Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment

and follow-up

SUPPLEMENTARY MATERIAL

SCREENING, DIAGNOSIS, PATHOLOGY AND MOLECULAR BIOLOGY

Section 1. Breast cancer screening

Breast cancer screening programmes have been initiated for women at average risk
of developing breast cancer in order to optimise outcomes through early detection.
Screening in women with a strong family history or known germline BRCA1/2
mutations (gBRCA1/2m) and other high-risk pathogenic variants (PVs) should follow
the ESMO Clinical Practice Guideline (CPG) for risk reduction and screening of
cancer in hereditary breast-ovarian cancer syndromes (HBOC).1

The European Commission Initiative on Breast Cancer (ECIBC) recommends

population-based mammography screening every 2 years for average-risk women
50-69 years of age, with conditional recommendations for women in younger and
older age groups.2 The greatest mortality reduction has been shown in the age group
50-69 years, while evidence for the effectiveness of mammography screening in
women 45-49 or >70 years is increasing.3-6 Either tomosynthesis or digital
mammography are recommended for screening.7,8

The magnitude of the effect of mammography screening on breast cancer mortality

reduction is uncertain.9 In a UK-based review of randomised controlled
mammography trials, a 20% relative reduction in breast cancer mortality was
estimated in women 50-70 years of age.8,10 Recent studies have demonstrated that
screening from 40 years of age reduces the risk of death from breast cancer by up to
50%.3,4,6,11,12

There is no consensus regarding recommendations for ultrasound (US) or magnetic

resonance imaging (MRI) as supplementary screening methods in women with high
breast density without a strong family history.13-15 Furthermore, these methods are
not recommended by the ECIBC.2

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Section 2. Diagnosis and imaging

Diagnosis is based on clinical examination in combination with imaging, which

should include bilateral diagnostic mammography and US of both breasts and
regional lymph nodes (LNs).16 Two-dimensional digital mammography should be
used in the symptomatic setting. Where available and appropriate, digital breast
tomosynthesis (with or without synthetic mammography) and contrast-enhanced
mammography can be considered as alternatives.17

MRI is recommended in case of uncertainties following standard imaging and in

special clinical situations such as:

• Familial breast cancer associated with gBRCA1/2m and other high-risk PVs
• Lobular cancers (including detection of extensive multifocality, contralateral
breast cancer or to plan conservative surgery)
• Suspicion of multifocality and/or multicentricity
• Discrepancy between conventional imaging and clinical examination
• When the findings of conventional imaging are inconclusive (e.g. a positive
axillary lymph node with an occult primary tumour)
• Presence of breast implants

Section 3. Hereditary breast cancer

Genetic counselling, testing and patient management for carriers of gBRCA1/2m and
other high-risk PVs should follow the ESMO CPG for risk reduction and screening of
cancer in HBOC.1

Germline PVs in BRCA1/2 account for 5%-10% of all breast cancers and are
associated with an elevated lifetime risk of developing breast and ovarian cancers,
as well as other malignancies.18 The use of multigene panel tests is increasing.
These tests yield an 8%-9% detection rate of PVs in genes associated with
increased breast cancer risk, about half of which are a gBRCA1/2m.19 Other relevant
high- and moderate-penetrance germline PVs are found in TP53, PALB2, ATM and
CHEK2, although management recommendations vary according to the mutation
and the gene penetrance is generally lower than for BRCA1/2.1

2
Identification of germline mutations informs disease management and follow-up;
patients with gBRCA1/2m and other PVs may opt for different locoregional breast
cancer management and contralateral surgical prophylaxis, and warrant more
intensive risk-reducing measures for other malignancies such as ovarian cancer. 1
High-risk patients with gBRCA1/2m may be candidates for adjuvant therapy with a
poly (ADP-ribose) polymerase (PARP) inhibitor.

Germline testing for PVs in BRCA1/2 should be offered for patients who meet the
respective national criteria and for those who are candidates for adjuvant olaparib
therapy.20,21

Section 4. Histomorphological assessment, biomarkers and molecular

pathology

The aim of pretreatment pathological evaluation of breast cancer is to provide a

complete histomorphological, immunohistochemical and, if necessary, molecular
assessment of breast cancer at the time of diagnosis (Supplementary Table S1).
Evaluation should include histology from the primary tumour and histology/cytology
of the axillary nodes (if node involvement is suspected). For pre-therapeutic
characterisation, a core needle biopsy (2-4 cores) should be carried out on the
tumour and suspicious LNs (if this will change the treatment plan). The tissue should
be formalin-fixed paraffin-embedded (FFPE) with standardised fixation time.

Pathological diagnosis should be made according to the World Health Organization

(WHO) classification of tumours22 and the eighth edition of the Union for International
Cancer Control (UICC) tumour–node–metastasis (TNM) staging system
(Supplementary Tables S2-S4).23

Histological grade, tumour-infiltrating lymphocytes (TILs)24 and the presence of

ductal carcinoma in situ (DCIS) and lymphovascular invasion are typical elements of
the basic tumour characterisation. The most important immunohistochemistry (IHC)
biomarkers are estrogen receptor (ER), progesterone receptor (PgR), human
epidermal growth factor receptor 2 (HER2) and a proliferation marker such as Ki-67;
reporting is based on the American Society of Clinical Oncology/College of American
Pathologists guidelines for assessment of hormone receptor (HR) status (i.e. ER and
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PgR)25 and HER2 status.26 For Ki-67 and TILs, the International Ki-67 in Breast
Cancer Working Group27 and International TILs Working Group 201428 guidelines
should be used. TIL scoring provides prognostic and predictive information but TIL
thresholds for medical decision making have not been established and should not be
used alone for treatment decisions.

