Contemporary Management of

Early Breast Cancer

What’s New?
Part 1- Introduction to Disease
Concepts

Dr Mastura Md Yusof
Consultant Clinical Oncologist
March 2023
 Breast Cancer (eBC)
Introduction
• Breast cancer is curable in ~70–80% of patients with early-stage, non-metastatic
disease1.
• BC is a heterogeneous disease in terms of therapeutic response, dissemination
patterns to distant sites, patient outcomes and importantly at the histology and
molecular level because treatment strategies differ according to molecular
subtype/features - the activation of human epidermal growth factor receptor 2
(HER2, encoded by ERBB2), hormone receptors (oestrogen receptor (ER) and
progesterone receptor (PR) and gBRCA mutations.
• As such breast cancer has become a model for how we approach cancer treatment
presently- translating our understanding of the biologic diversity of the disease to
become the basis for the development of numerous therapeutic advances to
achieve significant improvements in survival.
 Introduction
• Breast cancer is the most common cancer and a major health problem among women worldwide.
• More than one million women are diagnosed annually (~ 30% of female cancers) and 1 in 9 women face
the risk of developing breast cancer in their lifetime.
• Breast cancer mortality is higher in many low- and middle-income countries, due to poor awareness and
screening uptake, delayed presentation causing late stage at diagnosis, long waiting time and limited
access to treatment
• Several studies have also shown that breast cancer presents earlier (~10 years younger, 40-50 years of
age) in Asian women than in their western counterparts ( 60–70 years of age) and the proportion of young
patients (<35 years of age) is also higher ( up to 25%) compared to~10% in developed countries.2
• In Malaysia, breast cancer is the most common cancer type overall, and among females.
• Within the period of 2012-2016, 21,634 cases of female breast cancer were diagnosed compared with 18,206 cases
in 2007-2011 report.

• The ASR was 34.1 per 100,000 populations which is considerably higher than the average global incidence in both
developed (6.9 per 100,000) and less developed regions (4.6 per 100,000) (Jemal et al., 2011).

• Breast cancer accounted for 18.1% of all cancer cases reported, and 32.1% of all female cases. Only 48% of cases
were diagnosed at early stage I/II in contrast to international figure of almost 60% with early stage at presentation.
 Breast cancer : Malaysia

Relative 5-year Breast Cancer Survival Rate:

Burden of Breast Cancer Malaysia -International comparison
The risk of dying from
Accounted for 34.1% breast cancer in the
1 of all cancer among developed world is
females in Malaysia1 lower owing to
expanding access to
high- quality
Mortality-to-incidence prevention, early
2 ratio 48% detection, and
treatment services to
( international ration is 15%)
all women, not
neglecting the vast
Almost half (48%) of the differences in access
3 patients are presented in to these services
Stage III & IV1

Ref: 1. Azizah, A., et al. "Malaysia National cancer registry report (MNCR)." National Cancer Institute, Ministry of Health: Putrajaya, Malaysia (2019). 2. . Liu S et al. Clin Cancer Res. 2018;24:2594-2604 3. A review of breast cancer research in Malaysia, Med J Malaysia . 2014 Aug;69 Suppl A:8-22. 3. Pathmanathan, N, 4
et al. "Human epidermal growth factor receptor 2 status of breast cancer patients in Asia: results from a large, multicountry study." Asia‐Pacific Journal of Clinical Oncology 12.4 (2016): 369-379.
Risk Factors
With or without risk factors or family history : any woman experiencing breast symptoms or breast
changes, such as a lump, localized pain, nipple symptoms or skin changes, require appropriate
diagnostic evaluation, as do women who have positive screening test (MMG, MRI)

Important to acknowledge
that about 10% of all
cases of breast cancer
are related to genetic
predisposition or family
history.
The most common
germline mutations
associated with breast
cancer are : BRCA1 and
BRCA2 genes, with an
average cumulative
lifetime risk of about
70%.

