Breast

Cancer
Pocket Guideline 2024
 Distributed with support from Stemline. Stemline
has not influenced the content of this publication.

2
 ESMO POCKET GUIDELINES

GUIDELINES COMMITTEE
Chair: Elizabeth Smyth; Deputy Chair: Emanuela Romano; Subject Editors: Teresa Amaral, Paolo Ascierto, Kjetil
Boye, Michel Ducreux, Caroline Even, Karim Fizazi, Nadia Harbeck, Mats Jerkeman, Angela Lamarca, Natasha
Leighl, Ana Oaknin, Sanjay Popat, Christina Ruhlmann; International Coordinator of Guidelines Adaptation in
Asia Pacific: Takayuki Yoshino; Staff: Tiziana Aske, Claire Bramley, Sammi Cham, Sarah Edwards, Lisa Farrar,
Svetlana Jezdic, Lone Kristoffersen, Valérie Laforest, Keith McGregor, Ioanna Ntai, George Pentheroudakis, Kiley
Pitsos, Hayley Redston, Francesco Rho. Medical writing support: Kstorfin Medical Communications (KMC) Ltd.

ESMO CLINICAL PRACTICE GUIDELINES

ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with
metastatic breast cancer
Gennari A, André F, Barrios CH, Cortés J, de Azambuja E, DeMichele A, Dent R, Fenlon D, Gligorov J, Hurvitz SA,
Im S-A, Krug D, Kunz WG, Loi S, Penault-Llorca F, Ricke J, Robson M, Rugo HS, Saura C, Schmid P, Singer CF,
Spanic T, Tolaney SM, Turner NC, Curigliano G, Loibl S, Paluch-Shimon S and Harbeck N, on behalf of the ESMO
Guidelines Committee
Ann Oncol 2021;32(12):1475-95
https://www.annalsofoncology.org/article/S0923-7534(21)04498-7/fulltext
ESMO Metastatic Breast Cancer Living Guideline v1.1 (May 2023)
Curigliano G, Castelo-Branco L, Gennari A, Harbeck N, Criscitiello C and Trapani D, on behalf of the Clinical
Practice Guideline author group
https://www.esmo.org/living-guidelines/esmo-metastatic-breast-cancer-living-guideline
Risk reduction and screening of cancer in hereditary breast-ovarian cancer syndromes: ESMO
Clinical Practice Guideline
Sessa C, Balmaña J, Bober SL, Cardoso MJ, Colombo N, Curigliano G, Domchek SM, Evans DG, Fischerova D,
Harbeck N, Kuhl C, Lemley B, Levy-Lahad E, Lambertini M, Ledermann JA, Loibl S, Phillips K-A and
Paluch-Shimon S, on behalf of the ESMO Guidelines Committee
Ann Oncol 2023;34(1):33-47
https://www.annalsofoncology.org/article/S0923-7534(22)04193-X/fulltext

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 ESMO POCKET GUIDELINES (CONT’D)

Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
Loibl S, André F, Bachelot T, Barrios CH, Bergh J, Burstein HJ, Cardoso MJ, Carey LA, Dawood S, Del Mastro L,
Denkert C, Fallenberg EM, Francis PA, Gamal-Eldin H, Gelmon K, Geyer CE, Gnant M, Guarneri V, Gupta S,
Kim SB, Krug D, Martin M, Meattini I, Morrow M, Janni W, Paluch-Shimon S, Partridge A, Poortmans P,
Pusztai L, Regan MM, Sparano J, Spanic T, Swain S, Tjulandin S, Toi M, Trapani D, Tutt A, Xu B, Curigliano G
and Harbeck N, on behalf of the ESMO Guidelines Committee
Ann Oncol. 2024;35(2):159-82.
https://www.annalsofoncology.org/article/S0923-7534(23)05104-9/fulltext

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 ESMO GUIDE TO EVALUATION OF DATA

ESMO POCKET GUIDELINES PROVIDE YOU WITH A CONCISE SUMMARY OF THE

FUNDAMENTAL RECOMMENDATIONS MADE IN THE PARENT GUIDELINES IN AN EASILY
ACCESSIBLE FORMAT.

This quick reference booklet provides you with the most important content of the
ESMO Clinical Practice Guidelines (CPGs) on the management of breast cancer
(including metastatic breast cancer, hereditary breast cancer syndromes and early
breast cancer). Key content includes diagnostic criteria, staging of disease, treatment
plans and follow-up. The ESMO CPGs on breast cancer are intended to provide you
with a set of recommendations for the best standards of care for breast cancer, using
evidence-based medicine. Implementation of ESMO CPGs facilitates knowledge uptake
and helps you to deliver an appropriate quality of focused care to your patients.

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

Please visit http://www.esmo.org to view the full guidelines.

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6
 TABLE OF CONTENTS

9-28

METASTATIC BREAST CANCER (MBC)

DIAGNOSIS..................................................................................................................... 9
STAGING AND RISK ASSESSMENT............................................................................... 11
MANAGEMENT OF MBC................................................................................................ 12
Luminal breast cancer................................................................................................. 12
HER2-positive breast cancer....................................................................................... 15
Triple-negative breast cancer...................................................................................... 19
Hereditary breast cancer............................................................................................. 21
Site-specific management.......................................................................................... 22
New drugs................................................................................................................... 26
PERSONALISED MEDICINE........................................................................................... 26
LONG-TERM IMPLICATIONS AND SURVIVORSHIP......................................................... 26
Side-effects................................................................................................................. 26
Palliative care.............................................................................................................. 27
Patient perspective...................................................................................................... 27

29-38

HEREDITARY BREAST CANCER SYNDROMES

INCIDENCE AND EPIDEMIOLOGY................................................................................... 29
POST-TEST COUNSELLING AND FOLLOW-UP OF INDIVIDUALS WITH
HEREDITARY BREAST AND OVARIAN CANCER SYNDROME (HBOC).............................. 31
Genetic counselling..................................................................................................... 31
Follow-up..................................................................................................................... 31
BREAST CANCER RISK MANAGEMENT......................................................................... 31
Screening for women with high-risk pathogenic variants.......................................... 31
Lifestyle factors and breast cancer risk...................................................................... 34
Risk-reducing medication........................................................................................... 35
Risk-reducing surgery................................................................................................. 35
Approach to male carriers of high-risk pathogenic variants....................................... 35
Screening for additional malignancies........................................................................ 36
COUNSELLING, RISK-REDUCTION AND SCREENING IN THE PRESENCE OF
OTHER MODERATE-HIGH RISK PATHOGENIC VARIANTS................................................ 36

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 TABLE OF CONTENTS (CONT’D)

REPRODUCTIVE AND ENDOCRINOLOGICAL ISSUES IN INDIVIDUALS WITH HBOC......... 37

Contraception.............................................................................................................. 37
Fertility........................................................................................................................ 37
Management of menopausal symptoms..................................................................... 37
UNIQUE PSYCHOLOGICAL ISSUES FOR INDIVIDUALS WITH HBOC................................ 37
PERSONALISED MEDICINE AND FUTURE DIRECTIONS................................................. 38

39-63
EARLY BREAST CANCER (EBC)
SCREENING.................................................................................................................. 39
DIAGNOSIS, PATHOLOGY AND MOLECULAR BIOLOGY................................................... 39
STAGING AND RISK ASSESSMENT............................................................................... 43
MANAGEMENT OF EBC................................................................................................. 48
General treatment principles....................................................................................... 48
Patient communication and shared decision making.................................................. 48
Locoregional treatment............................................................................................... 48
Systemic treatment..................................................................................................... 52
Special situations........................................................................................................ 58
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP..................................... 61
General follow-up considerations................................................................................ 61
Long-term implications............................................................................................... 61
Reproductive and sexual health considerations.......................................................... 63
Psychosocial considerations....................................................................................... 63

64-66
GLOSSARY

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 METASTATIC BREAST CANCER

DIAGNOSIS
• The recommended diagnostic work-up for metastatic breast cancer (MBC) is shown in
the figure below

DIAGNOSTIC WORK-UP AND STAGING OF MBC

Patients with newly diagnosed or recurrent MBC

Biopsy of metastatic lesion

to confirm diagnosis

Reassess biomarkers
ER, PgR, HER2*
Patients with Patients with ER+,
TNBC tumours All patients HER2– tumours

PD-L1 by IHC, gBRCAm, PIK3CA mutation status,

HER2-low by IHC/ISH gBRCAm, HER2-low by IHC/ISH
(PALB2 assessment optional) (PALB2 assessment optional)

Assessments only where corresponding therapies are available: MSI, TMB, NTRK

Optional assessments with potential to guide treatment: ESR1 (in ER+, HER2– tumours if further
AI-based therapy is considered), somatic BRCA mutations, HER2-low status by IHC/ISH

Staging: History and physical examination, haematology, biochemistry, tumour markers, CT of the chest
and abdomen and bone scintigraphy (or PET-CT), brain imaging (symptomatic patients or according to
subtype if the presence of CNS metastases will alter the choice of therapy)

*If there are important differences in ER, PgR and HER2 status between the primary tumour and recurrence, patients should be
managed according to receptor status of the recurrent disease biopsy
AI, aromatase inhibitor; CNS, central nervous system; CT, computed tomography; ER, oestrogen receptor; ESR1, oestrogen
receptor 1; gBRCAm, germline BRCA1/2 mutation; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry;
ISH, in situ hybridisation; MBC, metastatic breast cancer; MSI, microsatellite instability; NTRK, neurotrophic tyrosine receptor
kinase; PALB2, partner and localiser of BRCA2; PD-L1, programmed death-ligand 1; PET, positron emission tomography; PgR,
progesterone receptor; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; TMB, tumour mutation
burden; TNBC, triple-negative breast cancer

9
 • Patients with newly diagnosed or recurrent MBC should have a biopsy to confirm the
histology and assess oestrogen receptor (ER), progesterone receptor (PgR) and human
epidermal growth factor receptor 2 (HER2) status
° Biopsies of bone metastases should be avoided due to the technical limitations of
biomarker detection in decalcified tissue
• If there are important differences in ER, PgR and HER2 status between the primary
tumour and recurrence, it is not known which biological features should drive
treatment decision making
° The biological features of the disease at baseline, degree of biomarker heterogeneity,
type of treatment received that could potentially induce a selection of clones
resistant to a specific targeted therapy and the burden of disease should all be
considered
° Tumour heterogeneity should be considered for each new line of treatment;
a rebiopsy may be appropriate in cases of mixed response
• Other therapeutically-relevant biomarkers that should be assessed include:
° Germline BRCA1/2 mutation (gBRCA m) status in HER2-negative MBC
° Programmed death-ligand 1 (PD-L1) status in triple-negative breast cancer (TNBC)
° Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in
ER/PgR-positive, HER2-negative MBC
• Genomic profiling and further diagnostic tests (e.g. on tumour tissue or circulating
tumour DNA) should only be carried out if the result will change the treatment
approach or if the patient can access an appropriate clinical trial
• The following should be evaluated when corresponding therapies are available:
° Microsatellite instability (MSI)
° Tumour mutation burden
° Neurotrophic tyrosine receptor kinase (NTRK) fusion

10
STAGING AND RISK ASSESSMENT
• Imaging work-up for staging should include computed tomography (CT) of the chest/
abdomen and bone scintigraphy
° [ F]2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)-CT may
18

be used as an alternative to CT and bone scans

• The imaging modality chosen at baseline should also be used for disease monitoring
to ensure comparability
• There is no evidence that any staging or monitoring approach provides an overall
survival (OS) benefit over any other
• The interval between imaging and the start of treatment should be ≤ 4 weeks
• Evaluation of response should be every 2-4 months, depending on disease dynamics,
location, extent of metastasis and type of treatment
° Disease monitoring intervals should not be shortened as this does not provide an OS
benefit, but may cause emotional and financial harm
° Less frequent monitoring is acceptable, particularly for indolent disease
° If disease progression is suspected, additional tests should be carried out in a timely
manner, irrespective of the planned intervals
• Repeat bone scans are a mainstay of evaluation for bone-only/predominant
metastases
° Image interpretation may be confounded by a possible flare during the first few
months of treatment
° PET-CT might provide earlier guidance in monitoring bone-only or bone-predominant
metastases but prospective trials are needed to study the impact on treatment
decisions and OS
• Magnetic resonance imaging (MRI) is recommended for suspected cord compression
• Brain imaging should not be routinely carried out in all asymptomatic patients at initial
MBC diagnosis or during disease monitoring
° Patients with asymptomatic HER2-positive disease or TNBC have higher rates of
brain metastases (BMs) at initial MBC diagnosis, which may warrant subtype-
oriented brain imaging if detection of central nervous system (CNS) metastases will
affect the choice of systemic therapy
° Patients with symptomatic disease should always undergo brain imaging, preferably
with MRI