Ki-67 expression levels are most informative for prognosis of luminal breast cancer
when the level is ≤5% (low proliferation, low risk) or ≥30% (high proliferation, high
risk) because technical reliability of distinguishing values between 5% and 30% is
limited. A decrease of Ki-67 (≤10%) after short term (4-6 weeks) preoperative
endocrine therapy (ET) in postmenopausal patients with HR-positive, HER2-negative
breast cancer is prognostic and may indicate endocrine responsiveness.29,30

Although HER2-low status is currently only relevant in the metastatic setting, it

should be reported in early breast cancer (EBC) as a basis for possible future
therapeutic decisions; it may also have implications for the design of external quality
assurance programmes. HER2 low is defined as IHC 1+ or 2+ and in situ
hybridisation (ISH) negative in metastatic disease.31 For reporting of HER2 results, it
is important to state the IHC score as 0, 1+, 2+ or 3+.

HER2-negative tumours with 1%-9% ER and/or PgR expression (ER low/PgR low)
behave similarly to and have similar clinical outcomes to triple-negative breast
cancers (TNBCs). Many HR 1%-9% IHC-positive cancers show molecular features
of HR-negative cancer and are therefore unlikely to benefit from ET. However, an
uncertain proportion of these patients with HR-low cancers may have a sufficient
level of HR expression to benefit from ET. In the absence of randomised clinical trial
evidence to demonstrate benefit from adjuvant ET, treatment recommendations
should be individualised based on patient preferences, with careful consideration of
the risk versus benefit from long-term ET. Tumours with low HR expression
constitute a biologically mixed entity and are considered HR low, not HR negative.32
Therefore, patients with HR 1%-9% IHC-positive cancers should be included in trials
designed for HR-negative cancers to generate more evidence.

In contrast to metastatic TNBC, programmed death-ligand 1 (PD-L1) expression is

not currently relevant for therapeutic decisions in EBC.33 TNBC should be informed

4
by IHC and is defined as ER <1%, PgR <1% and HER2 score 0, 1 or 2+ with
negative FISH or chromogenic ISH.

Participation in external quality assurance programmes is strongly recommended. If

assessment of biomarkers is not possible in a preoperative biopsy, or if results are
not consistent with pathological features, repeat assessment in the surgical sample
is recommended.

For prognostication and treatment decision making, tumours can be grouped into
surrogate intrinsic subtypes,34 defined by routine histology and IHC data, as luminal
A like, luminal B like, HER2 positive and triple negative. Luminal A-like tumours are
typically low grade, strongly ER positive/PgR positive and HER2 negative and have
low proliferation. Luminal B-like tumours are HR positive but may have variable
degrees of ER/PgR expression, are higher grade and have higher proliferation than
Luminal A-like tumours. Gene expression assays (e.g. EndoPredict, MammaPrint,
Oncotype DX, Prosigna and others) have been introduced in many countries for
prognostic assessment of HR-positive, HER2-negative breast cancer. The assays
differ in terms of genes as well as technology, but all can identify a low- to
intermediate-risk group that might not benefit from adjuvant chemotherapy (ChT).
Gene expression tests should only be used in a clinically intermediate-risk situation
(based on IHC biomarkers and clinical parameters). It is recommended to use only
one assay for any individual patient.

Prognosis in patients who received neoadjuvant ChT and did not obtain a
pathological complete response (pCR) can be estimated by the pretreatment clinical
stage and post-treatment pathological stage plus ER status and tumour grade35,
which also has been validated for luminal tumours.36

Tumour mutation testing is important for treatment decisions in metastatic breast

cancer,37 however, clinical utility has not yet been demonstrated in EBC and it is not
mandatory. Mutations should be reported using the ESMO Scale for Clinical
Actionability of molecular Targets (ESCAT) reporting system (Supplementary Table
S8).38

Regarding histological assessment of lesions, a core needle biopsy is preferred to

fine-needle aspiration (FNA) because invasiveness—a prerequisite for starting

5
neoadjuvant therapy—cannot be demonstrated in FNA samples. Microcalcifications,
mainly only visible on mammogram, should be biopsied with a vacuum-assisted
device.8 If systemic neoadjuvant therapy is likely/expected, marking the primary
tumour with a clip is recommended. If suspicious locoregional LNs are detected, at
least one in each region should be biopsied and preferably also marked.

When there is an intermediate risk after standard IHC and clinical assessment, a
gene expression test should be carried out in HR-positive, HER2-negative tumours
to identify low-risk tumours that would not benefit from treatment with ChT. Ki-67
analysis after short preoperative ET may add information about tumour endocrine
responsiveness; Ki-67 ≤10% post-ET is considered to indicate endocrine
responsiveness and low risk. If preoperative ET is used in HR-positive, HER2-
negative disease, gene expression analysis must be carried out in the diagnostic
pretreatment biopsy, not in the surgical specimen. PD-L1 testing in EBC is not
required for clinical decision making.

STAGING AND RISK ASSESSMENT

Section 5. Staging and risk assessment

Disease stage and final pathological and clinical assessment of surgical specimens
should be made according to the WHO classification of tumours22 and the eighth
edition of the UICC TNM staging system.23 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). [18F]2-fluoro-2-deoxy-D-glucose (FDG)–positron emission
tomography (PET)–CT scanning may be useful for high-risk patients and when
conventional methods are inconclusive.