Guidelines for genetic

testing after taking
personal & family history,
doing risk assessment
and genetic counselling
 Hereditary vs. Sporadic breast cancer
Majority of breast cancers occur
sporadically. BRCA 1 & BRCA 2
Approximately 5-10 percent of breast
cancer is caused by pathogenic or
harmful) variants in the BRCA1&2 Hereditary
genes. genes and
unknown genes
There are increasing data on variants of
rarer genes with high to moderate risks Sporadic breast
for the development of breast cancer cancers
which account for a smaller percentage
of hereditary breast cancers such as 6%
tumor protein p53 (TP53), partner and
localizer of BRCA2 (PALB2), phosphatase 10%
and tensin homolog (PTEN), checkpoint
kinase 2 (CHEK2), and ataxia- 90%
telangiectasia mutated (ATM).
Inherited Breast Cancer Syndromes
 Germline mutations in BRCA1&2
- Implications in eBC BRCA TESTING INDICATIONS
gBRCA 1&2 mutation: • A personal history of breast cancer diagnosed before age 45
• A personal history of breast cancer diagnosed before age 50 and a second primary
• The only biomarker recommended for breast cancer, one or more relatives with breast cancer, or an unknown or limited
testing besides ER,PR &HER2 family medical history
• Predict the pCR rate to neoadjuvant • A personal history of triple negative breast cancer diagnosed at age 60 or younger
chemotherapy in TNBC and high-risk • A personal history of two or more types of cancer
luminal breast cancer,
• A personal history of ovarian cancer
• Confer a survival benefit in TNBC • A personal history of male breast cancer
• Identifies patients with TNBC or HER2- • A personal history of breast cancer and one or more relatives with breast cancer
negative, HR+ breast cancer at high diagnosed before age 50, two or more relatives diagnosed with breast cancer at any
age, one or more relatives with ovarian cancer, one or more relatives with male breast
risk for recurrence who might benefit cancer, or two or more relatives with prostate cancer or pancreatic cancer
from adjuvant PARPi therapy.
• A personal history of breast cancer and Ashkenazi (Eastern European) Jewish
• Occurs in 15–20% of all TNBC and ancestry
10–15% of HER2-negative, HR+ • A personal history of prostate cancer or pancreatic cancer with two or more relatives
breast cancer with BRCA-associated cancers
• BRCA1-associated breast cancers are • A history of breast cancer at a young age in two or more blood relatives, such as your
mostly of triple-negative phenotype (70%– parents, siblings or children
85%)
PALB2 mutations are prevalent in about 0·6–3·9% of • A relative with a known BRCA1 or BRCA2 mutation
familial breast cancers but its utility in eBC management • One or more relatives with a history of cancer that would meet any of these criteria for
is still not well established gene testing
 Screening and Prevention
• Screening asymptomatic women with a
mammography is a secondary prevention
strategy aimed at detecting the disease at an
early stage to enable effective treatment.
• It reduces breast cancer mortality by at
least 20% in at least 8 RCTs with most
benefit seen in women 50–69 years of age.
• .MRI screening in mutation carriers
• Highly sensitive for cancer detection
compared to combined MMG and breast
US (90–93% vs, 48–63%) in prospective
trials of asymptomatic women at high risk of
breast cancer .

• gBRCA1/2m carriers can have primary

prevention strategy by undergoing bilateral
mastectomy and bilateral salpingo-
oophorectomy.
• Medical prevention with tamoxifen,
raloxifene or aromatase inhibitor reduce
Diagnosis and Pathology
 Work up of women with symptoms or following a positive screening
Triple Test for Diagnosis
CLINICAL
EXAMINATIO
IMAGING NEEDLE BIOPSY
N
Bilateral US breast
Bilateral Breast MRI ( if 2–3 cores- to obtain adequate
& US axilla
MMG necessary) tissue/cells to perform:
• Personal Assess 1.Histological type
medical lumps/local Presence of 2. Grade , Ki67
history Occult breast breast
symptoms image- guided tumour implants 3. ER PR and HER2 status
• family
percutaneous
history
Bilateral biopsy. US or stereotactic guided
Uni/multifocal Hereditary
+/- digital /multicentric breast cancer FNAC of primary tumour is
• menopausal Preoperative not recommended
breast characterize assessment of
status tomosynthes and biopsy
Inconclusive newly
is (near-3D imaging suspected diagnosed In multifocal and multicentric
• full physical modality of or discordant
MMG) axillary lymph lesions on invasive tumours, at least 2 largest
examination choice for nodes US/MMG lobular eparate lesions should be
young women cancers biopsied if possible

US-guided fine-needle
aspiration or core biopsy of
suspicious lymph nodes
 Breast Cancer Final Pathology
Information obtained at surgical
Information obtained at biopsy
resection
or at surgical resection
• Peritumoral vascular or lymphatic emboli
• Histological type according • Excision margins (mm)
to the current WHO
classification • Tumour grade
• Histological grade • Tumour size, single or multiple tumours
according to the Elston- • Lymph node status
and Ellis-modified Scarff–
Bloom–Richardson system • Pathological stage according to the Union for International
• Hormone receptor status Cancer Control TNM system
(oestrogen receptor (ER) • Ki67 score according to the international group guidelines
and progesterone receptor)
• Response to neoadjuvant therapy
• Human epidermal growth • PCR , non PCR
factor receptor 2 (HER2)
status • Ductal carcinoma in situ component type, grade and
percentage
• Tumour recurrence score ( if available)
 Breast Cancer Subtypes in Malaysia1