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 MANAGEMENT OF METASTATIC BREAST CANCER
• Systemic therapy is the standard of care in MBC but may be supplemented with
locoregional treatments (LRTs) according to the disease status of the individual patient
° A multidisciplinary team is a prerequisite for optimal management
• Treatment decisions should be made irrespective of patient age, but comorbidities,
patient characteristics and patient preferences need to be considered
• Rechallenge with drugs previously used in the early breast cancer (BC) setting is a
reasonable option provided that the disease-free interval (DFI) is ≥ 12 months after the
last drug administration and that no toxicities remain
• Patients with MBC should be encouraged to consider participation in clinical trials early
in their disease course
Luminal breast cancer
• Management options for ER-positive, HER2-negative MBC are shown in the figure on
the next page
• Premenopausal women may be treated in the same way as postmenopausal women as
long as they undergo ovarian function suppression (OFS) or ovarian ablation
° If a rapid response is required, bilateral oophorectomy may be preferable over
gonadotropin-releasing hormone agonists
• Primary endocrine resistance is defined as:
° Relapse during the first 2 years of adjuvant endocrine therapy (ET)
° Progressive disease (PD) within the first 6 months of first-line ET for MBC
• Secondary (acquired) resistance is defined as:
° Relapse during adjuvant ET but after the first 2 years
° Relapse within 12 months of completing adjuvant ET
° PD 6 months after initiating ET for MBC
First-line treatment
• A cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor combined with ET is the standard
of care first-line therapy for patients with ER-positive, HER2-negative MBC
° An aromatase inhibitor (AI)–CDK4/6 inhibitor combination is recommended for
patients who did not relapse on an AI or within 12 months of stopping adjuvant AI
° Fulvestrant–CDK4/6 inhibitor is recommended for patients who relapsed on adjuvant
AI therapy or within 12 months of stopping adjuvant AI
• ET alone in the first-line setting should be reserved for patients with comorbidities or a
performance status that precludes the use of CDK4/6 inhibitor combinations

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 MANAGEMENT OF ER-POSITIVE, HER2-NEGATIVE MBC

Patients with ER+, HER2– MBC

If imminent organ failure
PD or intolerable toxicities
ET–CDK4/6 inhibitor*,† ChT
Somatic mutation testing
(tissue or liquid) If HER2-low:
PD
Germline BRCA1/2 testing + PALB2 Trastuzumab deruxtecan§

No imminent organ failure Imminent organ failure or short

and long PFS on prior ET PFS on endocrine-based therapy

Everolimus–exemestane*
If germline
Everolimus–fulvestrant*,‡ If PIK3CAm+: If ESR1m+:
BRCA/PALB2 m+:
Switch ET ± CDK4/6 inhibitor Fulvestrant–alpelisib Elacestrant
PARP inhibitor
Fulvestrant monotherapy

PD ChT

If HER2-0 PD If HER2-low

Sacituzumab Trastuzumab
govitecan deruxtecan

ChT
Sacituzumab govitecan if not used before

13
 *OFS if the patient is premenopausal
†
If relapse < 12 months after end of adjuvant AI: Fulvestrant–CDK4/6 inhibitor*; if relapse > 12 months after end of adjuvant AI:
AI–CDK4/6 inhibitor*
‡
Preferred if the patient is ESR1 mutation positive
§
Trastuzumab deruxtecan can also be given following adjuvant ChT in the setting of fast progression (DESTINY-Breast04/EMA
indication)
AI, aromatase inhibitor; CDK4/6, cyclin-dependent kinase 4 and 6; ChT, chemotherapy; EMA, European Medicines Agency; ER,
oestrogen receptor; ESR1, oestrogen receptor 1; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; m,
mutation; MBC, metastatic breast cancer; OFS, ovarian function suppression; PALB2, partner and localiser of BRCA2; PARP,
poly (ADP-ribose) polymerase; PD, progressive disease; PFS, progression-free survival; PIK3CA, phosphatidylinositol-4,5-
bisphosphate 3-kinase catalytic subunit alpha

Second-line treatment
• The optimal sequence of endocrine-based therapy after progression on CDK4/6
inhibitors is uncertain
° Treatment choice depends on prior therapy, duration of response to prior ET, disease
burden, patient preference and treatment availability
• In patients who required first-line chemotherapy (ChT) due to imminent organ failure,
or who did not have access to a CDK4/6 inhibitor in the first-line setting, ET–CDK4/6
inhibitor is acceptable as subsequent therapy
• Determination of somatic PIK3CA and oestrogen receptor 1 (ESR1) mutations, as
well as germline BRCA1/2 and partner and localiser of BRCA2 (PALB2 ) mutations, is
recommended in patients who relapse after ET–CDK4/6 inhibitor
• The choice of second-line therapy (ChT versus endocrine-based therapy) should be
based on disease aggressiveness, extent and organ function, and should consider the
associated toxicity profiles
• Fulvestrant–alpelisib is an option for patients with PIK3CA-mutated tumours, prior
exposure to an AI (± CDK4/6 inhibitor) and appropriate glycated haemoglobin levels
° Hyperglycaemia can occur with alpelisib so collaboration with a diabetes specialist
is recommended
• Everolimus–exemestane is a second-line treatment option
° Capecitabine is a good alternative in patients unlikely to tolerate everolimus–exemestane
° Tamoxifen or fulvestrant can also be combined with everolimus
° Stomatitis prophylaxis with steroid mouthwash must be used during everolimus
treatment
• Elacestrant is approved and is an option for patients with ER-positive, HER2-negative,
ESR1-mutated advanced or metastatic breast cancer progressing after at least one
line of ET
• A poly (ADP-ribose) polymerase (PARP) inhibitor (olaparib or talazoparib) should be considered
for patients with germline pathogenic BRCA1/2 mutations and is an option for patients
with somatic pathogenic (or likely pathogenic) BRCA1/2 or germline PALB2 mutations
• At least two lines of endocrine-based therapy are preferred before moving to ChT
14
• In patients with imminent organ failure, ChT is preferred
Beyond second line
• Treatment decisions should consider sensitivity to previous treatments, time to
progression, gBRCAm status, tumour biology and mechanisms of resistance that may
have arisen during previous treatments
• For endocrine-sensitive tumours, continuation of ET with agents not previously
received in the metastatic setting may be an option
• For endocrine-resistant tumours where targeted agents have already been used or
ruled out due to lack of therapeutically-relevant molecular alterations, ChT should
be considered
• Sequential single-agent ChT is generally preferred over combination strategies
° Single-agent ChT options include anthracyclines, taxanes, capecitabine, eribulin,
vinorelbine and platinums
° The optimal ChT sequence in MBC has not been established
° When a rapid response is needed due to imminent organ failure, combination ChT
is preferred
• Rechallenge with anthracyclines or taxanes is feasible in patients with a DFI
≥ 12 months
° Liposomal anthracyclines or protein-bound paclitaxel may be considered for the
rechallenge, if available
° Anthracycline lifetime cumulative dose limits must be considered; cardiac monitoring
is mandatory
• Bevacizumab (if available) plus taxane or capecitabine is a first-line ChT option
• If capecitabine is used, patients should undergo germline variant testing for lack of the
enzyme, dihydropyrimidine dehydrogenase, before treatment starts
• ChT should generally be continued until PD or intolerable toxicity, except for
anthracyclines where the cumulative dose limit must be considered
• Sacituzumab govitecan should be considered for patients with HR-positive/HER2-0
MBC after at least two lines of ChT
• Trastuzumab deruxtecan should be considered for patients with HER2-low MBC after
at least one line of ChT
HER2-positive breast cancer
First-line treatment
• First- and second-line management options for HER2-positive MBC are shown in the
figure on the next page

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16
FIRST- AND SECOND-LINE TREATMENT OF HER2-POSITIVE MBC

Patients with HER2+ MBC

1st-line treatment 2nd-line treatment or progression during

neoadjuvant or adjuvant treatment*

HR+ HR– Active BMs No, unknown

or stable BMs

ChT No ChT ChT No ChT Local intervention Local intervention

contraindicated contraindications contraindicated contraindications indicated† not indicated

Trastuzumab Docetaxel Trastuzumab– Docetaxel 1-10 BMs, > 10 BMs, Tucatinib–

(± pertuzumab) (or paclitaxel) + pertuzumab (or paclitaxel) + favourable unfavourable capecitabine– Trastuzumab
+ ET trastuzumab– until trastuzumab– prognostic prognostic trastuzumab deruxtecan
pertuzumab progression pertuzumab factors factors (preferred)
≥ 6 cycles ≥ 6 cycles or
followed by followed by Trastuzumab
trastuzumab– pertuzumab– Resection SRT deruxtecan
pertuzumab– trastuzumab
ET until until progression
progression SRT WBRT

*Including neoadjuvant dual blockade or adjuvant T-DM1

†
Keep on current systemic therapy unless PD outside CNS
BM, brain metastasis; ChT, chemotherapy; CNS, central nervous system; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; MBC, metastatic breast
cancer; PD, progressive disease; SRT, stereotactic radiotherapy; T-DM1, ado-trastuzumab emtansine; WBRT, whole brain radiotherapy
• The gold-standard first-line treatment for HER2-positive MBC is trastuzumab–
pertuzumab–docetaxel, regardless of hormone receptor (HR) status
° Docetaxel should be given for at least 6 cycles, if tolerated, followed by maintenance
trastuzumab–pertuzumab until PD
° An alternative taxane (e.g. paclitaxel or nab-paclitaxel) may be used
• ET may be added to trastuzumab–pertuzumab maintenance therapy for HER2-positive,
HR-positive tumours
° OFS should be added for pre- and perimenopausal women
• In patients with HER2-positive, HR-positive disease who are not suitable for first-line
ChT, ET (e.g. an AI) with HER2-targeted therapy (e.g. trastuzumab, trastuzumab–
pertuzumab, trastuzumab–lapatinib or lapatinib), may be recommended
° Single-agent ET without HER2-targeted therapy is not routinely recommended
unless comorbidities (e.g. cardiac disease) preclude the safe use of
HER2-directed therapies
• If ChT is contraindicated in patients with HER2-positive, HR-negative disease,
HER2-targeted therapy without ChT (e.g. trastuzumab or trastuzumab–pertuzumab)
may be used
° If taxanes are contraindicated, a less toxic ChT partner may be considered
(e.g. capecitabine or vinorelbine)
• Patients with metastatic recurrence within 6-12 months of receiving adjuvant
trastuzumab–pertuzumab should follow second-line therapy recommendations
° Patients with distant metastatic recurrence within 12 months of adjuvant
trastuzumab (without pertuzumab) may receive first-line trastuzumab–pertuzumab–
taxane or second-line therapy
Second-line treatment
• Trastuzumab deruxtecan is the preferred second-line therapy after progression on a
taxane and trastuzumab
• If trastuzumab deruxtecan is not available, ado-trastuzumab emtansine (T-DM1) is
an option
• In selected patients with BMs, second-line tucatinib–capecitabine–trastuzumab or
trastuzumab deruxtecan may be used
Third-line treatment and beyond
• Third- and further-line management options for HER2-positive MBC are shown in the
figure on the next page
• The choice of third-line treatment depends on prior second-line therapy, patient
characteristics, toxicity profiles and availability

17
18
THIRD-LINE AND BEYOND TREATMENT OF HER2-POSITIVE MBC
Patients with HER2+ MBC

3rd-line treatment
and beyond

No, unknown
Active BMs
or stable BMs

Local intervention Local intervention Tucatinib–capecitabine–

indicated* not indicated trastuzumab or
Trastuzumab deruxtecan†
or T-DM1†
1-10 BMs, > 10 BMs, Tucatinib–
favourable unfavourable capecitabine–
prognostic factors prognostic factors trastuzumab