Validated gene expression profiles may complement pathology assessment and help
with adjuvant ChT decision making in clinically intermediate-risk situations.

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Assessment of distant metastases (bone, liver and lung) is recommended only in
patients with stage IIb and higher disease (especially with extended LN
involvement), patients with a high risk of recurrence at first diagnosis and/or in
symptomatic patients.37,39 Brain imaging should not be routinely carried out in
asymptomatic patients. The minimum imaging work-up for staging includes
computed tomography (CT) of the chest and abdomen and bone scintigraphy. FDG–
PET–CT may be used instead of CT and bone scintigraphy.37

MANAGEMENT OF LOCAL AND LOCOREGIONAL DISEASE

Section 6. General treatment principles

Where available, treatment should be carried out in specialised breast units/centres

and provided by a multidisciplinary team specialised in breast cancer, consisting of
at least medical oncologists, breast surgeons, gynaecologists, radiation oncologists,
breast radiologists, breast pathologists and breast nurses (or similarly trained and
specialised health care practitioners).40,41 Such centres are defined as specialised
institutions or departments that care for a high volume of breast cancer patients, e.g.
a minimum of 150 new EBC cases per year. The breast unit/centre should have in-
house plastic/reconstructive surgeons, psychologists, physiotherapists, fertility
specialists and geneticists or be able to refer patients to such specialists in other
centres. Participation in clinical trials is recommended.

Treatment of EBC involves a combination of local modalities [surgery, radiotherapy

(RT)], systemic treatments (ChT, ET, molecularly targeted therapies,
immunotherapy) and supportive measures, delivered in diverse sequences. The use
of predictive biomarkers (i.e. ER, PgR, HER2, Ki-67 and approved gene expression
signatures) is well established in aiding treatment recommendations.

Particular attention must be paid to the treatment of EBC in special populations, e.g.
very young or elderly patients. However, age is a continuous variable and cut-offs in
studies are always arbitrarily chosen. For clinical decision making, biological age is
more important than chronological age.42

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In younger premenopausal patients, fertility issues should be discussed and
guidance on fertility-preservation techniques should be provided before the initiation
of any systemic treatment.43-47 For details about fertility preservation, please refer to
the ESMO CPG for fertility preservation and post-treatment pregnancies in post-
pubertal cancer patients.48

Section 7. Patient communication and shared decision making

Following a diagnosis of breast cancer, patients find themselves in a new and

unfamiliar landscape. Intensity of stress and specific pressures vary from patient to
patient and should be addressed individually with management tailored to the
individual’s needs. Patients should be actively involved in all management decisions.

As part of optimising breast cancer outcomes and survivorship, all patients should
have equitable access to the full range of reproductive care options that may be
necessary at different points in their breast cancer journey, including pregnancy
counselling, contraception and fertility preservation.

Information on diagnosis and treatment choice should be given repeatedly (both

verbally and in writing) in a comprehensive and easily understandable manner, using
patient-centred websites or similar sources of information. Most patients will
remember the information provided to them in a fragmented way. Patients need
space, both physically and timewise, to process and comprehend information about
their diagnosis so they can cope psychologically with the treatment plan.

Section 8. Special situations

Elderly patients. Due to the limited data from randomised studies, strong
recommendations cannot be made regarding the use of (neo)adjuvant systemic
therapies in this population. Full doses of drugs should be used whenever feasible.
In patients suitable for standard ChT, single-agent capecitabine or docetaxel have
been demonstrated to be inferior to the standard multidrug regimen [doxorubicin–
cyclophosphamide [AC] or cyclophosphamide–methotrexate–fluorouracil (CMF)].49,50
Sequential, single-agent therapy (e.g. doxorubicin followed by paclitaxel and then
cyclophosphamide) is as effective as combination ChT (e.g. AC followed by
paclitaxel) and is associated with lower acute toxicity, making this approach an
option for any patient, especially older patients.51,52 A geriatric multidimensional
8
assessment should be carried out prior to treatment decisions; the G8 tool can be
used as a screening tool to select patients needing a full geriatric assessment.53

Male breast cancer. Most breast cancer cases in male patients are luminal-like
ductal invasive carcinoma and occur in older men. Tamoxifen is the standard
adjuvant ET; aromatase inhibitors (AIs) must be combined with gonadotropin
hormone-releasing hormone (GnRH) analogues.54 ChT and anti-HER2 therapy and
regimens using other targeted novel agents as indicated [e.g. immunotherapy,
cyclin-dependent kinase 4/6 (CDK4/6) or PARP inhibitors] should follow the same
recommendations as for female patients with breast cancer.55-57 Population-based
studies have indicated that ~20% of male patients with breast cancer will have an
inherited risk factor; therefore, genetic counselling and testing should be
considered.58

Other special situations. Sarcomas (primary, secondary and angiosarcomas) are

generally managed with surgery alone; adjuvant irradiation or ChT in some settings
may be considered.59 Lymphoma isolated to the breast, including breast implant-
associated anaplastic large-cell lymphoma (BIA-ALCL), is often treated with surgery
alone, with good outcomes after complete resection.60 For BIA-ALCL with incomplete
resections or advanced disease, systemic therapies have been used. Other types of
lymphomas of the breast should follow lymphoma-specific guidelines.61

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Supplementary Table S1. Summary of biomarkers used in standardised histopathological, immunohistochemical and
molecular pathology assessment in EBC