Breast cancer ER PR HER2

Hormone receptor positive negative

HER2 Receptor negative positive positive negative

Subtypes HR+HER2- HR+HER2+ HR-HER2+ HR-HER2-

50% 15% 15% 20%

1.Cheng Har Yip et al. A review of breast Declining prognosis

cancer research in malaysia Med J
 • Tumour grade reflects the
Tumour Grade (G1-G3)) potential aggressiveness
of the breast cancer and
is a strong prognostic
factor.
• it can be used to identify
patients at low risk or high
risk for adverse outcomes,
who may be eligible for
neoadjuvant and/or
adjuvant therapies
• Histologic grade represents the degree of differentiation, which reflects the resemblance of tumor cells to normal
breast cells.

• Histologic grading needs to be performed accurately, on properly fixed specimen preferably on needle biopsy
specimen, at diagnosis
• Assessment is made according to the Elston- and Ellis-modified Scarff–Bloom–Richardson system-based on three
tumour features: the proportion of cancer cells that are in tubule formation, anisokaryosis (the variation of nuclear
size and shape between the cells) and the number of mitoses (cell divisions).

• Each feature is scored with a three-tier system, and the final grade (G1, G2 or G3) is determined by adding the
individual scores.
 Nuclear Proliferation Rate -Ki67

What is the definition of High Ki67?

• Values of 10% or less are generally

considered low risk, and values
between 20% and 29% are
considered as a minimum criterion
for high proliferation.
• Nonetheless the cut off for the
value has not been prospectively
validated so when dealing with
Ki67 is a nuclear antigen that is an excellent marker of intermediate Ki67 values, say
active cell proliferation in the normal and tumour cell between 10-30%, it should not be
populations . used as the sole criterion for
indicating adjuvant chemotherapy
It has been proposed as a useful clinical marker for in luminal B tumours.
breast cancer subtype classification, prognosis, and
prediction of therapeutic response to
neoadjuvant/adjuvant therapy. For example, its level can
be used to differentiate between luminal A-like and B-like
breast cancers without gene expression profiling
 Breast Pathology and molecular classification
• With deeper understanding of the molecular alterations driving BC growth, clinical management of breast
cancer shifted from being based on stage and tumour burden to (being guided by) biology-centred approaches
• Generally 2 types of classifications have been developed to group BC into subtypes:
1. The intrinsic classification of Perou and Sorlie(2000)1, directly determined the tumour classification by
performing a multigene assay such as Prosigna (NanoString Technologies) or Blueprint (Agendia) on the FFPE
tumour tissue. few breast cancer centres routinely determine molecular subtype by a multigene assay
• Four subtypes of breast cancer: luminal A and luminal B (expressing the oestrogen receptor (ER)),
basal-like and human epidermal growth factor receptor 2 (HER2)- enriched (without ER expression).
• The intrinsic classification influences the profile (timing, sites) of metastatic disease. Eg. Luminal A
tumours tend to relapse late (after 5 years of first presentation) and often metastasize to bone and
lymph nodes (as do luminal B, HER2-negative tumours). TNBCs are prone to early recurrences
(within 2–3 years of first pres-entation) and tend to form visceral (lung) and brain metastases and has
highest association with germline BRCAm. HER2-positive breast cancers show better prognosis with
anti HER2 therapy, but they escape therapy through brain metastasis.
2. The clinical classification indirectly reconstructed based on histological and immunohistochemically
determined molecular characteristics (oestrogen receptor [ER], progesterone receptor [PgR]) and HER2 status, as
well as tumour proliferation measured by Ki67 as follows:
• luminal A-like subtype (ER or PR positive, or both, HER2 negative, low proliferation)
• luminal B-like subtype (ER or PR positive, or both, HER2 negative, high proliferation)
• HER2 subtype, non-luminal (HER2 positive,ER and PR negative) or luminal (HER2 positive,ER or PR positive, or both);
• basal-like subtype (HER2 negative and ER and PR negative; triple negative breast cancer)
 Molecular and histological classifications of breast cancer
have important implications for therapy
The most frequent
histological
subtypes of
invasive breast
cancers are; ductal
. carcinoma (NOS)
The intrinsic and lobular
subtypes of Perou carcinoma;
and Sorlie are followed by
based on a 50- preinvasive
gene expression cancers : ductal
signature carcinoma in situ
(PAM50), its use is and lobular
limited to research carcinoma in situ
purposes for now.

