risk early stage HR+ HER2 - cancer
Tumours confined to
breast region but…

• Bigger size > 5 cm

• Involves skin/chest wall
• + ax lymph nodes
• Grade3
• High ki67
• Very young age < 35
• BRCAm cancers

Can we give more than

just chemotherapy
High Risk Factors for Micrometastases and Relapse in Breast Cancer in a glance

Tumour Subtypes
lymph node- High grade, Young age
HR- Higher Tumour
positive
HER2+ Stage high Ki67 (<35)
disease
TNBC

Tumour Subtypes, grade, KI67 and prognosis

 High Risk HR+ HER- eBC

Adjuvant Neoadjuvant

Progressive
Dose Dense CT Standard CT PCR Non PCR
during NACT
RT RT
Extended ET Extended ET
RT RT
Extended ET Extended ET

capecitabine
Refused CT/
not chemo
⇢ “EARLYRELAPSERS”
candidate
Unmet need
Chemotherapy, radiotherapy and standard hormone therapy may not be sufficient
for HR+ HER2 - patients with high risk features to prevent early and recurrences,
circumvent endocrine resistance and prolong survival
• ≈ 1/3 of HR+/HER2− patients initially diagnosed with early-stage
disease experience disease recurrence3

In HR+HER2- eBC, the

risk for recurrence of ER-
positive breast cancers
persists for a prolonged
period, with
approximately 50% of
recurrences occurring 5
years after initial
diagnosis3

Catalanotti V, Bertaglia V, Tariq N, Califano R (2014) Treatment of Advanced Breast Cancer

(ABC): The Expanding Landscape of Targeted Therapies. J Cancer Biol Res 2(1): 1036.

3.. Breast Cancer Res Treat 78:105-118, 2003

CDK 4/6 inhibitors in high risk
Hormone Receptor Positive HER2
negative eBC
 Besides Estrogen, growth of Hormone Receptor+ BC is dependent on
cyclin D kinases system within the cell cycle

In HR positive BC, ER activation

upregulates and potentiates
growth signalling pathways, via NF-κB
Pl3K/Akt ER/PR/AR cancer cell growth and
Wnt/β-catenin
STATs proliferation can be blocked
the CDK4/6 activity within the MAPKs
by inhibiting the CDK 4/6
FGFR
cell enzymes p53
Active tumor
suppressor p21
Cyclin D
G0 pRB CDK4/6
E2F
p16
M G1 Restriction point
E2F
G2 Gene transcription P P P Cyclin E
S
pRB
CDK2
Inactive

Lange. Endocr Relat Cancer. 2011;18:C19. Kundsen. Trends Cancer. 2017;3:39. Otto. Nat Rev Cancer.
2017;17:93. Corona. Drug Des Devel Ther. 2018.12:321. Tripathy. Clin Cancer Res. 2017;23:3251-3262.
 CDK4/6i in combination with standard endocrine therapy for
HR+/HER2−negative early breast cancer
-monarchE, PALLAS, and PENELOPE-B.

https://dailynews.ascopubs.org/do/10.1200/ADN.21.200483/full/dn20_ee_advani_table.jpg
Background
♦ Approximately 20% of patients with HR+, HER2- early breast cancer (EBC) will experience disease
recurrence within the first 10 years1
- Certain clinical and/or pathological features including high expression of Ki-67 have been shown
to be associated with a higher recurrence rate2,3
♦ Abemaciclib, an oral, continuously dosed, CDK4 & 6 inhibitor is approved for HR+, HER2- advanced
breast cancer in combination with ET4,5
♦ At the second preplanned interim analysis (IA2) with 323 invasive disease-free survival (IDFS) events,
monarchE achieved its primary endpoint by demonstrating superior IDFS when abemaciclib was
combined with ET compared to ET alone in patients with HR+, HER2-, node-positive, high risk, EBC6
- p=0.0096, HR (95% CI): 0.747 (0.598, 0.932)
♦ Here we report results from the primary outcome (PO) IDFS analysis which was planned to occur at
approximately 390 IDFS events

1EarlyBreast Cancer Trialists' Collaborative G. Lancet 2015;386:1341-1352; 2Network NCCN: Breast Cancer (Version 4.2020), 2020; 3Dowsett MN. et al. J Natl Cancer Inst 2011
103(22):1656-64; 4Sledge GW et al. J Clin Oncol 2017; 35:2875-2884; 5Goetz MP et al. J Clin Oncol 2017;35:3638-46; 6Johnston SD et al JCO 2020
 MonarchE Study Design