Method Biomarker Use GoR Comments, pitfalls and open

questions

Classical Histological Pathological diagnosis and basic prognostic A TILs are not currently required for
H&E tumour type, characterisation of tumour therapy decisions but might become
pathology invasiveness, relevant in the future
grading, TILs

IHC and IHC panel: Standard IHC workup as a basis for major A HR-low tumours (ER/PgR 1%-9%) are
ISH ER, PgR, therapy decisions and prognostic assessment biologically TNBC and may behave as
HER2, Ki-67 such
Definition of intrinsic subtypes
ISH: for HER2 status should be reported as IHC
HER2 IHC 0, 1+ or 2+ (either negative or positive by
2+ ISH) and 3+

Defined HER2-low tumours (1+ or 2+ with

guidelines for negative ISH) are relevant for MBC and
each marker; may become so for EBC in the future
participation
in external

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 quality Ki-67 may also be evaluated after a short
assurance course of preoperative ET to indicate
programmes endocrine responsiveness (Ki-67 ≤10%)

Gene Gene Validated prognostic assessment A May be carried out in HR-positive,

expression signatures HER2-negative tumours in the
profiling intermediate risk category (defined by
(many IHC and clinical assessment)
different May be carried out in diagnostic core
validated biopsy
test
options)

NGS gBRCA1/2 Clinically important information for surgical A Testing is relevant for TNBC and HR-
testing management, follow-up and cancer screening positive, HER2-negative breast cancer
and has become a patient selection marker for
systemic adjuvant olaparib therapy in HER2-
negative tumours

EBC, early breast cancer; ER, estrogen receptor; ET, endocrine therapy; gBRCA1/2, germline BRCA1/2, GoR, grade of
recommendation; H&E, haematoxylin–eosin; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC,
immunohistochemistry; ISH, in situ hybridisation; MBC, metastatic breast cancer; NGS, next-generation sequencing; PgR,
progesterone receptor; TIL, tumour-infiltrating lymphocyte; TNBC, triple-negative breast cancer.
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Supplementary Table S2. Clinical classification of breast tumours according to
the UICC TNM eighth edition

T (primary tumour)

TX Primary tumour cannot be assessed

T0 No evidence of primary tumour

Tis Carcinoma in situ

Tis (DCIS) Ductal carcinoma in situ

Tis (LCIS) Lobular carcinoma in situ

Tis (Paget) Paget disease of the nipple not associated with invasive carcinoma
and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast
parenchyma. Carcinomas in the breast parenchyma associated with
Paget disease are categorised based on the size and characteristics
of the parenchymal disease, although the presence of Paget disease
should still be noted

T1 Tumour ≤2 cm in greatest dimension

T1mi Microinvasion ≤0.1 cm in greatest dimensiona

T1a >0.1 cm but ≤0.5 cm in greatest dimension

T1b >0.5 cm but ≤1 cm in greatest dimension

T1c >1 cm but ≤2 cm in greatest dimension

T2 Tumour >2 cm but ≤5 cm in greatest dimension

T3 Tumour >5 cm in greatest dimension

T4 Tumour of any size with direct extension to chest wall and/or to skin
(ulceration or skin nodules)b

T4a Extension to chest wall (does not include pectoralis muscle invasion
only)

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T4b Ulceration, ipsilateral satellite skin nodules or skin oedema (including
peau d'orange)

T4c Both 4a and 4b

T4d Inflammatory carcinomac

N (regional LNs)

NX Regional LNs cannot be assessed (e.g. previously removed)

N0 No regional LN metastasis

N1 Metastasis in movable ipsilateral level I, II ALN(s)

N2 Metastasis in ipsilateral level I, II ALN(s) that are clinically fixed or

matted; or in clinically detectedd ipsilateral internal mammary LN(s) in
the absence of clinically evident ALN metastasis

N2a Metastasis in ALN(s) fixed to one another (matted) or to other

structures

N2b Metastasis only in clinically detectedd internal mammary LN(s) and in

the absence of clinically detected ALN metastasis

N3 Metastasis in ipsilateral infraclavicular (level III axillary) LN(s) with or

without level I, II ALN involvement; or in clinically detectedd ipsilateral
internal mammary LN(s) with clinically evident level I, II ALN
metastasis; or metastasis in ipsilateral supraclavicular LN(s) with or
without axillary or internal mammary LN involvement

N3a Metastasis in infraclavicular LN(s)

N3b Metastasis in internal mammary and ALNs

N3c Metastasis in supraclavicular LN(s)

M (distant metastasis)

M0 No distant metastasis

M1 Distant metastasis

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Excisional biopsy of a LN or biopsy of a sentinel node, in the absence of assignment
of a pT, is classified as a clinical N, e.g. cN1. Pathological classification (pN) is used
for excision or sentinel LN biopsy only in conjunction with a pathological T
assignment.