Lapatinib–capecitabine
Resection SRT Trastuzumab Lapatinib–trastuzumab§
deruxtecan ‡ Trastuzumab–ChT§
Margetuximab–ChT§,║
SRT WBRT Neratinib–ChT§,║
*Keep on current systemic therapy unless PD outside CNS
†
If not received as second-line therapy
‡
If not previously used, including all other drugs that are also a second-line treatment option
§
There are no data for any of these combinations after tucatinib- and/or trastuzumab deruxtecan-based therapy
║
FDA approved, not EMA approved
BM, brain metastasis; ChT, chemotherapy; CNS, central nervous system; EMA, European Medicines Agency; FDA, Food and Drug Administration; HER2, human epidermal growth factor receptor 2;
MBC, metastatic breast cancer; PD, progressive disease; SRT, stereotactic radiotherapy; T-DM1, ado-trastuzumab emtansine; WBRT, whole brain radiotherapy
• The most active treatment options appear to be tucatinib–capecitabine–trastuzumab,
trastuzumab deruxtecan and T-DM1
• In later lines of therapy, lapatinib is an evidence-based therapy option to be used
preferably in combinations (e.g. with capecitabine, trastuzumab or ET)
• Neratinib and margetuximab can be considered for late-line treatment [both Food and
Drug Administration (FDA) approved, not European Medicines Agency (EMA) approved]
° The most appropriate setting might be in patients who have exhausted all standard
therapy options; however, there is no evidence for sequencing a tyrosine kinase
inhibitor (TKI) after a TKI
• Continued anti-HER2-based therapy is the current standard for patients with HER2-
positive tumours
° If other anti-HER2 therapies have been exhausted, are not considered suitable or are
not available, trastuzumab beyond progression should be considered
Triple-negative breast cancer
• Management options for metastatic TNBC (mTNBC) are shown in the figure on the
next page
First-line treatment
• For PD-L1-positive tumours, the preferred option is ChT in combination with an
immune checkpoint inhibitor (ICI)
° In case of PD-L1 immune cell positivity, atezolizumab–nab-paclitaxel is an option for
de novo MBC or when the DFI is ≥ 12 months (EMA approved, not FDA approved)
° In case of combined positive score (CPS) ≥ 10, pembrolizumab plus paclitaxel,
nab-paclitaxel or carboplatin–gemcitabine can be considered in de novo advanced
disease or when the DFI is ≥ 6 months
• For gBRCAm and PD-L1-negative disease, the preferred options are olaparib, talazoparib
or carboplatin (see section on hereditary BC on pages 21 and 22)
• For gBRCA- wild type and PD-L1-negative disease, the initial treatment is ChT
° The choice of ChT depends on previous treatments, disease presentation, DFI and
patient considerations
° Taxane monotherapy is the most frequently used option
° Anthracyclines can be used in cases with no prior exposure or if rechallenge
is possible
° In case of imminent organ failure, combination therapy with a taxane and/or
anthracycline with bevacizumab (first line only) is preferred

19
20
MANAGEMENT OF mTNBC
Patients with mTNBC

Search theragnostic markers

PD-L1+ gBRCAm PD-L1–,

gBRCA-WT

Imminent organ failure No imminent organ failure

Preferred:
ChT-based Anthracycline–taxane-
PARP inhibitor- Preferred: Taxane
Atezolizumab– therapy based combination
based therapy or anthracycline
nab-paclitaxel*,† (platinum§ Alternative:
(preferred over monotherapy
Pembrolizumab–ChT*,‡ preferred over Taxane–bevacizumab or
ChT)
taxane) capecitabine–bevacizumab

Sacituzumab govitecan (preferred) or ChT

If HER2-low: Trastuzumab deruxtecan ChT: Eribulin, capecitabine or vinorelbine

*May be considered as monotherapy in further lines in case of high PD-L1 positivity and no previous exposure to ICI
†
EMA approved, not FDA approved
‡
ChT physician’s choice of nab-paclitaxel, paclitaxel or gemcitabine–carboplatin
§
If not used previously
ChT, chemotherapy; EMA, European Medicines Agency; FDA, Food and Drug Administration; gBRCAm, germline BRCA1/2 mutation; HER2, human epidermal growth factor receptor 2; ICI, immune
checkpoint inhibitor; mTNBC, metastatic triple-negative breast cancer; PARP, poly (ADP-ribose) polymerase; PD-L1, programmed death-ligand 1; WT, wild type
Progression after anthracyclines and taxanes
• Sacituzumab govitecan is the preferred treatment option after prior ChT
• After progression on sacituzumab govitecan, all ChT recommendations for HER2-
negative disease also apply for TNBC, such as eribulin, capecitabine and vinorelbine
• ICI monotherapy is not recommended in later lines
° Pembrolizumab may be an option for patients with tumours strongly positive for
PD-L1 if they have not received prior ICI therapy or do not have access to a
clinical trial
• For patients with HER2-low MBC, trastuzumab deruxtecan should be considered after
at least one line of ChT
• Antiandrogen therapy or inhibitors targeting PI3K or AKT are not recommended outside
a clinical trial
Maintenance
• No Phase III study has specifically addressed the question of maintenance therapy
in TNBC
• ICI maintenance is acceptable in patients who have received an initial ChT–ICI
combination, in the absence of safety issues
• Bevacizumab maintenance may be used after an initial bevacizumab–taxane or
bevacizumab–capecitabine combination
Hereditary breast cancer
• Patients with HER2-negative MBC and germline pathogenic (or likely pathogenic)
variants in BRCA1 or BRCA2 should be offered a PARP inhibitor (olaparib or talazoparib)
as an alternative to ChT, irrespective of HR status
° Prior treatment with anthracyclines–taxanes is not required before offering PARP
inhibitor treatment to patients with MBC and gBRCAm; nor should patients with
HR-positive disease be required to demonstrate complete endocrine resistance
• Platinum-based ChT (single agent or combined with paclitaxel) is associated
with a substantial progression-free survival (PFS) benefit in patients with MBC
and gBRCA m
• There are no studies directly comparing PARP inhibitors with a platinum agent, but in
pivotal trials, health-related quality of life (QoL) was better with PARP inhibitors
• There are no studies comparing PARP inhibitors with ET (alone or with targeted
therapies) in patients with HR-positive disease

21
 • The optimal sequencing of PARP inhibitors with other active treatments, such as
ChT–ICI in mTNBC or ET–targeted therapy in HR-positive disease, is unknown
° Sequencing decisions should be based on factors such as prior treatment response,
disease burden, PD-L1 status, PIK3CA status, HR status and the relative toxicities of
the different approaches
• When a PARP inhibitor is considered, patients should be offered genetic testing for
pathogenic variants in BRCA1 and BRCA2 regardless of age, family history or BC subtype
Site-specific management
Primary stage IV disease
• For patients with newly diagnosed stage IV BC and an intact primary tumour,
therapeutic decisions should ideally be discussed in a multidisciplinary context
• LRT of the primary tumour in the absence of symptomatic local disease does not lead
to an OS benefit and is not routinely recommended
• In patients with local symptoms caused by the primary tumour or metastatic disease,
the use of local treatment modalities should be evaluated
• Surgery of the primary tumour may be considered for patients with bone-only
metastasis, HR-positive tumours, HER2-negative tumours, patients of < 55 years,
patients with oligometastatic disease (OMD) and those with a good response to initial
systemic therapy
OMD
• A proportion of patients with MBC may present or recur with limited metastatic
disease, referred to as OMD
• The clinical challenge is whether treatment should follow a palliative approach or be
escalated to pursue complete and sustained remission (curative approach)
• Management options for OMD are shown in the figure on the next page
• The dynamics in chronic metastatic conditions should be reviewed to identify induced
or recurrent OMD
• A complete imaging history should be available for decisions on OMD care
• Patients with OMD should be discussed in a multidisciplinary context to individualise
management
• Multimodality treatment approaches involving LRT [e.g. high conformal radiotherapy
(RT), image-guided ablation, selective internal RT and/or surgery], combined with
systemic treatments, are recommended and should be tailored according to disease
presentation in the individual patient

22
MANAGEMENT OF OMD

Patients with a suspicion of OMD

Biopsy confirmation (when appropriate)

Systemic imaging staging, preferably with PET scan

Patients with a diagnosis of OMD*

MDT discussion
Informed discussion with patient, aligning expectations

Consider site of metastases (CNS, bone, visceral, etc.)

as they may require different approaches
Consider management of the primary tumour and axilla in
patients with synchronous OMD
Consider systemic treatment to document response as
a first approach
Consider local approach (surgery, RT, RFA, etc.)

Continue systemic treatment when appropriate†

*Consider elements in current definitions, i.e. limited or low-volume metastatic disease; up to five lesions in total, not
necessarily in the same organ; all potentially amenable to receive local treatment
†
The duration of systemic treatment remains a topic of debate
CNS, central nervous system; MDT, multidisciplinary team; OMD, oligometastatic disease; PET, positron emission tomography;
RFA, radiofrequency ablation; RT, radiotherapy

23
 • Some subtypes of BC may be very sensitive to systemic treatment
° The ideal therapy sequence has not been defined
° It is reasonable to document tumour response with systemic treatment before
suggesting localised RT or surgery
• Local ablative therapy to all metastatic lesions may be offered on an individual basis
after discussion in a multidisciplinary setting
Bone metastases and bone-modifying agents
• A multidisciplinary approach is essential to manage patients with bone metastases
and to prevent skeletal-related events (SREs)
• Appropriate diagnostic imaging (i.e. CT for fracture risk and MRI for suspected cord
compression) is recommended to define the extent of disease and the risk of fractures
• An orthopaedic evaluation is advised in case of significant lesions in long bones or
vertebrae, as well as in patients with metastatic spinal cord compression (MSCC) to
discuss the possible role of surgery
• RT is recommended for lesions at moderate risk of fracture and those associated with
moderate to severe pain
° A single 8-Gy RT fraction is as effective as fractionated schemes in uncomplicated
bone metastases
° RT should be delivered after surgery for stabilisation or after separation surgery
for MSCC
• Bone-modifying agents (BMAs; e.g. bisphosphonates or denosumab) are
recommended for patients with bone metastases, regardless of symptoms
• Zoledronate can be administered every 12 weeks in patients with stable disease after
3-6 monthly treatments
• Denosumab should be administered every 4 weeks and is more effective than
zoledronate in delaying first and subsequent SREs
• For patients progressing on a BMA, it is unclear if changing to another agent with a
different mechanism of action is of benefit
° In patients progressing on intravenous bisphosphonates, denosumab could be
an alternative
• Before BMA initiation, patients should have a complete dental evaluation (and
should ideally complete any required dental treatment) and calcium and vitamin D
supplements should be prescribed
• The optimal duration of BMA therapy has not been defined but it is reasonable to
interrupt therapy after 2 years for patients in remission

24
BMs and leptomeningeal metastases
• BMs should be managed according to the recommendations outlined in the European
Association of Neuro-Oncology (EANO)–ESMO Clinical Practice Guideline (CPG) for the
management of patients with BMs from solid tumours (see: https://www.esmo.org/
guidelines/guidelines-by-topic/neuro-oncology/brain-metastasis-from-solid-tumours)
• The presence of BMs should be explored by brain imaging in all patients who present
with clinical signs or symptoms of raised intracranial pressure, seizures or new
neurological deficits
• In mTNBC or HER2-positive MBC, brain imaging could be considered in asymptomatic
patients, based on the high probability of BMs in these subtypes, if detection of CNS
metastases will alter the choice of systemic therapy
• The diagnostic work-up of patients with suspected BMs should include cranial MRI
° If MRI is not available, contrast CT can be used
• Patients with a single BM should be considered for surgery whenever possible;
stereotactic radiosurgery (SRS) is recommended for patients with a limited number
(1-4) of BMs
° SRS may also be considered for patients with a higher number of BMs (4-10),
provided the cumulative tumour volume is < 15 mL
• Whole brain RT (WBRT) should be considered in case of multiple BMs
• In HER2-positive MBC, anti-HER2 therapies may be considered in patients not
requiring immediate local therapy
° Tucatinib (together with trastuzumab and capecitabine) has demonstrated a
significant OS improvement in patients with active BMs
° The use of intrathecal trastuzumab remains investigational
• In patients with HER2-negative BC, ChT may be considered
• Leptomeningeal metastases (LMs) should be treated according to the
recommendations outlined in the EANO–ESMO CPG for the management of patients
with LMs from solid tumours (see: https://www.esmo.org/guidelines/guidelines-by-
topic/neuro-oncology/leptomeningeal-metastasis)
• Methotrexate, cytarabine (including liposomal cytarabine) or thiotepa are commonly used
for intrathecal treatment of LMs, but they have not demonstrated improvements in OS
• RT should be considered for patients with symptomatic LMs, either as localised RT for
nodular lesions or as WBRT for extensive nodular or linear LMs

25
 New drugs
• Despite progress in treating MBC, the disease remains incurable and effective
treatment options are limited for some patient populations
• Several antibody–drug conjugates, utilising antibodies, linkers and chemotherapeutics,
have entered the clinical trial pipeline for a variety of BC subtypes and eligible patients
should be encouraged to participate in these trials

PERSONALISED MEDICINE
• Standard therapies for MBC are personalised based on biomarkers
• In addition, there are now several tissue and site-agnostic approvals. For example:
° Larotrectinib and entrectinib are approved for patients with solid tumours expressing
an NTRK gene fusion
° Pembrolizumab is FDA approved for patients with unresectable or metastatic
MSI-high/mismatch repair deficient solid tumours who have PD and no alternative
treatment options [EMA approval in this setting is not tumour agnostic but is for
specific tumour types (excludes BC)]
° These biomarkers should be tested once subtype-specific standard therapies have
been exhausted
• New drugs are being evaluated that have documented activity across several MBC
subtypes, and may require assessment of new biomarkers (e.g. human epidermal
growth factor receptor 3) once therapeutic efficacy and biomarker validation have
been completed