HR+, HER2-, high risk early

breast cancer Abemaciclib (150mg twice daily for up to 2 yearsb)
N = 5637a + Standard of Care Endocrine Therapy
High risk​ defined as: (5 to 10 years as clinically indicated)
• ≥4 positive axillary lymph nodes (ALN) R
OR 1:1
• 1-3 ALN and at least 1 of the below:
o Tumor size ≥5 cm
Standard of Care Endocrine Therapyb
Stratified for:
o Histologic grade 3 (5 to 10 years as clinically indicated)
• Prior chemotherapy
o Centrally tested Ki67 ≥20% • Menopausal status
• Region Endocrine therapy of physician’s choice
Other criteria:
• Women or men
• Pre-/ postmenopausal Primary Objective: Invasive disease-free survival (STEEP criteria)
• With or without prior
Key Secondary Objectives: Distant relapse-free survival, Overall
adjuvant/neoadjuvant chemotherapy
• No distant metastases
survival, Safety, Patient reported outcomes, and Pharmacokinetics

a Recruitment from July 2017 to August 2019;

b Treatment period = first 2 years on study treatment after randomization Johnston S et al. J Clin Oncol. Sept 2020
Conclusions
♦ At 3.6 months median follow-up, abemaciclib combined with standard ET
- Demonstrated a reduction in the risk of developing IDFS and DRFS events for patients with HR+, HER2-, high risk
EBC
- Resulted in a statistically significant improvement in IDFS in patients with high (≥20%) Ki-67 tumors
• Abemaciclib combined with ET reduced the risk of developing an IDFS event in patients whose tumors have high
clinicopathological risk factors as defined in monarchE, independent of Ki-67 level
• This is the first time a prespecified threshold of ≥20% for Ki-67 has been used to prospectively evaluate the utility of
central Ki-67 using a standardized assay in a phase III registration trial
– Among patients with high clinicopathological risk factors, patients with high Ki-67 tumors had an even greater risk
of recurrence than those with low Ki-67 tumors, confirming the prognostic value of Ki-67
– These results suggest that Ki-67 ≥20% can be used together with clinicopathological features of nodal
involvement, tumor size, and grade to identify patients with HR+, HER2- early breast cancer at high risk of
recurrence
Safety was consistent with IA2 and the known safety profile of abemaciclib
- Most discontinuations due to AEs occurred within the first 5 months of study treatment
- Most patients who required a dose hold or reduction were able to remain on study treatment

♦ Study is ongoing, until the final assessment of overall survival

 Given in combination with hormone therapy resulted in a
monarchE:
• 37% Abemaciclib
decrease in Combined
the risk with
of Adjuvant
breast Endocrine
cancer Therapy for
recurrence or
High Risk Early Breast Cancer
death compared to standard adjuvant hormone
therapyalone for patients at high risk.
HR+, HER2-, high risk early Abemaciclib (150mg twice daily for up to 2 years ) b
N = 5637a
breast cancer + Standard of Care Endocrine Therapy
(5 to 10 years as clinically indicated)
High risk​ defined as:
• ≥4 positive axillary lymph nodes (ALN) R
OR 1:1
• 1-3 ALN and at least 1 of the below:
o Tumor size ≥5 cm
Standard of Care Endocrine Therapyb
o Histologic grade 3
o Centrally tested Ki67 ≥20%
Stratified for: (5 to 10 years as clinically indicated)
• Prior chemotherapy
• Menopausal status
• Region

Other criteria:
• Women or men
• Pre-/ postmenopausal
• With or without prior Primary Objective: Invasive disease-free survival (STEEP criteria)
adjuvant/neoadjuvant chemotherapy Key Secondary Objectives: Distant relapse-free survival, Overall
• No distant metastases survival, Safety, Patient reported outcomes, and Pharmacokinetics

a Recruitment from July 2017 to August 2019;

b Treatment period = first 2 years on study treatment after randomization Johnston S et al. J Clin Oncol. Sept 2020
 CDK4/6-Inihibitors