ALN, axillary lymph node; DCIS, ductal carcinoma in situ; FNA, fine-needle
aspiration; LCIS, lobular carcinoma in situ; LN, lymph node; Tis, carcinoma in situ;
TNM, tumour–node–metastasis; UICC, Union for International Cancer Control.
aMicroinvasion is the extension of cancer cells beyond the basement membrane into
the adjacent tissues with no focus >0.1 cm in greatest dimension. When there are
multiple foci of microinvasion, the size of only the largest focus is used to classify the
microinvasion. Do not use the sum of all individual foci. The presence of multiple foci
of microinvasion should be noted, as it is with multiple larger invasive carcinomas.
bInvasion of the dermis alone does not qualify as T4. Chest wall includes ribs,
intercostal muscles and serratus anterior muscle but not pectoral muscle.
cInflammatory carcinoma of the breast is characterised by diffuse, brawny induration
of the skin with an erysipeloid edge, usually with no underlying mass. If the skin
biopsy is negative and there is no localised measurable primary cancer, the T
category is pTX when pathologically staging a clinical inflammatory carcinoma (T4d).
Dimpling of the skin, nipple retraction or other skin changes, except those in T4b and
T4d, may occur in T1, T2 or T3 without affecting the classification.
dClinically detected is defined as detected by clinical examination or by imaging
studies (excluding lymphoscintigraphy) and having characteristics highly suspicious
for malignancy or a presumed pathological macrometastasis based on FNA biopsy
with cytological examination. Confirmation of clinically detected metastatic disease
by FNA without excision biopsy is designated with a (f) suffix, e.g. cN3a(f).

Reproduced from Brierley et al. with permission.23

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Supplementary Table S3. Pathological classification of breast tumours
according to the UICC pTNM eighth edition

pTNM Pathological classification

pT – Primary tumour: The pathological classification requires the examination of

the primary carcinoma with no gross tumour at the margins of resection. A case
can be classified pT if there is only microscopic tumour in a margin. The pT
categories correspond to the T categoriesa

pN – Regional LNs: The pathological classification requires the resection and

examination of at least the low ALNs (level I). Such a resection will ordinarily
include ≥6 LNs. If the LNs are negative, but the number ordinarily examined is not
met, classify as pN0

pNX Regional LNs cannot be assessed (e.g. previously removed, or not

removed for pathological study)

pN0 No regional LN metastasisb

pN1 Micrometastases; or metastases in 1-3 axillary ipsilateral LNs; and/or in

internal mammary nodes with metastases detected by SLNB but not
clinically detectedc

pN1mi Micrometastases (>0.2 mm and/or >200 cells, but none >2.0 mm)

pN1a Metastasis in 1-3 axillary LN(s), including at least one >2 mm in greatest
dimension

pN1b Internal mammary LNs

pN1c Metastasis in 1-3 ALNs and internal mammary LNs

pN2 Metastasis in 4-9 ipsilateral ALNs, or in clinically detectedc ipsilateral

internal mammary LN(s) in the absence of ALN metastasis

pN2a Metastasis in 4-9 axillary LNs, including at least one that is >2 mm

pN2b Metastasis in clinically detected internal mammary LN(s), in the

absence of ALN metastasis

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 pN3a Metastasis in ≥10 ipsilateral ALNs (at least one >2 mm) or metastasis in
infraclavicular lymph nodes

pN3b Metastasis in clinically detectedc internal ipsilateral mammary LN(s) in

the presence of positive ALN(s); or metastasis in more than 3 ALNs
and in internal mammary LNs with microscopic or macroscopic
metastasis detected by SLNB but not clinically detected

pN3c Metastasis in ipsilateral supraclavicular LN(s)

Post‐treatment ypN

Post‐treatment yp ‘N’ should be evaluated as for clinical (pretreatment) ‘N’

methods. The modifier ‘sn’ is used only if a SN evaluation was carried out after
treatment. If no subscript is attached, it is assumed the axillary nodal evaluation
was by axillary node dissection

The X classification will be used (ypNX) if no yp post‐treatment SN or axillary

dissection was carried out

N categories are the same as those used for pN

ALN, axillary lymph node; FNA, fine-needle aspiration; H&E, haematoxylin–eosin;

IHC, immunohistochemistry; ITC, isolated tumour cell; LN, lymph node; p,
pathological; SLNB, sentinel lymph node biopsy; SN, sentinel node; TNM, tumour–
node–metastasis; UICC, Union for International Cancer Control.
aWhen classifying pT the tumour size is a measurement of the invasive component.
If there is a large in situ component (e.g. 4 cm) and a small invasive component (e.g.
0.5 cm), the tumour is coded pT1a.
bITCs are single tumour cells or small clusters of cells ≤0.2 mm in greatest extent
that can be detected by routine H&E stains or IHC. An additional criterion has been
proposed to include a cluster of <200 cells in a single histological cross section.
Nodes containing only ITCs are excluded from the total positive node count for
purposes of N classification and should be included in the total number of nodes
evaluated.

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cClinically detected is defined as detected by imaging studies (excluding
lymphoscintigraphy) or by clinical examination and having characteristics highly
suspicious for malignancy or a presumed pathological macrometastasis based on
FNA biopsy with cytological examination. Not clinically detected is defined as not
detected by imaging studies (excluding lymphoscintigraphy) or not detected by
clinical examination.

Reproduced from Brierley et al. with permission.23

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Supplementary Table S4. Staging of breast tumours according to the UICC
TNM eighth edition

Stage T N M

Stage 0 Tis N0 M0

Stage IA T1a N0 M0

Stage IB T0, T1 N1mi M0

Stage IIA T0, T1 N1 M0

T2 N0 M0

Stage IIB T2 N1 M0

T3 N0 M0

Stage IIIA T0, T1, T2 N2 M0

T3 N1, N2 M0

Stage IIIB T4 N0, N1, N2 M0

Stage IIIC Any T N3 M0

Stage IV Any T Any N M1

mi, micrometastases; Tis, carcinoma in situ; TNM, tumour–node–metastasis; UICC,

Union for International Cancer Control.
aT1 includes T1mi.