LONG-TERM IMPLICATIONS AND SURVIVORSHIP

• In MBC, regular evaluation of disease status and therapy-related toxicities should
include clinical assessments, blood tests, imaging and patient-reported outcomes (PROs)
Side-effects
• The most common side-effect of BC treatment is fatigue, which can appear early in
treatment, be overwhelming and is not eased by rest
° Contributing factors should be considered, including concomitant medications,
anaemia and PD
° Recommended management includes dose reduction of current treatment and
physical activity with intermittent rest periods
• Nausea and vomiting are common side-effects of many therapies and may be
managed using both prophylaxis and rescue medications
• Bone marrow suppression occurs with the majority of therapies used to treat BC
° Management includes myeloid growth factors, transfusions and dose reduction/delay
26
• An interdisciplinary approach is critical, including specialised oncology and/or breast
care nurses to proactively screen for and manage treatment-emergent toxicities
• Patients should be informed about the side-effect profiles of recommended systemic
treatments
° All treatment should include formal patient education regarding side-effect
management
• Particular attention must be paid to the risk of side-effects in specific populations,
such as elderly patients and those with comorbidities, to ensure therapy adherence
• Proactive symptom management and education helps to alleviate side-effects and
improves QoL
• Careful assessment of side-effects should occur at each visit
° Electronic PROs may be useful in this context
• QoL assessments should be incorporated into treatment efficacy evaluations
• Dose reduction and delay are effective strategies to manage toxicity in advanced disease
Palliative care
• Palliative care should be integrated early and offered in both inpatient and
outpatient settings
• Patients should be offered optimal symptom control, psychological, social and spiritual
support, in addition to receiving the best available treatment
• Many areas of care need to be managed, including pain, dyspnoea, cachexia, fatigue,
depression and anxiety
• Comorbidities, previous treatments, age and patient preferences should also be
considered
• Shared decision making between the patient and healthcare professionals, as well as
good communication and relationship building with the patient, family members and
caregivers, is paramount to ensure a mutual understanding of treatment expectations
• The emotional toll of caring for patients who are dying also has an impact on
healthcare staff, and processes should be in place to support their mental health
Patient perspective
• For all patients with BC or MBC, receiving optimal care as part of a multidisciplinary
approach is of greatest importance
• Besides access to optimal treatment, patient information and education is particularly
important
° Only well-informed and educated patients can be equally involved in treatment
choices, leading to improved treatment outcomes

27
 • A common concern for patients with MBC is that they don’t want to suffer cancer-
related and/or treatment-related effects
° For every new line of treatment, patients expect disease progression to stop, but not
at any cost
• Patients often emphasise that QoL is more important to them than PFS or OS
° The definition of good QoL can differ from patient to patient depending on personal
preferences, cultural and religious perspectives and age
• In addition to psychosocial support, patient support groups or online closed groups can
provide safe places for patients and give them emotional support

28
 HEREDITARY BREAST CANCER SYNDROMES
INCIDENCE AND EPIDEMIOLOGY
• Hereditary breast and ovarian cancer syndrome (HBOC) is defined:
° Clinically by family history criteria
° Molecularly by identification of germline pathogenic variants (PVs) in clinically-validated
HBOC genes
• HBOC genes are broadly classified as:
° High-risk genes, which increase cancer risk by at least fourfold
° Moderate-risk genes, which increase cancer risk by two- to fourfold
• Lifetime cancer risks for HBOC-associated PVs are shown in the table on the next page
• Individuals with significant family history should be offered genetic testing, using
multigene panels of clinically-validated HBOC genes
• The genetic basis of around half of clinical HBOCs is currently unknown, or unexplained
by single-gene variants
• Conversely, approximately half of individuals who harbour PVs in HBOC genes do not
have a suggestive family history
° Clinicians should be aware that family history-based testing misses about half of
HBOC gene carriers
° Strategies to identify these high-risk individuals are being developed
• HBOC has been estimated to underlie ~10% of breast cancers (BCs)
• Molecularly, ~6% of patients with BC harbour PVs in HBOC genes
° Half (~3%) in BRCA1, BRCA2 and other high-risk genes [e.g. partner and localiser of
BRCA2 (PALB2)]
° Half (~3%) in moderate-risk genes [e.g. ATM serine/threonine kinase (ATM),
checkpoint kinase 2 (CHEK2)]
• The prevalence of molecular HBOC in unaffected individuals varies based on family
history and ethnicity
° Some populations harbour founder PVs with high carrier frequencies (e.g. 1:40 for
BRCA1 and BRCA2 PVs in Ashkenazi Jews)
° Studies carried out in non-founder populations suggest that the carrier frequency for
high-risk genes (i.e. BRCA1, BRCA2, PALB2 ) is approximately 1:150

29
 LIFETIME CANCER RISKS FOR HBOC-ASSOCIATED PVS
TUBO-OVARIAN PANCREATIC COLON OTHER
BC*
CANCERS† CANCER‡ CANCER§ CANCERS
Yes Yes Yes
ATM No Prostate: 30%
25-30% < 5% < 5%
Yes
BARD1 No No No No
~20%
Yes Yes Yes
BRCA1 No
> 60% 40-60% < 5%
Yes Yes Yes
BRCA2 No Prostate: 33%
> 60% 15-30% < 5%
Yes
BRIP1 No No No No
5-10%
Yes (LBC) Diffuse gastric
CDH1 No No No
40% cancer: 35-45%
Yes Yes
CHEK2 No No
25-30% 15%
Yes Yes Yes
PALB2 No No
40-60% 3-5% 2-3%
Yes Yes Thyroid: 20%
PTEN No No
40% 10% Endometrial: 20%
Yes Yes
RAD51C No No No
20% 10%
Yes Yes
RAD51D No No No
10% 10%
Gastric: 30%
Yes Yes Yes
STK11 No Sertoli-Leydig:
40% 10-30% 30%
10-20%
Sarcoma, brain,
Yes leukaemia,
TP53 No Possibly Possibly
40% adrenocortical
carcinoma
Lifetime risk in general “average risk” population: *BC 11%, †ovarian cancer 1.3%, ‡pancreatic cancer 1.6%, §colon cancer 4%
ATM, ATM serine/threonine kinase; BARD1, BRCA1 associated ring domain 1; BC, breast cancer; BRIP1, BRCA1 interacting helicase
1; CDH1, cadherin 1; CHEK2, checkpoint kinase 2; HBOC, hereditary breast and ovarian cancer syndrome; LBC, lobular breast
cancer; PALB2, partner and localiser of BRCA2; PTEN, phosphatase and tensin homologue; PV, pathogenic variant; RAD51C, RAD51
paralogue C; RAD51D, RAD51 paralogue D; STK11, serine/threonine kinase 11; TP53, tumour suppressor protein p53

30
POST-TEST COUNSELLING AND FOLLOW-UP OF INDIVIDUALS WITH HEREDITARY
BREAST AND OVARIAN CANCER SYNDROME
Genetic counselling
• Post-test genetic counselling should include discussion of the medical and
psychological implications for the individual and their family
° Medical implications include the impact on treatment of any current cancer and
interventions for prevention or early detection of future cancers
• Risk assessment should be comprehensive and individualised, taking into account the
specific gene and variant identified, as well as other individual non-genetic (e.g. age,
reproductive history) and genetic risk factors
• When available, validated tools such as CanRisk (https://www.canrisk.org/) should be
used to aid decision making
• Counselling must include clear explanations of the familial implications, indicating which
relatives (both female and male) need to be informed and offered counselling and testing
° Enhancing awareness and availability of testing in at-risk relatives should be a priority
Follow-up
• Follow-up is lifelong for individuals with HBOC and may involve serial imaging,
risk-reducing surgery, risk-reducing medication (RRMed) and quality of life issues
• Risk management should be carried out in specialised high-risk clinics that are
multidisciplinary and should include psychologists, if possible

BREAST CANCER RISK MANAGEMENT

• Recommendations for BC screening and risk reduction in carriers of BRCA1 and
BRCA2 PVs are shown in the figures on the next pages
Screening for women with high-risk pathogenic variants
• Women with HBOC should be offered intensified screening if they do not opt for a
risk-reducing mastectomy (RRM)
• In women with PVs in BRCA1, BRCA2 or PALB2, intensified screening should start
at the age of 30 or 5 years earlier than the age at diagnosis of the youngest family
member with BC
• Breast magnetic resonance imaging (MRI) should be considered the essential
component of intensified screening programmes
° Clinical breast examination is of no value as a screening tool
• Annual screening intervals are recommended, except for BRCA1 PV carriers, in which
6-monthly screening should be considered

31
32
BC SCREENING AND RISK REDUCTION IN CARRIERS OF BRCA1 PVS
BRCA1 PV

BC risk

Screening Risk reduction

Intensified surveillance with MRI from BRRM RRMed

age 30 or 5 years younger than the
youngest family member with BC
Imaging should be carried out at
6-monthly intervals If BRRM & reconstruction carried out, consider baseline MRI following RRMeds may be
If MRI not available for surgery - if negligible residual breast tissue, no further imaging screening considered if BRRM is
6-monthly screening, consider: not being adopted
- In carriers 30-39 years of age, or risk does not
US ± mammography warrant RRS
- In carriers ≥ 40 years of age,
mammography ± US

BC, breast cancer; BRRM, bilateral risk-reducing mastectomy; MRI, magnetic resonance imaging; PV, pathogenic variant;
RRMed, risk-reducing medication; RRS, risk-reducing surgery; US, ultrasound
 BC SCREENING AND RISK REDUCTION IN CARRIERS OF BRCA2 PVS

BRCA2 PV

BC risk

Screening Risk reduction

Intensified surveillance with MRI from BRRM RRMed

age 30 or 5 years younger than the
youngest family member with BC
Imaging should be carried out annually
If BRRM & reconstruction carried out, consider baseline MRI following RRMeds may be
surgery - if negligible residual breast tissue, no further imaging screening considered if BRRM
is not being adopted
or risk does not
warrant RRS

BC, breast cancer; BRRM, bilateral risk-reducing mastectomy; MRI, magnetic resonance imaging; PV, pathogenic variant;
RRMed, risk-reducing medication; RRS, risk-reducing surgery

33
 • If 6-monthly screening is considered, this may be best achieved with an annual MRI
and (depending on availability, resources and local guidelines) the following imaging
between MRIs:
° Ultrasound (US) with or without mammography in carriers 30-39 years of age
° Mammography with or without US in carriers ≥ 40 years of age
• There is currently no evidence to base a recommendation on the appropriate end date
of intensified screening
° The decision may be based on individual factors such as breast density, comorbidities
and the patient’s priorities
• There is no evidence to support continued routine breast imaging after RRM. However,
it is reasonable to carry out a baseline MRI in the first year after RRM to evaluate the
amount of residual breast tissue, with further decisions on imaging screening made on
a case-by-case basis
• Intensified screening should continue after breast-conserving treatment or unilateral
mastectomy for non-metastatic hereditary BC
• Intensified breast screening should be considered in women with ovarian cancer who
have no evidence of recurrence in a prolonged remission
• There should be rigorous quality assurance of intensified screening programmes,
including benchmarking of programme sensitivity, false-positive rates, recall rates and
availability of MRI-guided biopsy
Lifestyle factors and breast cancer risk
• Physical exercise most days at moderate or strenuous intensity should be encouraged
if appropriate (more is better)
° Individuals should avoid being overweight or obese
° Breastfeeding should be encouraged
• Alcohol is associated with an increased risk for BC in the general population
° Although studies have not demonstrated a clear association for BRCA1/2 PV carriers,
individuals should be advised to minimise alcohol intake
• Use of hormonal contraception and combined hormone replacement therapy are
associated with increased BC risk in the general population, but it is not clear if this is
also true for BRCA1/2 PV carriers
° Decisions about hormonal contraception should balance the possible increase in BC
risk against contraceptive efficacy, convenience and reduction in risk of ovarian cancer