1 Sumi NJ et al. ACS Chem Biol 2015;10:2680-2686.

2 Gelbert LM et al. Invest New Drugs 2014;32:825-837.
3 Chen P et al. Mol Cancer Ther 2016;15:2273-2281.
In hormone-receptor- positive, HER2-negative) eBC ;
when patients need chemotherapy,
Neoadjuvant or adjuvant?
• In early breast cancer, preoperative chemotherapy is equally effective as
postoperative chemotherapy regarding disease-free survival and overall survival.
However, neoadjuvant chemotherapy is preferred over adjuvant whenever there
is an indication for adjuvant chemotherapy.
• Eventhough this subtype is not as chemosensitive as TNBC or HER2+ subtype,
information about pathological complete response might help to inform patients
about their prognosis after surgery and allow eligibility to have additional adjuvant
strategy or enter clinical trials for patients without pathological complete
response.
• Adjuvant chemotherapy ideally should be started within the first 3-6
few weeks after surgery for best outcome

• .
Bone modifying therapy in eBC
• In early breast cancer, aromatase inhibitor use may cause bone loss
• Current guidelines call for risk assessment after commencing adjuvant therapy and bisphosphonate
treatment, if appropriate
• Initially trials focused on the the usefulness of adjuvant bisphosphonates for prevention and therapy
of treatment-induced bone loss, in both premenopausal and postmenopausal women.
• Later, adjuvant bisphosphonates was investigated for its potential to prevent bone and even other
metastases. The beneficial effect appears to be confined to postmenopausal patients, or to
premenopausal patients receiving adjuvant ovarian suppression.
• A large EBCTCG meta-analysis, showed that adjuvant bisphosphonates reduced the prevalence of
breast cancer recurrence in bone, and improved breast cancer survival, with clear evidence for a
benefit only in postmenopausal women.

• Its use however isn’t mandatory, only after discussing with patients
according tp their risks and side effects profile
Chemotherapy
 Figure 1
In hormone-receptor- positive, HER2-negative) eBC ;
which patients need chemotherapy? High Risk Factors in hormone
receptor-positive, HER2-
negative early breast cancer;
“when adjuvant chemotherapy
is indicated

• Stage 3
• > 3 LN +
• Tumour size
• High Genomic score
• Age ≤ 35
• Premenopausal with 1-3 LN+
• Premenopausal with 1-3 LN+
and RS ≤ 25
• High grade and lower ER/PR
High Ki67
• High Grade

Annals of Oncology 2019 301194-1220DOI: (10.1093/annonc/mdz173)

Copyright © 2019 THE AUTHORS Terms and Conditions
 ers Author Manuscripts
German study on Luminal type early breast cancer; tumour burden in the form
of the degree of nodal involvement is the prevailing
Page 14
risk factor for distant
recurrence and death from breast cancer
Europe PMC Funders Author Ma

Early breast cancer | LMU breast center | www.lmu-brustzentrum.de | 05.04.2023 30

Pan et al, NEJM 2018
Indications for Chemotherapy in eBC
• The use of chemotherapy generally reduces the risk of recurrence by about
30% in selected patients.
• The indication for neoadjuvant or adjuvant chemotherapy depends on clinical and
pathological factors that affect the risk for recurrence such as:
• more advanced stage disease
• nodal involvement
• tumour size,
• less endocrine-responsive disease (low expression of ER, PR, or both)
• high grade or high proliferative index
• lymphovascular invasion
• Patient’s age ( very young vs non)
• High genomic score on multigene assay
• In general, the absolute benefit from chemotherapy depends on the risk of recurrence
whereby an estimated recurrence risk of more than 10% over the course of 10 years
indicates that the patient requires (neo)adjuvant chemotherapy. Lancet 2021; 397: 1750–69
 In hormone-receptor- positive, HER2-negative) eBC ;
when patients need chemotherapy,
Which regimen?
Generally, recommended regimens do not differ between neoadjuvant and adjuvant settings.

www.thelancet.com Vol 389 March 18, 2017

In general, who doesn’t need chemotherapy?