The surrogate intrinsic subtypes used clinically, are based on histology and ER, PR , HER2 and Ki67. Tumours expressing
ER and/or PR are termed ‘hormone receptor-positive’; tumours not expressing ER, PR and HER2 are called ‘triple-negative’.
GES, gene expression signature. aESR1 mutations induced by aromatase inhibitor targeted therapy.
Studies evaluating the gene expression profiles/ patterns of breast cancers; classifiying
them into four intrinsic or molecular subtypes that have prognostic relevance to survival
HER2 Positive Breast Cancer
versus HER2 Low Breast cancer
Human epidermal growth factor receptor 2 status of breast cancer patients in Malaysia
(2011-2013)

n=17 Laboratory taking part

in data collection in both
public and private sector

HKB Laboratories PPUM, Gribbles, BP Lab,

HUSM not participating Perlis, Penang, NS, Putrajaya
HSZ

No of 1684
HRPBI HER2+ pts
HS % HER2 + 32.6%
PPUKM QEH
HTAA
SDMC
HKL
Pantai
Premier
Hosptal
Melaka
HSA SGH

Hos SF

Human epidermal growth factor receptor 2 status of breast cancer patients in Asia: Results from a large, multicountry study, Volume: 12, Issue: 4, Pages: 369-379, First
published: 23 June 2016, DOI: (10.1111/ajco.12514)
HER2 Expression
Routine evaluation of HER2 status is performed through analysis of breast cancer tissue using immunohistochemistry
(IHC) for HER2 protein assessment and/or in situ hybridization (ISH) for HER2 gene amplification. HER2 positive was
defined as IHC 3+ or HER2 gene amplification by FISH testing. IHC 0 is HER2 negative.
IHC 1+ or IHC 2+ but FISH negative were considered as HER2 negative before but recently this degree of HER2
expression, called HER2 low impacts treatment selection- currently in patients with metastatic breast cancer
but not surprisingly later- in those with eBC.

22
 Around 60% of metastatic breast cancers categorized as HER2 negative express low
levels of HER2 (HER2-low)1

Current paradigm Future paradigm

Guidelines recommend ‘HER2 positive3’ HER2+ HER2+

assessment of
HER2 status in all newly
HR+/HER2−
diagnosed patients with
BC and those patients
who develop metastatic HR+/HER2−
disease2 Currently ‘HER2
~50% of patients
HR+/ with BC have
negative3,4’ (~85%)
HER2-low tumors that express
low levels of
HER24,5

HR-/HER2-low
HER2-
HR−/HER2−
HR−/HER2−
(IHC 0)

1. Schettini F, et al. NPJ Breast Cancer. 2021;7(1):1. 2. Wolff AC et al. J Clin Oncol. 2018;36(20):2105-2122. 3. Burstein HJ. N Engl J Med. 2005;353(16):1652-1654. 4. Tarantino P et al. J Clin Oncol.
2020;38(17):1951-1962. 5. Marchiò C et al. Semin Cancer Biol. 2021;72:123-135. 23
Proposed paradigm of identifying HER2-low BC
IHC 01,a IHC 1+ IHC 2+ IHC 3+
No staining OR faint, Faint Weak to moderate Intense
incomplete staining in incomplete staining in complete staining in complete staining in
≤10% of tumor cells >10% of tumor cells >10% of tumor cells >10% of tumor cells

Equivocal
ISH ISH
Negative Positive

HER2 negative
HER2 negative HER2-low HER2 positive

• HER2-low is defined as a HER2 IHC score of 1+ or 2+/ISH negative2 HER2-

• Evidence-to-date is insufficient for defining HER2-low BC as an individual subtype2 (IHC 0)

aAn IHC score of 0 may reflect an artifactual limitation of the technique rather than the total absence of HER2 protein on the membrane, which could be defined as low HER2 expression.2
1. Wolff AC et al. J Clin Oncol. 2018;36(20):2105-2122. 2. Tarantino P et al. Cancer Discov. 2022;12:1-5.

24
 Staging - what procedure is necessary?1

• Staging process after a BC diagnosis involves a hunt for metastases.

• Routine staging examinations consist of chest XRAY, abdominal ultrasound.
• Because of their high sensitivity, CT scans of the abdomen/pelvis, bone scan or a
PET CT scan might be better suited for :
• Symptomatic patients ( e.g asymptomatic patients with large tumours T3 and
above (diameter >5 cm [incidence : 15%])
• Those at high risk for relapse (e.g patients with extensive nodal disease
(>three involved lymph nodes [incidence 4%]) or in aggressive cancer types
-such as HEr2+, TNBC, very,high Ki67
• Abnormal organ function test results – eg. Raised ALP may warrant a bone
scan or deranged LFT – a CT abdomen/pelvis

1. Gerber B et al. Breast Cancer Res Treat 2003; 82: 29–37

 Staging- what procedure is necessary?