34
Risk-reducing medication
• RRMed can be considered for primary risk reduction of BC and risk reduction of
contralateral disease in women who decline bilateral risk-reducing mastectomy
(BRRM) or who have a risk level that does not warrant surgery
° Data pertaining specifically to women with PVs in germline predisposition genes are
extremely limited
• RRMeds include selective oestrogen receptor modulators (e.g. tamoxifen, raloxifene)
and aromatase inhibitors (e.g. anastrozole, exemestane)
° Tamoxifen is the only option for premenopausal women
° Side-effect profiles should be considered when choosing between agents for
postmenopausal women (including increased risk of thrombosis, endometrial cancer
and osteoporosis)
Risk-reducing surgery
• BRRM is the most effective method for reducing BC risk for BRCA1/2 PV carriers
• BRRM should be discussed in carriers of other high-risk genes [tumour suppressor
protein p53 (TP53), phosphatase and tensin homologue (PTEN), serine/threonine
kinase 11 (STK11), cadherin 1 (CDH1) and PALB2 ] alongside family history
• BRRM is an extensive procedure that should be carefully discussed, taking into
consideration the benefits, complications and psychosocial impact
• A variety of BRRM techniques exist, from total mastectomy (TM) to skin-sparing
mastectomy (SSM) and nipple-sparing mastectomy (NSM), which aim to improve
cosmetic results
° Limited data suggest that NSM provides similar risk reduction and possibly superior
cosmetic outcomes compared with TM or SSM; therefore, NSM is a reasonable
alternative to TM
• Immediate reconstruction is safe and should be offered
• In all affected high-risk PV carriers, contralateral RRM lessens the incidence of
contralateral BC without a proven impact on overall survival
• In women with stage I-III high-risk PV-associated BC (not including TP53 ),
breast-conservation with therapeutic radiation is a safe alternative to RRM
• RRM may be considered on a case-by-case basis in women with ovarian cancer who
have no evidence of recurrence in a prolonged remission
Approach to male carriers of high-risk pathogenic variants
• There is evidence of an increased risk in male BC for nearly all HBOC genes; the most
compelling data is for men harbouring BRCA2 PVs

35
 • Annual mammography or US screening should be considered in male BRCA2 PV carriers
with additional high-risk features such as gynaecomastia or Klinefelter syndrome
° Screening should begin from the age of 50 years or 10 years earlier than the age at
diagnosis of the youngest male family member with BC
• Male BRCA2 PV carriers should be encouraged to be aware of physical changes in the
breast and to seek medical attention accordingly
Screening for additional malignancies
• Screening with annual contrast enhanced MRI and/or endoscopic US from age 50 (or
5-10 years younger than the affected relative) may be considered in BRCA1, BRCA2,
ATM, TP53 or PALB2 carriers with at least one first- or second-degree relative with
exocrine pancreatic cancer
• Annual blood prostate-specific antigen screening should be offered to male BRCA2
carriers from the age of 40 years and may be considered for male ATM carriers from
the age of 40 years

COUNSELLING, RISK-REDUCTION AND SCREENING IN THE PRESENCE OF OTHER

MODERATE-HIGH RISK PATHOGENIC VARIANTS
• Genetic testing for HBOC susceptibility often incorporates screening for PVs in genes
beyond BRCA1 and BRCA2
° The associated cancer risks vary widely between genes, as do the approaches to
screening and risk reduction
° It is important to differentiate “other genes” from BRCA1 and BRCA2 during counselling
• In the presence of CDH1, PTEN or STK11 PVs, intensified breast screening should start
at the age of 30 years or 5 years earlier than the age at diagnosis of the youngest family
member with BC; screening should start from the age of 20 years for TP53 PV carriers
° BRRM may be discussed on a case-by-case basis
• Women with PVs in ATM, BRCA1 associated ring domain 1 (BARD1), CHEK2 (truncating),
RAD51 paralogue C (RAD51C) or RAD51 paralogue D (RAD51D) should undergo
comprehensive, individualised assessment of BC risk to determine their eligibility for
breast MRI
• Validated risk assessment tools, such as CanRisk, may be used to aid individual
risk management

36
REPRODUCTIVE AND ENDOCRINOLOGICAL ISSUES IN INDIVIDUALS WITH HEREDITARY
BREAST AND OVARIAN CANCER SYNDROME
Contraception
• While hormone-based forms of contraception are not contraindicated, unaffected
carriers should be offered non-hormonal forms of contraception when feasible and
should minimise prolonged periods of exposure to exogenous hormones
• In women considering tamoxifen chemoprevention, concurrent use of the oral
contraceptive pill is contraindicated due to the elevated risk of venous thromboembolism
Fertility
• Healthy female carriers should be encouraged to complete childbearing before the
recommended age for risk-reducing bilateral salpingo-oophorectomy (RRBSO); if this
is not feasible, oocyte and embryo cryopreservation can be offered at a young age
• Individuals with highly penetrant cancer susceptibility syndromes should be informed
about prenatal diagnosis or preimplantation genetic testing (PGT), which may be used
to avoid passing on the hereditary PV to future offspring
° The pros and cons of these strategies should be clearly discussed, including potential
pregnancy termination in the case of prenatal diagnosis and the need for in vitro
fertilisation strategies with PGT
° Religious, cultural, ethical and socioeconomic issues, as well as country/centre
availability, are important factors affecting the individual’s choice to access
these technologies
Management of menopausal symptoms
• In unaffected BRCA1/2 carriers, discussing limitations and risks, short-term use
of hormone replacement therapy after RRBSO may be considered to alleviate
menopausal symptoms
• Bone assessment should be considered, tailored to individual risk factors. Preventive/
therapeutic measures should be considered as indicated
• Low-dose intra-vaginal oestrogens may be considered to manage genitourinary
symptoms of menopause

UNIQUE PSYCHOLOGICAL ISSUES FOR INDIVIDUALS WITH HEREDITARY BREAST AND

OVARIAN CANCER SYNDROME
• Observational studies of the psychological impact of HBOC have provided highly
variable results
° Some carriers experience elevated and sustained levels of psychological distress
° Individual risk factors include high levels of anxiety and depression prior to genetic
testing, cancer diagnosis, being unpartnered and a family history of cancer
37
 • The negative effects of BRRM can include distress about loss of sensation and
discomfort with reconstructed breasts, as well as decreased perceived attractiveness
and femininity
• Notable risk factors for decreased body image include poor reconstruction outcomes,
surgical complications and lack of information prior to surgery
• The need for further information and emotional support should be assessed before
disclosure of genetic test results, and individuals should be offered referrals for
psychological counselling and/or further support
• Sexual health concerns should be assessed, and individuals should be offered support
and resources, as needed, to address sexual dysfunction. Individuals should be asked
about sexual health concerns regardless of age, partner status or sexual orientation

PERSONALISED MEDICINE AND FUTURE DIRECTIONS

• Germline genetic testing has led to improvements in screening, risk reduction and
therapies for those with inherited cancer susceptibility; however, there is a need for more
individualised risk assessment to inform the timing and type of risk-reduction strategies,
such as RRM, and for optimal risk management in moderate penetrance genes
• Single nucleotide polymorphisms (SNPs) have been well validated to alter cancer risk,
both in the general population and in those with inherited cancer susceptibility
° A polygenic risk score (PRS) captures the risk associated with SNPs and can be used
in models such as CanRisk
° A PRS may be particularly important in individuals with inherited PVs in ATM or CHEK2
as some of these individuals will have a close to average risk of BC and others will
have a higher risk
° Modification by PRS is likely to become increasingly important as individuals without
a strong family history of cancer undergo genetic testing
• Another emerging field is early detection using liquid biopsies targeting tumour-derived
mutational, epigenetic or transcriptomic features
• Use of PRSs, novel risk-reduction strategies and liquid biopsy assays for early
detection should continue to be performed and assessed in the context of clinical trials

38
 EARLY BREAST CANCER
SCREENING
• Regular (every 2 years) mammography is recommended in average-risk women 50-69
years of age. Regular mammography may also be carried out in women 45-49 and
70-74 years, although there is less evidence of benefit
• Screening in women with a strong family history or known germline BRCA1/2
mutations (gBRCA1/2 m) 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 (https://www.esmo.org/guidelines/
guidelines-by-topic/hereditary-syndromes/risk-reduction-screening-hereditary-breast-
ovarian-cancer-syndromes)

DIAGNOSIS, PATHOLOGY AND MOLECULAR BIOLOGY

• A proposed algorithm for the diagnostic work-up and staging of early breast cancer
(EBC) is shown in the figure on the next page
• Diagnostic work-up is based on clinical examination and imaging, including bilateral
mammography and ultrasound (US) of both breasts and regional lymph nodes (LNs) or
two-dimensional digital mammography in the symptomatic setting
• Digital breast tomosynthesis (with or without synthetic mammography) and contrast-
enhanced mammography can be considered as alternatives, where available and
appropriate
• Magnetic resonance imaging (MRI) is recommended in case of uncertainties following
standard imaging and in special clinical situations (e.g. familial breast cancer
associated with gBRCA1/2 m and other high-risk PVs, lobular cancers, suspicion of
multifocality and/or multicentricity, presence of breast implants)
• 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 symptomatic patients
• Pre-treatment pathological assessment, including a complete histomorphological,
immunohistochemical and molecular assessment, if applicable, is recommended at
the time of diagnosis and should include primary tumour histology and axillary node
histology/cytology (if node involvement is suspected clinically)
• A summary of biomarkers used in the standardised histopathological,
immunohistochemical and molecular pathology assessment in EBC is shown in the table
on pages 41 & 42

39
 DIAGNOSTIC WORK-UP AND STAGING OF EBC

Diagnosis and staging of EBC

Bilateral mammogram and US of

both breasts and regional LNs
MRI for special situations

Core biopsy

Confirmed diagnosis

Assess biomarkers: ER, PgR, HER2, Ki-67

In HR+/HER2– N0-1 (if relevant for therapy decision):
Gene expression assays, endocrine response assessment
Test for gBRCA1/2m (if family history or therapeutic relevance)*

Disease staging and final pathological assessment according to WHO and UICC TNM8,
medical/family history, menopausal status, physical examination
Minimum blood work-up (a full blood count, liver and renal function tests, alkaline
phosphatase and calcium levels) before surgery and systemic (neo)adjuvant therapy
CT scan of the chest, abdominal imaging (US, CT or MRI scan) and a bone scan for patients
with: Clinically positive axillary nodes; large tumours (e.g. 5 cm); aggressive biology; and
clinical signs, symptoms or laboratory values suggesting the presence of metastases
Clip marking of the lesions if neoadjuvant treatment and BCS is planned

*Detailed rationale for gBRCA1/2 m testing is covered in the ESMO CPG for risk reduction and screening of cancer in hereditary
breast-ovarian cancer syndromes (https://www.esmo.org/guidelines/guidelines-by-topic/hereditary-syndromes/risk-reduction-
screening-hereditary-breast-ovarian-cancer-syndromes)
BCS, breast-conserving surgery; CPG, Clinical Practice Guideline; CT, computed tomography; EBC, early breast cancer; ER,
oestrogen receptor; ESMO, European Society for Medical Oncology; gBRCA1/2m; germline BRCA1/2 mutation; HER2, human
epidermal growth factor receptor 2; HR, hormone receptor; LN, lymph node; MRI, magnetic resonance imaging; N, node;
PgR, progesterone receptor; TNM8, tumour–node–metastasis eighth edition; UICC, Union for International Cancer Control; US,
ultrasound; WHO, World Health Organization

40
SUMMARY OF BIOMARKERS USED IN STANDARDISED HISTOPATHOLOGICAL,
IMMUNOHISTOCHEMICAL AND MOLECULAR PATHOLOGY ASSESSMENT IN EBC
COMMENTS, PITFALLS
METHOD BIOMARKER USE
AND OPEN QUESTIONS
Biomarkers currently used in EBC

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

HR-low tumours (ER/PgR

1-9%) are biologically TNBC
and may behave as such
HER2 status should be
IHC panel: ER, PgR,
reported as IHC 0, 1+ or 2+
HER2, Ki-67 Standard IHC work-up as
(either negative or positive by
ISH: For HER2 IHC 2+ a basis for major therapy
ISH) and 3+
Defined guidelines decisions and prognostic
IHC and ISH assessment HER2-low tumours (1+ or 2+
for each marker;
with negative ISH) are relevant
participation in external Definition of intrinsic
for MBC and may become so
quality assurance subtypes
for EBC in the future
programmes
Ki-67 may be evaluated after
a short course of preoperative
ET to indicate endocrine
responsiveness (Ki-67 ≤ 10%)

May be carried out in HR+,

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

Clinically important
information for surgical
management, follow-up
and cancer screening, Testing is relevant for TNBC
NGS Germline PVs/mutations
and has become a patient and HR+, HER2– breast cancer
selection marker for
systemic adjuvant olaparib
therapy in HER2– tumours