Reproduced from Brierley et al. with permission.23

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 Supplementary Table S5. Overview of adjuvant therapy for HR-positive, HER2-negative EBC

Stage ETa ChTb Targeted therapies Bisphos-

phonatesc

TN Type Duration Addition of Premenopausald Postmenopausale Abemaciclibf Olaparib for

of OFS in gBRCA1/2mg
treatment premenopausal
(years) women

T1ab Tamoxifen 5 Noh No No No No No

or (AI)
N0

T1c Tamoxifen 5 May consider for Low riski: may Low riski: no No No No
or AI higher riskh,i consider
N0
I especially if not
receiving OFS

High riski: yes High riski: yes

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 T2-3 Tamoxifen 7-10 Considerh Low riski: Low riski: no No No Yes
or AI consider
N0
especially if not
receiving OFS

High riski: yes High riski: yes

II
T1- Tamoxifen 7-10 Yesh Low riski: Low riski: no Consider Low riski: no Yes
T2 or AI consider
especially if not
N1
receiving OFS

Higher riski:
High riski: yes High riski: yes
yes

Any AIj 7-10 Yesh Yes Yes Yes Yes Yes

III

AI, aromatase inhibitor; ChT, chemotherapy; EBC, early breast cancer; ER, estrogen receptor; ET, endocrine therapy; gBRCA1/2,
germline BRCA1/2; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; LN, lymph node; m, mutation; N,

20
node; OFS, ovarian function suppression; OS, overall survival; PgR, progesterone receptor; RS, recurrence score; T, tumour; TN,
tumour–node.
aRisk stratification factors for ET include tumour size, extent of nodal involvement, tumour grade, degree of ER/PgR expression,
high Ki-67 or other proliferation measures and adverse genomic signature results. For lower-risk cancers, either tamoxifen or an AI
for 5 years is standard. With increased risk, AI becomes preferred to tamoxifen, longer durations become appropriate and OFS is
progressively added for younger women, especially those <35 years of age.
bFor node-negative tumours, non-anthracycline regimens may suffice as adjuvant ChT; anthracycline-, taxane- and alkylator-based
regimens are preferred for higher-stage cancers warranting ChT.
cAs adjuvant therapy for purposes of preventing distant metastatic recurrence.
dBenefits of ChT reflect tumour biology and menopausal status. Premenopausal women with lower-risk tumours who are not
advised/recommended to receive OFS may benefit more from ChT.
eThe role of ChT is largely determined by tumour pathobiology including high-risk genomic signature scores (preferred) or high
grade and/or high Ki-67 (>30%).
fLimited follow-up from a single study suggests that adjuvant abemaciclib may reduce recurrence in high-risk node-positive cancers
characterised by stage, grade and/or Ki-67 (>20%). In cases that are potential candidates for both abemaciclib and olaparib,
olaparib is preferred due to statistically significant OS benefit.
gAdjuvant olaparib is indicated in BRCA1 or BRCA2-associated cancers with high-risk features that would typically warrant ChT,
such as multiple positive LNs and/or residual disease after neoadjuvant ChT. In patients who are potential candidates for both
abemaciclib and olaparib, olaparib is preferred due to statistically significant OS benefit.
21
hUse of AI in premenopausal women demands OFS.
i‘Low risk’ implies low-risk genomic score (preferred; e.g. Endopredict 'Low'; MammaPrint ‘Low’ or 'Ultra Low'; Oncotype DX RS
≤15; Prosigna RS ≤60; luminal A on formal signature testing) and/or lower-risk features on traditional pathological analysis including
lower-grade histology, robust ER and PgR expression and lower measures of proliferation. ‘High risk’ implies high-risk genomic
score (Endopredict 'High'; MammaPrint ‘High’; Oncotype DX ≥26; Prosigna >60; luminal B) and/or higher-risk features on traditional
pathological analysis including higher-grade histology, lower ER and PgR expression and higher measures of proliferation.
jThere is no evidence of benefit for OFS beyond five years’ duration of therapy.

Table adapted with permission from St Gallen International Consensus Guidelines 2023.34 © 2023 European Society for Medical
Oncology. Published by Elsevier Ltd. All rights reserved.

22
Supplementary Table S6. Notable potential long-term side-effects related to adjuvant breast cancer treatmenta

Category Side effect

Nervous system Neurocognitive dysfunction

Neuropathy

Musculoskeletal and connective tissue Arthralgia

Myalgia

Psychosocial Chronic fatigue

Emotional reactions to the diagnosis and treatment

Exhaustion

Sleep disturbances

Reproductive and sexual Infertility

Ovarian dysfunction

Premature menopause

Sexual complaints

Vascular disorders Hot flashes

Lymphoedema

23
 Others Bone density loss

Cardiac dysfunction

Chronic hair loss and thinning

Dry mucosa (oral, genital, conjunctiva)

Nutritional (e.g. weight gain)

Secondary haematological malignancies (or other secondary

cancers)
aOccurrences are rare and patients generally recover; quality of life in general recovers by end of therapy to that of before
treatment start.