All patients
Large tumours (e.g. ≥5 cm)
Blood work-up
- full blood
count, liver and
High Risk - Clinically positive axillary node
Aggressive biology such as HEr2+, TNBC
renal function Signs/symptoms/lab values suggesting metastases
tests, alkaline
phosphatase
and calcium CT scan chest, abdomen Stage 1-2A
levels (CT or MRI scan) and a

ECHO for
bone scan
Low Risk - Luminals
Tumour < 1 cm
any subtype , low
cardiac
function PET-CT – especially in high genomic score
evaluation in risk patient
those planned
for anti HER2 Or when conventional Ultrasound liver and CXR
therapy methods are inconclusive
Breast Cancer Stages in a Glance
 Staging
American Joint Committee on Cancer (AJCC) tumour, node, metastasis (TNM) staging
system ( 8th edition)

• This staging
system takes into
consideration the
anatomical
information of the
disease extent
and the
prognostic
information
related to tumour
biology [tumour
grade, oestrogen
receptor (ER),
progesterone
receptor (PgR),
human epidermal
growth factor
receptor 2 (HER2)
and gene
expression data (if
available]
Management
New Therapy Concepts/ Principles
 Early Breast Cancer (Stage I-III):
treatment concepts
• Early breast cancer without detectable distant metastases is a potentially curable disease.
• Therapy concepts need to be decided in a multidisciplinary team meeting and shared decision
making with the patient.
• As an example : Primary surgery and removal of the tumour might not be the best option for
every patient even though this could be the patient’s initial logical request.
• Primary systemic therapy could be better suited, on the basis of the MDT meeting
recommendation and shared decision making with the patient, for certain biological tumour
subtypes such as triple-negative breast cancer or HER2- positive cancers

•Radiology •Clinical Oncology

•Pathology •Medical Oncology
•Surgeon •Radiation Oncology
•Plastic Surgeon •Others
•Psychologist
 Contemporary breast cancer management
Objective : Multidisciplinary approach ; involving locoregional (surgery, radiotherapy) and systemic
therapy that are escalated or de-escalated based on the principle of individualisation to patient’s
tumour biology and therapy response.

Treatment concepts for eBC has evolved drastically in the last 2 decades owing to:
I. Deeper knowledge and characterisation of its molecular hallmarks (ER, PR, HER2), Ki-67
nuclear proliferation marker, genomic markers (BRCA1&2) and immunomarkers (PD-L1, TILs).
II. De-escalation of surgery in the breast and axilla
III. Neoadjuvant combination therapy and risk-adapted post-neoadjuvant strategies, especially in
HER2-positive and triple-negative breast cancer
IV. Radiotherapy de-escalation schemes
V. Risk assessment with genomic test, recurrence gene score
VI. Improvement of systemic therapies include endocrine therapy for hormone receptor-positive
disease, chemotherapy, anti-HER2 therapy for HER2-positive disease, bone stabilizing agents,
poly(ADP-ribose) polymerase inhibitors for BRCA mutation carriers and, quite recently,
immunotherapy
 eBC : Current Management
Diagnosis Treatment planning varies depending
on:
2. Molecular markers
After diagnosis, [ER and PR HER2. 3. Histological
The diagnosis the 1. Disease stage;
multidisciplinary evaluation of tumor The molecular markers grade -grade 3
of breast
cancer is team will decide spread inside the dictate the systemic and Ki-67
usually
upon a suitable
breast, the location treatment hormone proliferative index
treatment plan/ therapy, chemotherapy,
achieved by sequence for and number of lymph (high if greater
bilateral nodes in the axilla/ anti HER2, than 20%) have a
each patient
mammogram, regional area & immunotherapy, higher risk of
breast US detection of distant targeted therapy,
PARPi systemic
and image- metastases. dissemination
guided Staging basically ( either single or this influence the
percutaneous determines combined regime) and
the treatment
choice of
core needle locoregional treatment
or tru-cut sequence systemic
biopsy. treatment
 Management of Early Breast Cancer today; What has changed ?(1)

Pathology Radiology Surgery

IHC markers ER, PR, HER2+, Breast MMG, US, MRI, Axillary US De-escalation of surgery in
HEr2 low the breast and axilla
Staging for distant metastases
Grade, proliferation marker
Biopsy Sentinel lymph node biopsy
Ki-67
CNB, Tru cut, HWLB
Genomic markers -BRCA1&2 US-guided FNA or CNB of ax node Reconstruction