HR+HER2- TNBC HER2+ DCIS/LCIS

pT1a-T1bN0 pT1aN0M0 pT1aN0M0 G1-

G1, Ki67<10 G1-2, Ki67<20% 2,Ki67<20%

pT1c-2N0 Some pT1bN0M0

Some pT1bN0M0 G1-2, Ki67<20%
G1-2, Ki67<20 with G1-2, Ki67<20% pts pts who are
Low genomic score who are elderly or elderly or with
on multigene assay with comorbidities comorbidities

pT1-2N1, G1-2,
Ki67< 20% with
low genomic score
 Multigene tests for early-
stage breast cancer to
predict recurrence risk and
guide adjuvant
chemotherapy decisions
Multigene tests for early-stage breast cancer to predict
recurrence risk and guide adjuvant chemotherapy decisions
(1)
• ER+, HER2- luminal tumours is the most common breast cancer subtype (around 50-70%).
• Very low clinico-pathological risk (such as patients with pT1a–b, pN0, G1 and high ER positive HER2- disease
do no require chemotherapy.
• There exist within the group - patients that will be categorised clinically as Low risk tumours - node-
negative small pT1-2N0, Grade 1-2, Ki67 <10% but genomically is high risk .
Meanwhile…
• There are patients who are categorised clinically as having high-risk tumours (Ki67 between 10% -
30%, N1 axillary LN positive(1-3 nodes ) but genomically is low to intermediate risk cancer.

Online Prediction tool such as Predict, Adjuvant! Online, Clinical Treatment Score post-5 years (CTS5) can
be used to predict breast cancer outcomes but….knowing that breast cancer has complex biology and
substantial heterogeneity, these tools are not “individualised”
So how can we select them better?
• To better stratify the risk by providing a more accurate indicators of recurrence risk and guide treatment
decisions ( which patients may derive benefit or which patients can avoid chemotherapy) researchers
had focused on the biological tumour characteristics using multigene assays aka Prognostic assays aka
aka Gene expression signatures .
Lancet 2021; 397: 1750–
 Multigene tests for early-stage breast cancer to predict
recurrence risk and guide adjuvant chemotherapy decisions
(2)
There are a variety of assays available:

1. Oncotype Dx
2. MammaPrint
Tests 1-4 are available via external vendor, in Malaysia.
3. Prosigna (PAM50)
4. EndoPredict
5. Breast Cancer Index
6. Genomic Grade Index

The 21 gene Oncotype Dx and 70 gene MammaPrint panels are the most widely used so far due to
the prospective nature of their trials in validating the tests- for Oncotype –dx ;TAILORx Trial and
WSG PlanB Trial for pN0 and RxPONDER [pN1].
For MammaPrint, the MINDACT trial showed that patient outcome is not compromised if
adjuvant chemotherapy is omitted in clinically high-risk and genomically low-risk eBC.

All other multigene assays have only been retrospectively validated.

The Breast Cancer Index is a another genomic test done in early-stage HR+ breast cancer patients
with node-negative or one to three positive nodes but the objective is to determine the need for
extended endocrine therapy after five years.
Lancet 2021; 397: 1750–
Multigene tests for early-stage breast cancer to predict recurrence risk
and guide adjuvant chemotherapy decisions (3)
Oncotype DX Breast Recurrence Score

The Oncotype DX Breast Recurrence Score, is a reverse transcriptase PCR

assay measuring the expression of 21 genes (16 breast carcinoma-related
and five reference genes ) of the breast tumour.

A recurrence score (RS) ranging from 0 to 100 will then be calculated to

divide into low ( score < 25) and high-risk (>25) .

The recurrence risk scores based on these genes are then heavily
correlated with age, HR status and proliferation-related genes to serve as a
prognostic biomarker in predicting the risk of recurrence at ten years and
benefits from chemotherapy in ER-positive, HER2-negative breast cancer
with 0–3 positive lymph nodes (N0-N1).

For the low-risk group, endocrine therapy is sufficient, whereas for the
high-risk group, benefits from chemotherapy surpass other potential side
effects
Lancet 2021; 397: 1750–
Oncotype DX® 21-Gene
Recurrence Score (RS) Assay
16 Cancer and 5 Reference Genes From 3 Studies
RS + 0.47 x HER2 Group Score
PROLIFERATION ESTROGEN
= - 0.34 x ER Group Score
Ki-67 ER
+ 1.04 x Proliferation Group
STK15 PR
Score
Survivin Bcl2
+ 0.10 x Invasion Group
Cyclin B1 SCUBE2
Score
MYBL2
+ 0.05 x CD68
GSTM1 BAG1
- 0.08 x GSTM1
INVASION - 0.07 x BAG1
Stromelysin 3 CD68
Cathepsin L2 REFERENCE
Category RS (0-100)
Beta-actin Low risk RS <18
HER2 GAPDH
Int risk RS ≥18 and <31
GRB7 RPLPO
HER2 GUS High risk RS ≥31
TFRC Paik et al. N Engl J Med. 2004;351:2817-2826.
ECOG, SWOG, NCCTG, CALGB, NCIC, ACOSOG, and NSABP
funder : NCI