41
 COMMENTS, PITFALLS
METHOD BIOMARKER USE
AND OPEN QUESTIONS
Biomarkers currently not mandatory in EBC

Standardised Not relevant for therapy

methodology and decisions in EBC. Relevant
validated antibodies in metastatic TNBC only. For
IHC PD-L1 Reporting of different treatment decisions, testing
scoring systems can be carried out in the
(immune cell staining; primary breast tumour or the
CPS) in parallel most recent metastasis

Mutations in PIK3CA, Biomarkers for

Relevant in metastatic
NGS - tumour ESR1, HER2, BRCA1/2 therapeutic strategies in
disease only
and other genes the metastatic setting

CPS, combined positive score; EBC, early breast cancer; ER, oestrogen receptor; ESR1, oestrogen receptor 1; ET, endocrine
therapy; 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; PD-L1,
programmed death-ligand 1; PgR, progesterone receptor; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic
subunit alpha; PV, pathogenic variant; TIL, tumour-infiltrating lymphocyte; TNBC, triple-negative breast cancer

• Assessment should include histological type, grade and immunohistochemistry

(IHC) evaluation of oestrogen receptor (ER), progesterone receptor (PgR) and human
epidermal growth factor receptor 2 (HER2) biomarkers and a proliferation marker such
as Ki-67. Fluorescence in situ hybridisation testing should be carried out in cases of an
equivocal HER2 IHC score (HER2 2+)
° For histological assessment, a core needle biopsy is preferred to fine-needle
aspiration (FNA) because invasiveness (a prerequisite for starting neoadjuvant
therapy) cannot be demonstrated in FNA samples
• For prognostication and treatment decision making, tumours should be grouped into
biological subtypes, defined by routine histology and IHC results, as luminal A-like,
luminal B-like, HER2-positive and triple-negative
• In cases of hormone receptor (HR)-positive, HER2-negative EBC with uncertainty about
indications for adjuvant chemotherapy (ChT) (after consideration of all clinical and
pathological factors), gene expression assays and endocrine response assessment in
the preoperative setting can be used
• HER2-negative, HR-low (i.e. 1-9% ER and/or PgR expression) tumours are a heterogenous
group, some of which behave biologically similarly to triple-negative breast cancer (TNBC)
• HER2-low status is currently only relevant in the metastatic setting, but HER2 should
be reported as 0, 1+, 2+ or 3+ in EBC as a basis for possible future therapeutic
decisions

42
• Tumour-infiltrating lymphocytes (TILs) may add prognostic and predictive information,
particularly in TNBC and HER2-positive breast cancer, but there are no distinct TIL
thresholds for treatment decisions
• Programmed death-ligand 1 expression levels should not be used to guide
immunotherapy treatment decisions in early TNBC
• Germline testing and subsequent genetic counselling for PVs in BRCA1/2 should be
offered to patients who meet the respective national criteria and to those who are
candidates for adjuvant olaparib therapy

STAGING AND RISK ASSESSMENT

• Disease stage and final pathological and clinical assessment of surgical specimens should
be made according to the World Health Organization (WHO) classification of tumours and
the eighth edition of the Union for International Cancer Control (UICC) tumour–node–
metastasis (TNM) staging system, as shown in the tables below and on the next pages

CLINICAL CLASSIFICATION OF BREAST TUMOURS ACCORDING TO THE UICC TNM

EIGHTH EDITION
PRIMARY TUMOUR (T)

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

Paget disease of the nipple not associated with invasive carcinoma and/or
carcinoma in situ (DCIS and/or LCIS) in the underlying breast parenchyma.
Tis (Paget) 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 dimension*

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

43
 PRIMARY TUMOUR (T)

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

T3 Tumour > 5 cm in greatest dimension

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

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

Ulceration, ipsilateral satellite skin nodules or skin oedema (including peau

T4b
d’orange)

T4c Both 4a and 4b

T4d Inflammatory carcinoma‡

REGIONAL LNs (N)

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)

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

N2 clinically detected§ 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

Metastasis only in clinically detected§ internal mammary LN(s) and in the

N2b
absence of clinically detected ALN metastasis

Metastasis in ipsilateral infraclavicular (level III axillary) LN(s) with or without

level I, II ALN involvement; or in clinically detected§ ipsilateral internal mammary
N3
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)

44
 DISTANT METASTASIS (M)

M0 No distant metastasis

M1 Distant metastasis

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
*Microinvasion 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.
†
Invasion of the dermis alone does not qualify as T4. Chest wall includes ribs, intercostal muscles and serratus anterior muscle
but not pectoral muscle
‡
Inflammatory 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
§
Clinically 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)
ALN, axillary lymph node; c, clinical; DCIS, ductal carcinoma in situ; FNA, fine-needle aspiration; LCIS, lobular carcinoma in situ;
LN, lymph node; M, metastasis; N, node; p, pathological; T, tumour; Tis, carcinoma in situ; TNM, tumour–node–metastasis; UICC,
Union for International Cancer Control
Brierley JD et al, eds. TNM Classification of Malignant Tumours, 8th edition. Oxford: John Wiley & Sons, Inc. 2016. Reprinted with
permission from John Wiley & Sons, Ltd

PATHOLOGICAL CLASSIFICATION OF BREAST TUMOURS ACCORDING TO THE UICC

pTNM EIGHTH EDITION
PRIMARY TUMOUR (pT)

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 categories*

REGIONAL LNs (pN)

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

Regional LNs cannot be assessed (e.g. previously removed, or not removed for
pNX
pathological study)

pN0 No regional LN metastasis†

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

pN1
mammary nodes with metastases detected by SLNB but not clinically detected‡

45
 REGIONAL LNs (pN)

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

Metastasis in 4-9 ipsilateral ALNs, or in clinically detected‡ ipsilateral internal

pN2
mammary LN(s) in the absence of ALN metastasis

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

Metastasis in clinically detected internal mammary LN(s), in the absence of ALN

pN2b
metastasis

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

pN3a
infraclavicular LNs

Metastasis in clinically detected‡ internal ipsilateral mammary LN(s) in the presence

pN3b of positive ALN(s); or metastasis in > 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 (pre-treatment) ‘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

*When 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
†
ITCs 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
‡
Clinically 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 clinical examination
ALN, axillary lymph node; FNA, fine-needle aspiration; H&E, haematoxylin–eosin; IHC, immunohistochemistry; ITC, isolated
tumour cell; LN, lymph node; N, node; p, pathological; SLNB, sentinel lymph node biopsy; SN, sentinel node; T, tumour;

46
TNM, tumour–node–metastasis; UICC, Union for International Cancer Control; yp, post-neoadjuvant pathological
Brierley JD et al, eds. TNM Classification of Malignant Tumours, 8th edition. Oxford: John Wiley & Sons, Inc. 2016. Reprinted with
permission from John Wiley & Sons, Ltd

STAGING OF BREAST TUMOURS ACCORDING TO THE UICC TNM EIGHTH EDITION

STAGE T N M

0 Tis N0 M0

IA T1* N0 M0

Stage IB T0, T1 N1mi M0

T0, T1 N1 M0
Stage IIA
T2 N0 M0

T2 N1 M0
Stage IIB
T3 N0 M0

T0, T1, T2 N2 M0
Stage IIIA
T3 N1, N2 M0

Stage IIIB T4 N0, N1, N2 M0

Stage IIIC Any T N3 M0

Stage IV Any T Any N M1

*T1 includes T1mi

mi, micrometastases; M, metastasis; N, node; T, tumour; Tis, carcinoma in situ; TNM, tumour–node–metastasis; UICC, Union for
International Cancer Control
Brierley JD et al, eds. TNM Classification of Malignant Tumours, 8th edition. Oxford: John Wiley & Sons, Inc. 2016. Reprinted with
permission from John Wiley & Sons, Ltd

• 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
• A computed tomography (CT) scan of the chest, abdominal imaging (US, CT or MRI
scan) and a bone scan can be considered for patients with:
° Clinically positive axillary nodes
° Large tumours (e.g. 5 cm)
° Aggressive biology
° Clinical signs, symptoms or laboratory values suggesting the presence of metastases

47
 • The complete medical and family history must be evaluated, including menopausal
status (if in doubt, serum oestradiol and follicle-stimulating hormone levels should be
measured)
• [18F]2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)-CT
scanning may be used instead of CT and bone scintigraphy, particularly for high-risk
patients and when conventional methods are inconclusive

MANAGEMENT OF EARLY BREAST CANCER

General treatment principles
• A general overview of EBC management is shown in the figure opposite
• Where available, treatment should be carried out in specialised breast units/centres by
a specialised multidisciplinary team that can refer patients to other specialties
• Participation in clinical trials is recommended
• The treatment strategy for each patient should be based on an individual risk–benefit
analysis considering the tumour burden (size and location of the primary tumour,
number of lesions and extent of LN involvement) and biology (pathology, including
biomarkers and gene expression), as well as age, menopausal status, general health
status and patient preferences
• Age should be considered in relation to other factors and should not be the primary
determinant for treatment decisions
• Fertility and fertility preservation should be discussed with younger premenopausal
patients (irrespective of stage of disease) before the initiation of any systemic treatment
Patient communication and shared decision making
• Information on diagnosis and treatment choice should be given repeatedly (both
verbally and in writing) in a comprehensive and easily understandable manner
• The use of reliable, patient-centred websites or similar sources of information is
recommended
• Patients should be actively involved in all treatment decisions and should have equitable
access to the full range of reproductive care options including pregnancy counselling,
contraception and fertility preservation
Locoregional treatment
Surgery
• Breast-conserving surgery (BCS) with postoperative radiotherapy (RT) is the preferred
local treatment option for the majority of patients with EBC
48
 OVERVIEW OF EBC MANAGEMENT

Overview of EBC treatment

All HR+ Premenopausal patients HR+/HER2– HER2+ TNBC

receiving OFS and
postmenopausal patients

cT1 N0 ≥ cT2 or cN+ cT1a or cT1b N0 cT1c-4 or N+

ET Adjuvant Neoadjuvant Primary surgery Neoadjuvant Primary surgery Neoadjuvant

bisphosphonates* therapy† ± RT therapy ± RT therapy

Primary surgery Systemic Surgery ± RT Systemic Surgery ± RT

± RT treatment treatment

Systemic Systemic Systemic

treatment treatment treatment

*Bisphosphonates are approved for treating bone metastases and osteoporosis and not for prevention of relapse
†
If ChT is indicated it may be given in the neoadjuvant setting
c, clinical; ChT, chemotherapy; EBC, early breast cancer; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; N, node; OFS, ovarian function
suppression; T, tumour; TNBC, triple-negative breast cancer; RT, radiotherapy

49
 • If mastectomy is indicated/preferred, breast reconstruction should be offered, except for
primary inflammatory and other high-risk tumours where delays in systemic/radiation
treatment would compromise care
Management of axillary LN involvement
• Recommendations for the management of axillary LN (ALN) involvement in EBC are
shown in the figure opposite
• Sentinel LN biopsy (SLNB) is the standard axillary surgery in all clinical (c)N0 patients
° SLNB is associated with less shoulder stiffness, pain and arm swelling morbidity
than complete ALN dissection (ALND)
• In the absence of prior primary systemic therapy (PST), patients with micrometastatic
spread and those with limited sentinel LN (SLN) involvement (1-2 affected SLNs) in
cN0, following BCS with subsequent whole-breast RT, eventually including the lower
part of axilla and adjuvant systemic treatment, do not need further axillary surgery
• ALND following positive SLNB with < 3 involved SLNs is generally recommended
only in cases of expected high axillary disease burden or impact on further adjuvant
systemic treatment decisions
• Surgical planning following PST should consider the post-PST situation
° In patients with clinically negative and imaging-negative axilla, SLNB after PST is the
method of choice
° Any tumour deposits in SLNs following PST prompt ALND
° The routine use of SLNB is not recommended in patients with initial bulky nodal
involvement or in inflammatory breast cancer
RT
• Whole-breast RT is recommended after BCS
° Boost RT reduces local recurrence rates compared with no boost and is indicated for
patients with unfavourable risk factors for local control
• Hypofractionated schedules are recommended: Moderate (i.e. 15-16 fractions of ≤ 3
Gy per fraction daily for all indications of postoperative RT) and ultra-hypofractionated
[i.e. 26 Gy in five daily fractions for whole breast or chest wall (without reconstruction)
irradiation]
• Accelerated partial breast irradiation is an alternative treatment to whole-breast RT in
patients with invasive and in situ breast cancer at low local recurrence risk
° Any technique allowing full coverage of the entire target volume is suitable
• Post-mastectomy RT (PMRT) is recommended for high-risk EBC, including involved
resection margins, ≥ 4 involved ALNs, T3-T4 tumours and in the presence of
combinations of other risk factors