Recurrence score test - Biomarker placement

oncotype dx, mammaprint, IORT eligibility
prosigna Hookwire placement into the
tumor before surgery
Evaluate response to neoadjuvant Neoadjuvant therapy indication(s)
Surgical specimens XRAY to
therapy determine negative margins
Established role of radiologists in the Contemporary role of radiologists in
management of breast cancer : the management of breast cancer today
1. Diagnosis 1. At the event of multifocal or multicentric
• Should be performed using a bilateral suspicious tumours : each focus should
mammogram, US be confirmed by a core biopsy because
• MRI in select cases such features would alter the type of
• Lobular histology surgery
• Breast implant
• Multifocal/centric esp planning for biopsy 2. Suspicious lymph nodes; an FNA or
of most suspicious foci CNB must be performed/ could be
• Post neoadjuvant - scattered tumour considered
3. When malignancy is suspected due to
2. Ipsilateral axillary US should be the tumor volume and/or degree of
performed in suspicious tumours axillary spread and/or in young
esp if the breast tumor is >1 cm patients; to request for IHC testing ( ER
PR and HER2) to facilitate earlier
planning of neoadjuvant therapy
3. Image -guided percutaneous core 4. Biomarker /metallic marker implantation
biopsy into the tumours prior to neoadjuvant
therapy.
5. The placement of a hookwire into the
tumor before surgery for lesion
localisation and imaging studies of
surgical specimens help the pathologist
to evaluate for margins
Management of Early Breast Cancer today;
What has changed?(2)
Oncology Oncology
Radiotherapy Hormone
Neoadjuvant Adjuvant
Premenopausal
PCR vs non PCR post Tamoxifen
HER2+ neoadjuvant IORT Ovarian Suppression

Ki67
TNBC DCIS ( indications)
Postmenopausal
Adjuvant anti HER2
PCR vs non PCR
Large tumour, node Post MAC, post WLE Bone Directed
positive Adjuvant abemaciclib
indications Therapy
Hypofractionation
gBRCAm Adjuvant olaparib
FAST FORWARD Fertility
Therapy Terms
• In non metastatic breast cancer, operable
tumours undergo surgery. Then the majority of
patients also need some form of systemic
therapy.
• Systemic therapy that is given after surgery is
“adjuvant therapy”.
• “The administration of systemic therapy, either
chemotherapy, anti HER2 therapy, immunotherapy
or endocrine therapy, prior to definitive breast
surgery” is neoadjuvant systemic therapy ( NST)
• Systemic therapy that is given after NST and
surgery , if the surgical result or biomarkers
(non pCR) indicate increased risk of recurrence
is also called adjuvant therapy
The concept of neoadjuvant treatment in
eBC
• NST used to be the preferred choice in women with large tumours for
whom reducing the tumour burden is preferred.
• Allows downstaging and rendering inoperable cancers “operable”
• Facilitate breast conservation surgery
• But now, Even in patients with upfront VERY operable eBC, NST (mainly
chemotherapy with targeted agents) has been widely accepted as a
standard of care, especially in HER2-positive breast cancer and TNBC.
• This is because-
• It Provides safe and equivalent distance recurrence and survival to adjuvant
chemotherapy
• the information of pathological complete response (pCR), which is an
absence of cancer cells in the surgical specimen after NST, has
prognostic value (such as in HER2-positive disease or TNBC and may
impact on adjuvant treatment decisions.
• Highest pCR rates are observed in HER2 +, TNBC, ER-, G3 tumours
• pCR is associated with EFS
• Superior DFS and OS were seen in-those who had a pCR
 Neoadjuvant treatment in eBC
• The surgical result or biomarkers after NST , such as non PCR can indicate increased risk of
recurrence. This allows us to use additional systemic therapy in patients with non PCR to
improve survival, e.g in patients with TNBC ( CREATE –X, KN522) and HER2 ( KATHERINE)
, HR+HER2-( MonarchE)

• The general concept is to use the same systemic therapy as would be given postoperatively
before surgery, followed by surgery and irradiation and further post surgery adjuvant therapy,
if required.
• Taxane added to anthracycline chemotherapy increases pCR rate and improve OS
• pCR rate can be increased with carboplatin-based therapy in patients with TNBC but no
conclusive data on long-term outcomes are yet available.