TAILORx Trial Assigning IndividuaLized Options for Treatment (Rx)

Node-Neg, ER-Pos Breast Cancer
Register
Specimen
banking
Oncotype DX® Assay

RS 11-25
RS <10 Randomize RS >25
Hormone Hormone Rx Chemotherapy
Therapy vs +
Registry Chemotherapy + Hormone Rx
Hormone Rx
Primary study group
Tailor- X
 Example 1. Oncotype dx
Age <50, node negative pT2 ( 2.5cm), G2, Ki67 20%

At RS 23,with just hormone alone, distant recurrence risk at 9 years 1s 9%. Adding chemotherapy gives about 6.5%
absolute distant recurrence benefit . Final decision ; patient will have TC x 4 chemotherapy
Example 2. Node Negative Example 3. Node Negative
High Genomic score Low Genomic Score
Example 4. Node Positive pN1 Example 5. Node Positive pN1
Post menopausal age > 50, (3 LN+) Premenopausal age >50. pN1 ( 1 LN+)
MINDACT
(Microarray in Node-Negative Disease May Avoid
Chemotherapy Trial)
Evaluate clinico-pathological risk (Adjuvant!) AND 70-gene signature risk
32%
N=3300 N=780
55% Discordant cases 13%
Clinical pathological Clinical pathological
Clin-Path HIGH risk
AND AND
LOW risk 70-gene
70-gene signature 70-gene signature
HIGH risk Clin-Path LOW risk LOW risk
70-gene HIGH risk
n=1920

Use Clin-Path risk to

decide on adjuvant
R Use 70-gene risk to
decide on adjuvant
chemotherapy or not chemotherapy or not

chemotherapy No chemotherapy

All hormone responsive patients receive endocrine therapy

Buyse M et al, JNCI 2006

 Example 6. Mammaprint
Age 40, node negative pT1c ( 1.8cm), G2, Ki67 15%

Gene expression results : high risk luminal B type. Without any treatment ( hormone/ CT) the average 10 year risk of
recurrence is 29%. If chemotherapy is added to hormone the distant metastases free survival is increased by 0.8% to 95.8%
MINDACT Results

MINDACT provides indisputable Level 1A, phase III, randomized prospective clinical evidence
that proves the superiority of MammaPrint 70-Gene Assay in predicting the benefit of
chemotherapy in early-stage breast cancer patients when compared to clinicopathological
risk assessment.
When must you avoid ordering
for MULTIGENE ASSAY? :
1. Very low clinicopathological risk (such as patients with pT1a–b,
pN0, G1 and high ER disease)
or

2. If clinicopathological factors all point towards high-risk disease

( such as Grade 3, TNBC, HER2 positive, pT3/4N0-N2, N3
disease
Multigene assay recurrent score to identify patients with HR+, HER2- early stage breast cancer with Low-
Intermediate Risk who can be spared the toxicity of chemotherapy
POSTMENOPAUSAL
Endopredict
MammaPrint
Oncotype DX
pT1-2N0M0, G1-2 , L ow genomic NO
Ki67 10-20% Prosigna score CHEMOTHERAPY
HR+, HER2- Breast Cancer Index,
luminal tumours Genomic Grade Index
pT1-2,N1, G1-2 Intermediate
Ki67 10-30% Genomic Score

High Genomic
CHEMOTHERAPY
Score

PREMENOPAUSAL

Low Genomic
Oncotype- Dx No chemotherapy
Score
HR+, HER2- pT1-2N0, G1-2,
luminal tumours Ki67 10-20%
High Genomic
chemotherapy
Score
 High Risk early Breast Cancer in germline BRCA carriers

It has been estimated that approximately 7-10% of breast cancers are associated with germlineBRCAm and additional 3%
have sBRCAm.1