24
Supplementary Table S7. Biomarkers and molecular targets for precision medicines and corresponding ESCAT scores

Clinical context Biomarker or Method of detection Drug match ESCAT

genomic scorea,b
alteration

HR positive Luminal A like ER and/or PgR IHC (1%-100%) Tamoxifen; AI NA

Luminal B like ER and/or PgR IHC (1%-100%) ChT–ET NA

Premenopause ER and/or PgR IHC (10%-100%) Tamoxifen NA

OFS–tamoxifen NA
OFS–AI NA
Postmenopause ER and/or PgR IHC (1%-100%) AI (with or without NA
prior tamoxifen)

High risk ER and/or PgR IHC (1%-100%) Abemaciclib (2 years) NA

+ ET

25
HER2 (ERBB2) HER2 negative IHC (0, 1+ or 2+) with ET and concomitant I-A20,21,b
negative negative FISH/CISH adjuvant olaparib

gBRCA1/2m NGS or Sanger

sequencing

HER2 (ERBB2) HER2 positive IHC (3+) or positive Anthracyclines– NA

positive FISH/CISH taxane
HER2 positive IHC (3+) or positive Taxane–carboplatin NA
FISH/CISH

HER2 positive IHC (3+) or Adjuvant HP–ChT NA

Positive FISH/CISH I-A62,c

Non-pCR HER2 positive IHC (3+) or T-DM1 (after NA

neoadjuvant ChT and I-A63,c
Positive FISH/CISH
anti-HER2 therapy)
pT1 pN0 HER2 positive IHC (3+) or Paclitaxel (12-weeks) NA
disease and trastuzumab (1
Positive FISH/CISH I-A64,c
year)

26
 Stage II-III HER2 positive IHC (3+) or Neoadjuvant systemic NA
ChT and anti-HER2
Positive FISH/CISH I-A65,c
therapy
N+ disease HER2 positive IHC (3+) or Adjuvant HP-ChT NA

Positive FISH/CISH I-A66,c

HER2 positive, High risk HER2 positive IHC (3+) or Neratinib (1 year) start NA
HR positive within 1 year of
Positive FISH/CISH I-A67,68,c
trastuzumab-
ER and/or PgR IHC (1%-100%) NA
containing therapy
positive

HER2 low HER2 negative IHC (1+ or 2+) with NA NA

negative FISH/CISH
TNBC ER negative IHC (<1%) Anthracycline-based NA
therapy followed by
PgR negative IHC (<1%)
taxane
HER2 negative IHC (0, 1 or 2+) with
negative FISH/CISH

27
 ER negative IHC (<1%) Taxane–carboplatin in NA
sequence with AC or
PgR negative IHC (<1%)
EC followed by taxane
HER2 negative IHC (0, 1, or 2+) with
negative FISH/CISH

ER negative IHC (<1%) Docetaxel– NA

cyclophosphamide
PgR negative IHC (<1%)

HER2 negative IHC (0, 1, or 2+) with

negative FISH/CISH

ER negative IHC (<1%) Taxane–carboplatin NA

PgR negative IHC (<1%)

HER2 negative IHC (0, 1, or 2+) with

negative FISH/CISH

Stage II-III ER negative IHC (<1%) Taxane–carboplatin NA

followed by AC–
PgR negative IHC (<1%)
pembrolizumab or
HER2 negative IHC (0, 1 or 2+) with
EC–pembrolizumab
negative FISH/CISH

28
AC, doxorubicin–cyclophosphamide; AI, aromatase inhibitor; ChT, chemotherapy; CISH, chromogenic in situ hybridisation; EC,
epirubicin–cyclophosphamide; ER, estrogen receptor; ESCAT, ESMO Scale for Clinical Actionability of molecular Targets; ET,
endocrine therapy; gBRCA1/2, germline BRCA1/2; HER2, human epidermal growth factor receptor 2; HP, trastuzumab–
pertuzumab; HR, hormone receptor; IHC, immunohistochemistry; m, mutation; OFS, ovarian function suppression; N, node;
NA, not applicable; NGS, next-generation sequencing; pCR, pathological complete response; PgR, progesterone receptor; T-
DM1, trastuzumab–emtansine; TNBC, triple-negative breast cancer.
aESCAT scores apply to alterations from genomic-driven analyses only. These scores have been defined by the guideline authors
and assisted as needed by the ESMO Translational Research and Precision Medicine Working Group. ESCAT defines the
relevance of a genomic alteration to a matched targeted therapy and does not apply to prognostic use or to guide local or systemic
cytotoxic agents.
bI-A, alteration–drug match is associated with improved outcome with evidence from randomised clinical trials showing the
alteration–drug match in a specific tumour type results in a clinically meaningful improvement of a survival endpoint. 38
cESCAT applicable if HER2 gene amplification by FISH/CISH.

29
 Supplementary Table S8. ESMO-MCBS table for therapies/indications in EBC

Therapy Disease setting Trial Control Absolute Hazard ratio QoL/toxicity ESMO-MCBS
survival gain (95% CI) scorea

Abemaciclib– Adjuvant treatment of monarchE69-72 Standard ET Ab

ET adult patients with HR- (Form 1)
positive, HER2- Phase III 4-year iDFS: 4-year iDFS iDFS: 0.664
negative, node-positive 79.4% gain: 6.4% (0.578-0.762)
EBC at high risk of NCT03155997
recurrence
Olaparib Adjuvant treatment of OlympiA20,21 Placebo A
adult patients with (Form 1)
gBRCA1/2 mutations Phase III 4-year iDFS: 4-year iDFS iDFS: 0.63
who have HER2- 75.4% gain: 7.3% (0.50-78)
negative, high-risk EBC NCT02032823
previously treated with 4-year OS: 4-year OS OS: 0.68
neoadjuvant or adjuvant 86.4% gain: 3.4% (0.47-0.97)c
ChT
Neratinib Extended adjuvant ExteNET67,68,73- Placebo Increased NEBd
treatment of adult 75 grade ≥3 (Form 1)
patients with early stage diarrhoea