In addition, NST allows time for decisions or planning on breast surgery such as
- Awaiting gBRCA results
- Awaiting reconstructive plans

• Primary endocrine therapy is used in ER-positive breast cancer when primary surgery is
contraindicated due to comorbidities, or in patients with endocrine-responsive tumours desiring
downstaging to breast conservation.
Surgery
Principles
• Surgery of the primary tumour is essential when we want to cure women with eBC
• Breast cancer is a heterogenous disease,- the one-size-fits-all” treatment approach is no
longer appropriate and patient’s wishes must be respected within the confine of performing a
surgical option that has equal oncological outcome, safety and quality of life an individual
patient.
• “In trend” approach now is “safely de-escalating surgery in eBC” - with breast conservation
surgery becoming the preferred primary surgical goal instead of mastectomy.
• Breast-conserving surgery plus whole breast radiation therapy renders equivalent overall survival
compared with mastectomy, overall and even in young women <40.
• Resection of the primary breast tumour is either upfront or after neoadjuvant therapy,
depending on tumour size, tumour to breast size relationship, tumour biology,
comorbidities and patient’s wish
• Breast-conserving surgery has been made possible by the widespread use of neoadjuvant systemic
therapy to downsize tumours and the development of advanced oncoplastic technique
• If mastectomy is oncologically required, breast reconstruction (such as implant surgery or
autologous tissue breast reconstruction) can be offered as an immediate or delayed procedure.
A flowchart illustrating the current guidelines in Norway in 2020.
There are many steps. Most decisions are made by a multidisciplinary team consisting of radiologists,
pathologists, oncologists, and breast surgeons. In some cases, there are plastic surgeons involved. It is
important to include the patients in the decisions in cases where the different available options are
equivalent in terms of prognosis .

Ann Med Surg (Lond). 2020 Aug; 56: 95–107.doi: 10.1016/j.amsu.2020.06.016

 Flowchart for surgery in the axilla in cases where patients are treated with primary surgery.
(Burstein, Curigliano et al., 2019).

BCT, breast conserving therapy. SLND, sentinel lymph node dissection. SLN, sentinel lymph node. ALND, axillary lymph node dissection
Flowchart for surgical treatment of the axilla in neoadjuvant treated patients.
Patients with pN2 or pN3 are advised to have a ALND. * SLNB with certain recommendations; SLNB + > 2 resected lymph
nodes. Dual tracing. Histological examination with H&E and IHC. Metastases >0,2
mm warrant ALND. In some institutions targeted axillary dissection (TAD) is advised. ** In these cases, ALND can be
omitted provided the above recommendations. When there is doubt, ALND is advised (Burstein, Curigliano et al.,2019).

cN, clinical nodal status. pN, pathological nodal status. SLNB, sentinel lymph node biopsy. ALND, axillary lymph node
dissection. NST, neoadjuvant systemic therapy.
Overview of breast and axillary surgery after
neoadjuvant systemic treatment (1)
• Primary surgery is highly effective in curing breast cancer for decades. Radical mastectomy
and axillary clearance (axilla lymph node dissection (ALND) used to the standard of care for
all patients
• However, breast cancer surgery has undergone multiple paradigm changes in the past 2
decades – it is now more “tailored” and has become ”less invasive” with procedures like
breast conserving surgery (BCS) and sentinel lymph node biopsy (SLNB) , or with IORT -
they are performed within a multi-modal therapy concepts (surgery, systemic treatment, and
radiation) in women with early-stage breast cancer.
• The introduction of neoadjuvant systemic therapy (NST) consisting of chemotherapy and
targeted antiHER2 therapy or immunotherapy according to the cancer subtype) has changed
the surgical management of both the primary breast and the axilla --converting approximately
40% of patients with HER2-positive breast cancer and TNBC initially requiring mastectomy to
breast-conserving surgery candidates
• NST allows for surgical downstaging and less invasive breast-conserving surgery in the
breast and axilla so patients have reduced rate of treatment-associated morbidity such as
lymphedema, chronic pain and arm mobility restrictions
 Overview of breast and axillary surgery after
neoadjuvant systemic treatment (2)
• The number of patients who achieve a pathologic complete response(pCR)
to NST (i.e. no residual cancer in the breast and axillary surgical specimen,
ypN0, ypT0) is increasing especially for HER2+ and triple- negative breast
cancer with large Ph 3 trials reporting pCR rates of 6070% and benefit in
event free survival. There is a growing evidence that patients with high- So, Currently ;
proliferative Luminal B breast cancer may benefit from NST too with
promising pCR rates
For the primary breast,
• More recent studies showed that both SLNB and BCS after NST are not
inferior to mastectomy and ALND in terms of recurrence rate and survival and breast conserving surgery
risk of local recurrence is driven by tumor biology rather than neoadjuvant vs. remains the standard of
adjuvant treatment care
• Breast conserving surgery (BCS) followed by radiotherapy (RT) showed
equivalent survival compared to mastectomy in the neoadjuvant and adjuvant For axillary disease, ALND,
setting. SLNB, or TAD are
• In terms of ALN after NST, evidence showed that False-negative ALN rates nowadays recommended
were largely determined by the number of sentinel lymph nodes retrieved. In a depending on the lymph
meta-analysis including 1921 patients with biopsy-proven nodal metastases, node status before and after
the sentinel lymph node identification rate was 90% with a 14% false-negative
rate ,which fell to 4% with removal of three or more sentinel lymph nodes NST.