BRCAm and HR+ BC

BRCAm are widely associated with TNBC subgroup and HR+

patients

TNBC _ the majority will be BRCA1 mutations

HR+ - the majority will be BRCA2 mutations

Calculations based on Winter et al, 2016

• TNBC=triple negative breast cancer, HER=human epidermal growth factor, mBC=metastatic breast cancer
• 1. Winter et al. Ann Oncol. 2016 Aug; 27(8): 1532–1538; 2. Atchley DP et al. J Clin Oncol 2008; 26:4282-4288; 3.Mavaddat N et al. Cancer Epidemiol Biomarkers Prev 2012;21:134-147;
4. Couch FJ et al J Clin Oncol 33:304-311; 3.
BRCA1 and BRCA2 are proteins, integral to cellular repair
pathway as a response to cell damage
PARP Inhibitor drugs target the
Homologous Recombination Repair Process preventing tumour cells from repair and leads
to cell death

PARP PARP inhibitor drugs

When DNA breaks occur
interfere with this process
PARP enzymes repair the
single strand break

Replicating
cells

Cancer cell with BRCA

Normal cell mutation

Double strand No effective

break is repaired
Tumour repair
Homologous
Recombination specific killing (No HR pathway)
cells Survive by PARP
Cell
Inhibitors
death
SSB = single strand binding protein; DSB = double strand binding protein; PARP = poly (ADP-ribose) polymerase;
HRD = homologous recombination deficiency.
 OlympiA: Adjuvant olaparib in patients gBRCAm breast cancer at
high risk of recurrence—Phase III study

Triple Negative Breast Cancer or Global study in approximately

HER2– HR+ breast cancer with a 25 countries and 300 sites
germline BRCA mutation and at
high risk of recurrence
For patients who received adjuvant
chemotherapy
• TNBC patients: axillary node- Primary Secondary Secondary
positive (any tumour size) or Olaparib endpoint endpoint endpoint
axillary node-negative (pN0) with 300mg* po bid
for 12 months Invasive Distant OS
invasive primary tumour Disease Disease
pathological size > 2 cm Randomise 1:1 Free Free
• HR+ patients: ≥ 4 pathologically N≈1320 Survival Survival
(STEEP
confirmed positive lymph nodes approach)
Placebo
Stratification by 12 months
For patients who received • Prior neoadjuvant
versus adjuvant
neoadjuvant chemotherapy chemotherapy
• TNBC patients: non pCR • Prior platinum
therapy for breast
• HR+ patients: non pCR AND a cancer
FSI July 2014
Status: Recruitment ongoing
CPS&EG score ≥3

ECOG PS 0–1

• *Tablet formulation (2 tablets twice daily) – HR+ patients could continue tamoxifen or AI in line with international guidelines
• ECOG=Eastern Cooperative Oncology Group; OS=overall survival; po=by mouth
• Clinicaltrials.gov identifier: NCT02032823
Setting up and MDT for your
patients/ centre
 MDT
“ To bring collaborative decision-making and concentrate clinical experience from multiple
specialties on single patient cases in a systematic fashion”
MINIMUM SET UP
Administration
Members Staff to coordinate
Perks
1.Oncologist Receive cases from drs (
Venue Timing and time phone/emails)
2.Surgeon Refreshment/ Food
Dedicated room Preferably morning or notification to invited
3.Radiologist discussant/ others by provided
Central located the least busy time of
4.Pathologist the day generated sms and CME points accorded
Equipped with emails-a day prior
5.Physician 1 hr minimum Networking
projectors/ wifi/ screens
6.others Register attendance Opportunity for clinical
Prepare forms to be trials or access program
filled with documented
recommendation

Coordination and carrying out the care to the patient and updating any outcome/ audit when necessary ,
Soukup T et al. Successful strategies in implementing a multidisciplinary team working in the care of patients with cancer: an overview and synthesis of the available literature. J Multidiscip Healthc. 2018
Soukup T et al. Successful strategies in implementing a multidisciplinary team working in the care of patients with cancer: an overview and synthesis of the available literature. J Multidiscip Healthc. 2018
Soukup T et al. Successful strategies in implementing a multidisciplinary team working in the care of patients with cancer: an overview and synthesis of the available literature. J Multidiscip Healthc. 2018
Soukup T et al. Successful strategies in implementing a multidisciplinary team working in the care of patients with cancer: an overview and synthesis of the available literature. J Multidiscip Healthc. 2018