30
 HER2- Phase III 5-year iDFS: 5-year iDFS iDFS: 0.73 (40% versus
overexpressed/amplified 87.7% gain: 2.5% (0.57-0.92) 2%)
breast cancer, to follow NCT00878709
adjuvant trastuzumab- 8-year OS: 8-year OS OS: 0.95
based therapy 90.2% gain: -0.1% (0.75-1.21)
ChT + 1 year Adjuvant treatment of APHINITY62,76,7 ChT + 1 year Increased A
of adult patients with 7 of placebo– grade 3 (Form 1)
pertuzumab– HER2-positive EBC at trastuzumab diarrhoea
trastuzumab high risk of recurrence Phase III during ChT
(node-positive or HR- 6-year iDFS: 6-year iDFS iDFS: 0.76 (9.8% versus
negative disease) NCT01358877 87.8% gain: 2.8% (0.64-0.91) 3.7%)

6-year OS: 6-year OS OS: NS

93.9% gain: 0.9% (immature)
Pertuzumab– Neoadjuvant treatment NeoSphere65,78 Trastuzumab C
trastuzumab– of adult patients with –docetaxel (Form 1)
docetaxel HER2-positive, locally Phase II
advanced, inflammatory pCR: 29.0% pCR gain:
or early-stage breast NCT00545688 16.8%

31
 cancer at high risk of
recurrence
Trastuzumab Patients with HER2- HERA79,80 ChT A
(1 year) positive EBC following (Form 1)
surgery, ChT Phase III 2-year DFS: 2-year DFS DFS: 0.54
(neoadjuvant or 77.4% gain: 8.4% (0.43-0.67)
adjuvant) and RT (if NCT00045032
applicable)
T-DM1 Adjuvant treatment of KATHERINE63 Trastuzumab A
patients with HER2- (Form 1)
positive EBC who have Phase III 3-year iDFS: 3-year iDFS iDFS: 0.50
residual invasive 77.0% gain: 11.3% (0.39-0.64)
disease in the breast NCT01772472
and/or LNs nodes after
neoadjuvant taxane-
based and HER2-
targeted therapy
Pembrolizuma Neoadjuvant treatment, KEYNOTE- Placebo– A
b–paclitaxel– and then continued as 52281,82 paclitaxel– (Form 1)
carboplatin monotherapy as carboplatin

32
 adjuvant treatment after Phase III 3-year EFS: 3-year EFS EFS: 0.63
surgery, for the 76.8% gain: 7.7% (0.48-0.82)
treatment of adults with NCT03036488
locally advanced, or pCR: 51.2% pCR gain:
early-stage TNBC at 13.6%
high risk of recurrence 3-year OS: 3-year OS OS: NS
86.9% gain: 2.8% (immature)

ChT, chemotherapy; CI, confidence interval; DFS, disease-free survival; EBC, early breast cancer; EFS, event-free survival; EMA,
European Medicines Agency; ESMO-MCBS, ESMO-Magnitude of Clinical Benefit Scale; ET, endocrine therapy; FDA, Food and
Drug Administration; gBRCA1/2, germline BRCA1/2; HER2, human epidermal growth factor receptor 2; HR, hormone receptor;
iDFS, invasive disease-free survival; ITT, intent to treat; LN, lymph node; NEB, no evaluable benefit; NS, not significant; OS, overall
survival; pCR, pathological complete response; QoL, quality of life; RT, radiotherapy; T-DM1, trastuzumab–emtansine; TNBC,
triple-negative breast cancer.
aESMO-MCBS v1.183 was used to calculate scores for therapies/indications approved by the EMA or FDA. The scores have been
calculated and validated by the ESMO-MCBS Working Group and reviewed by the authors (https://www.esmo.org/guidelines/esmo-
mcbs/esmo-mcbs-evaluation-forms).
bEMA approval was based on data from Cohort 1 of the monarchE study; however, analysis of Cohort 1 was not a prespecified
endpoint and the data are therefore not eligible for ESMO-MCBS scoring. Scoring is based on the ITT analysis.
c98.5% CI.
33
dEMA approval is restricted to patients with hormone receptor-positive HER2-positive breast cancer who completed adjuvant
trastuzumab-based therapy <1 year. This is based on an unplanned post hoc subgroup analysis and is not eligible for ESMO-
MCBS grading. Mature OS was not statistically significant.

34
Supplementary Table S9. Levels of evidence and grades of recommendation
(adapted from the Infectious Diseases Society of America-United States Public
Health Service Grading Systema)

Levels of evidence

I Evidence from at least one large randomised, controlled trial of good

methodological quality (low potential for bias) or meta-analyses of well-
conducted randomised trials without heterogeneity

II Small randomised trials or large randomised trials with a suspicion of

bias (lower methodological quality) or meta-analyses of such trials or of
trials with demonstrated heterogeneity

III Prospective cohort studies

IV Retrospective cohort studies or case–control studies

V Studies without control group, case reports, expert opinions

Grades of recommendation

A Strong evidence for efficacy with a substantial clinical benefit, strongly

recommended

B Strong or moderate evidence for efficacy but with a limited clinical benefit,
generally recommended
C Insufficient evidence for efficacy or benefit does not outweigh the risk or the
disadvantages (adverse events, costs, etc.), optional
D Moderate evidence against efficacy or for adverse outcome, generally not
recommended
E Strong evidence against efficacy or for adverse outcome, never
recommended
aBy permission of Oxford University Press on behalf of the Infectious Diseases
Society of America.84

35
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