(SLNB = sentinel lymph node biopsy; ALND = axillary lymph node dissection;
TAD = targeted axillary dissection; SLN = sentinel lymph nodes.
 Why wasn’t neoadjuvant systemic therapy applied before?
What were the concerns? Criticisms of the (EBCTCG) meta-
analysis
• Inability to reliably
distinguish between viable
and non-viable tumour on • The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
post- NST imaging meta-analysis of ten randomised trials (1983–2002) of neoadjuvant
therapy versus adjuvant therapy showed a 3·2% (95% CI 0·6–5·8%;
• The belief that patients still p=0·01) increase in locoregional recurrence in patients having BCS
require excision of the post-neoadjuvant therapy, compared with those having the planned
entire initial tumour volume surgery first.
for breast-conserving
surgery in patients with
larger tumours
• However :
• Fear that the cancer will • Many of the studies included in the meta-analysis were
grow during NST OLD ( in the 80s) and not optimally conducted
• Fear that the patient will not • Some did not require negative resection margins, Some
return to the surgeon after did not mandate for surgery at all, of the breast
NST and/or axilla
• Evidence from the • The locoregional recurrence rate in those requiring
EBCTCG metaanalysis neoadjuvant therapy to downstage to breast-conserving
that suggests that less surgery than in those who were candidates for breast-
surgeryafter NST may
be associated with higher conserving surgery at presentation is actually similar
local recurrence rates • The systemic therapy given then were different from now
 Neoadjuvant Systemic Therapy Clinical Scenarios : ALN
• There are multiple common clinical scenarios in these
patients :
Four prospective multicentre trials
1. (cN+)a
Patients with nodal positive breast cancer evaluating sentinel lymph node biopsy
who remain nodal positive after NST (cN+) , (the
ALN are either clipped or not clipped pre-NST) accuracy in clinically node-positive
patients receiving neoadjuvant
2. Patients with nodal positive disease before NST chemotherapy
(cN+) who convert to nodal negative disease (cN0)
after NST (the ALN are clipped pre NST)

3. Patients with nodal positive disease before NST

(cN+) who convert to nodal negative disease (cN0)
after NST (the ALN are NOT clipped pre NST)

4. Patients with nodal negative breast cancer (cN0)

,negative ALN on frozen section during SLNB
5. Patients with nodal negative breast cancer (cN0),
positive ALN on frozen section during SLNB
6. Patients with an exceptional response to NST
(cT0N0).
7. Patients with locally advanced disease at initial
presentation -T4 or N2/3 disease
acN+ - from clinical examination and/or imaging and/or positive histology if Lymph node is FNA’ed or needle

biopsied
 Neoadjuvant Systemic Therapy Clinical Scenarios : ALN Management
Scenarios Procedure False Nodal Guideline
negative Rate recurrence recommendation
rate
(cN+) who remain nodal positive after NST (cN+) ALND ALND
ALN clipped pre NST
(cN+) who remain nodal positive after NST (cN+) ALND ALND
ALN NOT clipped pre NST)

Locally advanced, cT4N0 or cN2-N3 disease ALND ALND

(cN+) who convert to nodal negative disease (cN0) after Targeted Axillary Dissection < 4% TAD
NST (ALN clipped pre NST) (TAD) - (SLNB + removal of
clipped nodes

(cN+) who convert to nodal negative disease (cN0) after SLNB with removal of ≥3 SLN 8% SLNB with removal
NST of ≥3 SLN
ALN NOT clipped pre NST
SLNB with removal of <3 SLN 13% SLNB with removal
of ≥3 SLN
(cN0) –then negative ALN on FS during SLNB SLNB with removal of at least 3 6-7% <1·5% SLNB
SLN
(cN0), positive ALN on FS during SLNB ALND ALND

SLNB = sentinel lymph node biopsy; ALND = axillary lymph node dissection; TAD = targeted axillary dissection; SLN = sentinel
 Fig. 1

Neoadjuvant and adjuvant treatment of patients with HER2-positive eBC

Treatment algorithm in HER2-positive early breast cancer.

The Breast 2022 62S12-S16DOI: (10.1016/j.breast.2022.01.006)