50
 MANAGEMENT OF ALN INVOLVEMENT IN EBC
Management of ALN involvement in EBC*

Primary surgery indicated† PST indicated†

cN0/iN0‡ cN+/iN+ cN0/pN0 at cN+/pN+ at primary

primary diagnosis diagnosis¶

Biopsy See figures on pages 53, 57

and 59 for neoadjuvant therapy
according to biological subtype

SLNB pNX pN+

ycN0/ypN0 ycN+/ypN+
SLN– SLN+ after neoadjuvant ChT after neoadjuvant ChT

No further ACOSOG-Z0011 AMAROS ACOSOG-Z0011 SLN– or SLN+# or

locoregional criteria met§ criteria met║ criteria not met§ or TAD– TAD+
treatment > 2 positive LNs

RT (basis
RT axilla) RT (axilla) ALND ALND Consider RT if pN+ at ALND (or RT) of
primary diagnosis regional LNs

51
 *Discuss in MDT whether number of LNs is important for systemic therapy allocation
†
See figure on page 49 for an overview of primary surgery and neoadjuvant therapy indications
‡
Imaging (axillary US is preferred but MRI and PET-CT may be used in specific cases where more detailed imaging is required)
§
Refers to ACOSOG-Z0011 trial eligibility criteria
║
Refers to AMAROS trial eligibility criteria. OTOASOR trial criteria can also be considered
¶
Inflammatory breast cancer and patients with N2 or N3 stage disease should receive ALND unless otherwise defined in a
clinical trial
#
If ITCs are detected, consider axillary and locoregional RT as an alternative to ALND if an impact on adjuvant systemic
treatments is not anticipated
ALN, axillary lymph node; ALND, axillary lymph node dissection; c, clinical; ChT, chemotherapy; CT, computed tomography; EBC,
early breast cancer; i, imaging; ITC, isolated tumour cell; LN, lymph node; MDT, multidisciplinary team; MRI, magnetic resonance
imaging; N, node; p, pathological; PET, positron emission tomography; PST, primary systemic therapy; RT, radiotherapy; SLN,
sentinel lymph node; SLNB, sentinel lymph node biopsy; TAD, targeted axillary dissection; US, ultrasound; yc, post-neoadjuvant
clinical; yp, post-neoadjuvant pathological

• PMRT should be considered in patients with intermediate-risk features (e.g.

lymphovascular invasion, age), including those with 1-3 positive ALNs
• Nodal RT is recommended for patients with involved LNs (the extent of target volumes
depends on risk factors including the number of involved LNs, N stage and response
to PST)
• If indicated, PMRT can be administered after immediate breast reconstruction
Systemic treatment
Neo(adjuvant) systemic therapy
• Neoadjuvant therapy should start as soon as diagnosis and staging are completed,
ideally within 2-4 weeks
• Adjuvant systemic therapy should be started without undue delays, ideally within
4-6 weeks
• Whenever adjuvant ChT is indicated, neoadjuvant use of the same regimen can also
be considered
• The use of dose-dense schedules of ChT, with granulocyte colony-stimulating factor
support, should be considered given their documented benefit over non-dose-dense
schedules
HR-positive, HER2-negative EBC
• Recommendations for the management of HR-positive, HER2-negative EBC are shown
in the figure opposite
° The role of endocrine therapy (ET) in HR+ EBC is also illustrated
• An overview of adjuvant therapy for patients with HR-positive, HER2-negative EBC is
provided in the table on page 54
• All luminal-like breast cancers should be treated with ET
• Most luminal A-like tumours do not require ChT, except those with high disease burden

52
SYSTEMIC TREATMENT OF HR-POSITIVE, HER2-NEGATIVE EBC

HR+/HER2– EBC*

Luminal A-like Luminal B-like

Low risk High risk

(Neo)adjuvant ChT
Adjuvant ET Stage III or high-risk stage II†
followed by ET

gBRCA1/2 testing‡

gBRCA1/2-WT or untested gBRCA1/2 m and stage III or high-risk non-pCR§

Abemaciclib for 2 years + ET Olaparib for 1 year + ET

*See figure on page 49 for the role of surgery in HR-positive, HER2-negative EBC
†
Stage N1 with primary tumour > 5 cm, and/or grade 3 and/or Ki-67 ≥ 20%
‡
If gBRCA1/2 testing is appropriate and feasible
§
Patients with HR-positive tumours and non-pCR after neoadjuvant ChT require a CPS+EG score ≥ 3 to receive olaparib
ChT, chemotherapy; CPS+EG, pre-treatment clinical stage and post-treatment pathological stage, oestrogen receptor and tumour
grade; EBC, early breast cancer; ET, endocrine therapy; gBRCA1/2; germline BRCA1/2; HER2, human epidermal growth factor
receptor 2; HR, hormone receptor; m, mutation; N, node; pCR, pathological complete response; WT, wild type

ROLE OF ADJUVANT ET IN HR-POSITIVE EBC

Adjuvant ET in HR+ EBC*

Premenopausal Postmenopausal

Luminal A-like stage I Luminal A-like stage II-III

Luminal B-like stage I-III
Tamoxifen followed by AI
AI
Tamoxifen OFS–tamoxifen AI followed by tamoxifen
OFS–AI Tamoxifen†

*See figure on page 49 for the role of surgery in HR-positive, HER2-negative EBC
†
Tamoxifen can be given for lower-risk tumours or if AIs are not tolerated
AI, aromatase inhibitor; EBC, early breast cancer; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HR,
hormone receptor; OFS, ovarian function suppression

53
54
ADJUVANT THERAPY FOR HR-POSITIVE, HER2-NEGATIVE EBC
TARGETED BISPHOS-
STAGE ET* ChT†
THERAPIES PHONATES‡

Addition
Duration of
of OFS in Olaparib for
TN Type treatment Premenopausal§ Postmenopausal║ Abemaciclib¶
premenopausal gBRCA1/2m#
(years)
women

T1ab Tamoxifen
5 No†† No No No No No
N0 or AI

I Low risk‡‡: May

T1c Tamoxifen May consider for consider especially Low risk‡‡: No
5 No No No
N0 or AI higher risk‡‡ if not receiving OFS High risk‡‡: Yes
High risk‡‡: Yes

Low risk‡‡:
T2-3 Tamoxifen ††
Consider especially Low risk‡‡: No
7-10 Consider No No Yes
N0 or AI if not receiving OFS High risk‡‡: Yes
High risk‡‡: Yes
II
Low risk‡‡:
Low risk‡‡: No
T1-T2 Tamoxifen Consider especially Low risk‡‡: No
7-10 Yes†† Consider Higher risk‡‡: Yes
N1 or AI if not receiving OFS High risk‡‡: Yes
Yes
High risk‡‡: Yes

III Any AI§§ 7-10 Yes†† Yes Yes Yes Yes Yes
*Risk 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
†
For 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
‡
As adjuvant therapy for purposes of preventing distant metastatic recurrence
§
Benefits 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
║
The 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%)
¶
Limited 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 greater and statistically significant OS benefit
#
Adjuvant 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 greater and statistically significant OS benefit
††
Use of AI in premenopausal women requires OFS
‡‡
“Low risk” implies low-risk genomic score (preferred) 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 and/or higher-risk features on traditional pathological analysis, including higher-grade histology, lower ER expression and
higher measures of proliferation
§§
There is no evidence of benefit for OFS beyond 5 years’ duration of therapy
AI, aromatase inhibitor; ChT, chemotherapy; EBC, early breast cancer; ER, oestrogen 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,
node; OFS, ovarian function suppression; OS, overall survival; PgR, progesterone receptor; T, tumour; TN, tumour–node
Table adapted with permission from St Gallen International Consensus Guidelines 2021

• In cases of uncertainty about indications for adjuvant ChT (after consideration of all
clinical and pathological factors), gene expression assays or endocrine response
assessment can be used to guide adjuvant ChT decisions
• Luminal B-like HR-positive, HER2-negative tumours should be treated with ChT
followed by ET. ChT should be considered in cases of high clinical risk (e.g. multinode-
positive, premenopausal node-positive, locally advanced) and 0-3 involved LNs with
high-risk features (e.g. high-risk gene expression assay result)
• Anthracycline, taxane and alkylator-based ChT regimens are standard but non-
anthracycline-based regimens may be appropriate for stage I and II cancers with
limited nodal involvement
• Premenopausal women should receive either tamoxifen alone (luminal A like, stage I),
or in case of a high risk of recurrence, ovarian suppression with either ovarian function
suppression (OFS)–tamoxifen or OFS–aromatase inhibitor (AI)
• Postmenopausal women should receive an AI or tamoxifen followed by an AI
° Tamoxifen can be given for lower-risk tumours or if AIs are not tolerated
• In the revised CPG, this was specified as:
• Bisphosphonates (up to 5 years) are recommended in women without ovarian function
(postmenopausal women or those undergoing OFS), especially if they are at high risk
of relapse or treatment-related bone loss, since they can lower the risk of tumour
recurrence and mitigate the side-effects of osteopenia/osteoporosis seen with AIs

55
 • Abemaciclib for 2 years in addition to ET after completion of locoregional therapy
should be considered in patients with stage III or high-risk stage II EBC
• Extended ET beyond 5 years should be considered in high-risk EBC; 7-8 years’
treatment duration seems sufficient for most patients at high risk
• Following completion of (neo)adjuvant and locoregional therapy, 1 year of adjuvant
olaparib is recommended for patients with gBRCA1/2m and HR-positive, HER2-
negative EBC with multiple positive LNs after primary surgery or residual high-risk EBC
after neoadjuvant ChT
• ET should be given concomitantly with adjuvant olaparib in gBRCA1/2m carriers
• Olaparib and abemaciclib should not be combined due to overlapping toxicities but
may be considered sequentially with olaparib given first
HER2-positive EBC
• Recommendations for the management of HER2-positive EBC are shown in the figure
opposite
• HER2-directed therapy (with initial concurrent ChT) should be given for 12 months,
covering both the neoadjuvant and/or adjuvant phases of treatment. Administration can
be combined, if indicated, with RT and ET. In selected low-risk situations, 6 months of
anti-HER2 therapy may be non-inferior
• Regular cardiac assessments are recommended prior to, during and after HER2-directed
therapy with the option of additional assessments prior to the start of any ChT treatment
• For patients with clinical stage II-III HER2-positive breast cancer (e.g. T > 2 cm or node-
positive), neoadjuvant systemic ChT with anti-HER2 therapy comprising trastuzumab–
pertuzumab (HP) is the preferred option
• For the ChT backbone, a regimen of anthracycline–taxane or taxane–carboplatin is
evidence-based, independent of neoadjuvant or adjuvant use
• Dual blockade with HP (versus trastuzumab alone) combined with ChT achieves higher
pathological complete response (pCR) rates and is recommended for neoadjuvant therapy
• Patients with residual invasive disease (non-pCR after neoadjuvant ChT and anti-HER2
therapy) should receive adjuvant treatment with trastuzumab emtansine for up to 14
cycles
• For patients with stage I (T1a-b N0) HER2-positive EBC, primary surgery may be
carried out followed by adjuvant paclitaxel for 12 weeks plus 1 year of trastuzumab if
the clinical stage is confirmed by pathology
• For patients with pathological stage II or III cancer treated with initial surgery, adjuvant
ChT combined with 1 year of anti-HER2 therapy should be given

56
 MANAGEMENT OF HER2-POSITIVE EBC

HER2+ EBC

cT1 cNO ≥ cT2* or cN+

Surgery and locoregional 6-8 cycles

RT if indicated ChT-HP

pT1 pN0 ≥ pT2 pN0 pN+ Surgery and locoregional

RT if indicated

12 weeks
6-8 cycles pCR Residual invasive disease
paclitaxel– 6-8 cycles
ChT–
18 cycles ChT–HP
trastuzumab
trastuzumab
cN0 at initial cN+ or pN+ at
diagnosis initial diagnosis
Complete
Complete
1 year of
1 year of HP T-DM1 up to 14 cycles
trastuzumab Complete 1 year Complete 1 year
If HR+, of trastuzumab of HP If HR+, adjuvant ET
If HR+,
adjuvant ET
adjuvant ET If HR+, adjuvant ET If HR+, adjuvant ET

*Tumours < 2cm can be considered for neoadjuvant therapy

c, clinical; ChT, chemotherapy; EBC, early breast cancer; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HP, trastuzumab–pertuzumab; HR, hormone receptor; N, node;
p, pathological; pCR, pathological complete response; RT, radiotherapy; T, tumour; T-DM1, trastuzumab emtansine

57
 • In patients with node-positive disease, the addition of pertuzumab to trastuzumab
should be strongly considered in the adjuvant setting irrespective of HR status
• Patients with high-risk HR-positive tumours may be considered for extended treatment
with neratinib (concurrent with ET) for 1 year after completion of 1 year of trastuzumab
TNBC
• Recommendations for the management of early TNBC is shown in the figure opposite
• TNBC tumours should be treated with ChT with or without an immune checkpoint
inhibitor (ICI) (pembrolizumab), except for some node-negative special histological
subtypes such as secretory or adenoid cystic carcinomas or very low clinical risk
[pathological (p)T1a pN0] tumours
• ChT should be administered for 12-24 weeks (four to eight cycles) depending on the
stage of the disease, type of selected regimen and regardless of whether an ICI is added
• For cT1c-4 N0, or any N-positive TNBC, neoadjuvant treatment is preferred
• cT2-4 N0 or any N-positive (stage II-III) TNBC should be treated with neoadjuvant ChT
plus pembrolizumab unless there are risk factors for excessive ICI-associated immune
toxicity
• Pembrolizumab should be administered every 3 weeks throughout the neoadjuvant
phase and for nine 3-week cycles during the adjuvant phase, regardless of pCR status
• Patients receiving pembrolizumab should be monitored very closely for the risk of
immune-related adverse events throughout treatment and following the ESMO CPG for
the management of toxicities from immunotherapy (https://www.esmo.org/guidelines/
guidelines-by-topic/supportive-and-palliative-care/toxicities-from-immunotherapy)
• An ICI should not be given solely as adjuvant therapy without prior neoadjuvant ICI
treatment
• In patients with gBRCA1/2m and high-risk TNBC (non-pCR or pathological stage II-III),
1 year of adjuvant olaparib should be administered
° The combination of ICIs and olaparib may be considered on an individual basis
• Patients with residual disease who did not receive ICIs should be offered adjuvant
capecitabine for six to eight cycles
° The combination of olaparib and capecitabine in patients with gBRCAm should not
be used
° The combination of ICI and capecitabine may be considered on an individual basis
Special situations
• Treatment of elderly patients should be adapted to biological (not chronological) age,
with consideration of less aggressive regimens in frail patients. In patients suitable for
standard ChT, a standard multidrug regimen should be used
58
 MANAGEMENT OF EARLY TNBC

gBRCA1/2 testing* Early TNBC†

cT1a or cT1b N0 cT1c-T4 or N+

Surgery and locoregional RT if indicated < cT2 N0 ≥ cT2 or N+

pT1a pN0 pT1b pNO > pT1b any pN 6-8 cycles: Taxane– 6-8 cycles: Taxane–
(carbo)platin–AC/EC‡,§ carboplatin followed by
AC/EC§ with pembrolizumab
Consider no 6-8 cycles 6-8 cycles
adjuvant systemic ChT systemic ChT
systemic Surgery and locoregional
therapy RT if indicated

pCR Residual disease

gBRCA1/2 m gBRCA1/2-WT gBRCA1/2m

Olaparib for 9 cycles 9 cycles Capecitabine for Olaparib for

1 year║ pembrolizumab¶ pembrolizumab¶ 6-8 cycles# 1 year║

59
 *See the ESMO CPG for risk reduction and screening of cancer in hereditary breast-ovarian cancer syndromes (https://www.esmo.
org/guidelines/guidelines-by-topic/hereditary-syndromes/risk-reduction-screening-hereditary-breast-ovarian-cancer-syndromes)
†
HER2-negative, HR-low tumours are a heterogenous group, some of which behave biologically similarly to TNBC; therapeutic
strategies should therefore be adjusted to this specific situation since this might lead to a higher response to ChT and reduced
efficacy of ET compared with classical HR-positive breast cancer
‡
These evidence-based regimens without ICIs are sequential: Anthracycline-based therapy followed by a taxane or taxane–
(carbo)platin or vice versa
§
The use of dose-dense schedules of ChT, with G-CSF support, should be considered given their documented benefit over
non-dose-dense schedules
║
Olaparib is indicated as adjuvant therapy for patients with gBRCA1/2m tumours and non-pCR or ≥ pT2 or ≥ pN1 if treated with
initial surgery
¶
Only if pembrolizumab was given preoperatively
#
Only for ICI-naive patients.
AC, doxorubicin–cyclophosphamide; c, clinical; ChT, chemotherapy; CPG, Clinical Practice Guideline; EC, epirubicin–
cyclophosphamide; ESMO, European Society for Medical Oncology; ET, endocrine therapy; gBRCA1/2, germline BRCA1/2; G-CSF,
granulocyte colony-stimulating factor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; ICI, immune
checkpoint inhibitor; m, mutation; N, node; p, pathological; pCR, pathological complete response; RT, radiotherapy; T, tumour;
TNBC, triple-negative breast cancer; WT, wild type

• A geriatric assessment should be carried out before making treatment decisions

• Tamoxifen is the standard adjuvant ET for male patients with breast cancer
• As with premenopausal women with breast cancer, a gonadotropin-releasing hormone
agonist (GnRHa) may be added in higher-risk male patients with breast cancer,
and a combination of AI–GnRHa should be considered in cases where tamoxifen is
contraindicated
• An AI must be administered with a GnRHa when used as adjuvant ET in male patients
with breast cancer
• In male patients with breast cancer, ChT, ET, anti-HER2, ICI, cyclin-dependent kinase
4/6 inhibitor and poly (ADP-ribose) polymerase inhibitor therapy indications and
regimens should follow the same recommendations as those for breast cancer in
female patients
• Ductal carcinoma in situ (DCIS) should be preferentially treated with BCS and
whole-breast RT or, in cases of extensive or multicentric DCIS, mastectomy
• Both tamoxifen and AIs may be used after local breast-conserving therapy (BCT) for
DCIS to prevent local recurrence and to decrease the risk of developing a second
primary breast cancer
• Following mastectomy for DCIS, tamoxifen or AIs might be considered to decrease the
risk of contralateral breast cancer in patients with a high risk of new breast tumours

60
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP
General follow-up considerations
• The aims of follow-up are:
° To detect local and/or regional recurrences or contralateral breast cancers that are
potentially curable
° To evaluate and treat therapy-related side-effects and complications
° To promote adherence to adjuvant systemic treatment
° To provide support to enable a return to normal life after breast cancer
° To detect second primary cancers
• Regular follow-up visits are recommended every 3 months in the first 3 years post-
treatment (every 6 months for low-risk EBC), every 6 months from years 4-5 and
annually thereafter. The interval of visits can be adapted to the risk of relapse and
patient needs
• Annual bilateral (after BCT) or contralateral mammography (after mastectomy) is
recommended plus US and breast MRI, when needed
• Breast cancer survivors should participate in national screening programmes for other
cancers
• In asymptomatic patients, laboratory tests (e.g. blood counts, routine chemistry,
tumour marker assessment) or other imaging are not recommended
• Symptom-directed investigations should be considered as indicated
• Regular bone density evaluation is recommended for patients on AIs or undergoing
OFS
• In asymptomatic patients with normal cardiac function who have received potentially
cardiotoxic treatment, cardiac follow-up should be carried out as clinically indicated
• For patients on tamoxifen, an annual gynaecological examination is recommended;
however, routine transvaginal US is not recommended
Long-term implications
• The number of survivors following treatment for an initial presentation of EBC
is increasing and so the long-term effects of treatment must be recognised and
monitored
• Notable potential long-term side-effects of adjuvant treatment for breast cancer are
summarised in the table on the next page

61
 NOTABLE POTENTIAL LONG-TERM SIDE-EFFECTS RELATED TO ADJUVANT BREAST
CANCER TREATMENT*

CATEGORY SIDE-EFFECT

Neurocognitive dysfunction
Nervous system
Neuropathy

Arthralgia
Musculoskeletal and
connective tissue
Myalgia

Chronic fatigue

Emotional reactions to the diagnosis and treatment

Psychosocial
Exhaustion

Sleep disturbances

Infertility

Ovarian dysfunction
Reproductive
and sexual
Premature menopause

Sexual complaints

Hot flushes
Vascular disorders
Lymphoedema

Bone density loss

Cardiac dysfunction

Chronic hair loss and thinning

Others
Dry mucosa (oral, genital, conjunctiva)

Nutritional (e.g. weight gain)

Secondary haematological malignancies (or other secondary cancers)

*Occurrences are rare and patients generally recover; quality of life in general recovers by end of therapy to that of before
treatment start

62
Reproductive and sexual health considerations
• Premature menopause, infertility and potential sexual dysfunction should be discussed
and addressed with each patient, when appropriate, before the start of adjuvant therapy
• Premenopausal women considering pregnancy should be informed that available
evidence suggests that pregnancy may be safe after breast cancer treatment
• For women desirous of pregnancy, temporary interruption of adjuvant ET after 18-30
months of ET, allowing a wash-out period of 3 months, and attempting to get pregnant
during a period of up to 2 years, followed by resumption of ET, does not appear to impact
short-term breast cancer outcomes in lower-risk HR-positive, HER2-negative EBC
Psychosocial considerations
• Patients should be encouraged to adopt a healthy lifestyle, exercise regularly, avoid
being overweight and minimise alcohol intake
• Long-term survivorship considerations, including psychological needs and issues
related to work, family and sexuality, should be addressed

63
 GLOSSARY

AI, aromatase inhibitor

ALN, axillary lymph node
ALND, axillary lymph node dissection
ATM, ATM serine/threonine kinase
BARD1, BRCA1 associated ring domain 1
BC, breast cancer
BCS, breast-conserving surgery
BCT, breast-conserving therapy
BM, brain metastasis
BMA, bone-modifying agent
BRRM, bilateral risk-reducing mastectomy
c, clinical
CDH1, cadherin 1
CDK4/6, cyclin-dependent kinase 4 and 6
CHEK2, checkpoint kinase 2
ChT, chemotherapy
CNS, central nervous system
CPG, Clinical Practice Guideline
CPS, combined positive score
CT, computed tomography
DCIS, ductal carcinoma in situ
DFI, disease-free interval
EANO, European Association of Neuro-Oncology
EBC, early breast cancer
EMA, European Medicines Agency
ER, oestrogen receptor
ESMO, European Society for Medical Oncology
ESR1, oestrogen receptor 1
ET, endocrine therapy
FDA, Food and Drug Administration
FDG, [18F]2-fluoro-2-deoxy-D-glucose
FNA, fine-needle aspiration
gBRCA1/2m, germline BRCA1/2 mutation
GnRHa, gonadotropin-releasing hormone agonist
HBOC, hereditary breast and ovarian cancer syndrome
HER2, human epidermal growth factor receptor 2
HP, trastuzumab–pertuzumab
HR, hormone receptor
ICI, immune checkpoint inhibitor
IHC, immunohistochemistry
LM, leptomeningeal metastasis
LN, lymph node

64
LRT, locoregional treatment
MBC, metastatic breast cancer
MRI, magnetic resonance imaging
MSCC, metastatic spinal cord compression
MSI, microsatellite instability
mTNBC, metastatic triple-negative breast cancer
NSM, nipple-sparing mastectomy
NTRK, neurotrophic tyrosine receptor kinase
OFS, ovarian function suppression
OMD, oligometastatic disease
OS, overall survival
p, pathological
PALB2, partner and localiser of BRCA2
PARP, poly (ADP-ribose) polymerase
pCR, pathological complete response
PD, progressive disease
PD-L1, programmed death-ligand 1
PET, positron emission tomography
PFS, progression-free survival
PgR, progesterone receptor
PGT, preimplantation genetic testing
PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
PMRT, post-mastectomy radiotherapy
PRO, patient-reported outcome
PRS, polygenic risk score
PST, primary systemic therapy
PTEN, phosphatase and tensin homologue
PV, pathogenic variant
QoL, quality of life
RAD51C, RAD51 paralogue C
RAD51D, RAD51 paralogue D
RRBSO, risk-reducing bilateral salpingo-oophorectomy
RRM, risk-reducing mastectomy
RRMed, risk-reducing medication
RT, radiotherapy
SLN, sentinel lymph node
SLNB, sentinel lymph node biopsy
SNP, single nucleotide polymorphism
SRE, skeletal-related event
SRS, stereotactic radiosurgery
SSM, skin-sparing mastectomy
STK11, serine/threonine kinase 11

65
 GLOSSARY (CONT’D)

T-DM1, ado-trastuzumab emtansine

TIL, tumour-infiltrating lymphocyte
TKI, tyrosine kinase inhibitor
TM, total mastectomy
TNBC, triple-negative breast cancer
TNM, tumour–node–metastasis
TP53, tumour suppressor protein p53
UICC, Union for International Cancer Control
US, ultrasound
WBRT, whole brain radiotherapy
WHO, World Health Organization

66
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Access the full ESMO Clinical Practice Guidelines

© 2024 European Society for Medical Oncology

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Clinical practice recommended in these guidelines may be different from the indications approved by the EMA. Please visit the EMA website
to review approved indications.

71
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