GUIDELINES WORKING GROUP

Chair: Andrs Cervantes; Co-Chair: George Pentheroudakis; Editorial Board: Enriqueta Felip, Nicholas Pavlidis,
Rolf A Stahel; Subject Editors: Dirk Arnold, Christian Buske, Paolo G Casali, Fatima Cardoso, Nathan Cherny,
Jrn Herrstedt, Alan Horwich, Ulrich Keilholz, Marco Ladetto, Lisa Licitra, Solange Peters, Philippe Rougier,
Cristiana Sessa; Deputy Subject Editors: Nicoletta Colombo, Elzbieta Senkus-Konefka; Staff: Keith H McGregor,
Claire Bramley, Jennifer Lamarre, Svetlana Jezdic.

ESMO CLINICAL PRACTICE GUIDELINES

Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and
follow-up
Senkus E, Kyriakides S, Penault-Llorca F, Poortmans P, Thompson A, Zackrisson S and Cardoso F, on behalf of
the ESMO Guidelines Working Group
Ann Oncol 2013;24(Suppl 6):vi723
http://annonc.oxfordjournals.org/content/24/suppl_6/vi7.full.pdf+html
Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis,
treatment and follow-up
Cardoso F, Harbeck N, Fallowfield L, Kyriakides S and Senkus E, on behalf of the ESMO Guidelines
Working Group
Ann Oncol 2012;23(Suppl 7):vii119
http://annonc.oxfordjournals.org/content//23/suppl_7/vii11.full.pdf+html
BRCA in breast cancer: ESMO Clinical Practice Guidelines
Balmaa J, Dez O, Rubio IT, and Cardoso F, on behalf of the ESMO Guidelines Working Group
Ann Oncol 2011;22(Suppl 6):vi314
http://annonc.oxfordjournals.org/content/22/suppl_6/vi31.full.pdf+html

ESO-ESMO CONSENSUS GUIDELINES

ESO-ESMO 2nd International Consensus Guidelines for advanced breast cancer (ABC2)
Cardoso F, Costa A, Norton L, Senkus E , Aapro M, Andr F, Barrios CH, Bergh J, Biganzoli L, Blackwell KL,
Cardoso MJ, Cufer T, El Saghir N, Fallowfield L, Fenech D, Francis P, Gelmon K, Giordano SH, Gligorov J,
Goldhirsch A, Harbeck N, Houssami N, Hudis C, Kaufman B, Krop I, Kyriakides S, Lin UN, Mayer M, Merjaver
SD, Nordstrm EB, Pagani O, Partridge A, Penault-Llorca F, Piccart MJ, Rugo H, Sledge G, Thomssen C,
vant Veer L, Vorobiof D, Vrieling C, West N, Xu B and Winer E
Important note: These Guidelines were developed by ESO and ESMO and are published simultaneously
in The Breast (The Breast 2014, http://dx.doi.org/10.1016/j.breast.
2014.08.009) and Annals of Oncology (Ann Oncol 2014;25:http://dx.doi.org/10.1093/annonc/mdu385)
and both must be cited.

Distributed with support from Celgene

Celgene has not influenced the content
of this publication
2

ESMO POCKET GUIDELINES PROVIDE YOU WITH A CONCISE SUMMARY OF THE

FUNDAMENTAL RECOMMENDATIONS MADE IN THE PARENT GUIDELINES IN AN
EASILY ACCESSIBLE FORMAT.
This quick reference booklet provides you with the most important content of the
full ESMO Clinical Practice Guidelines (CPG) on the management of breast cancer
(primary breast cancer and BRCA in breast cancer) and the ESO-ESMO Consensus
Guidelines on Advanced Breast Cancer. Key content includes diagnostic criteria,
staging of disease, treatment plans and follow-up. The ESMO CPG and ESO-ESMO
Consensus Guidelines on breast cancer are intended to provide you with a set of
recommendations for the best standards of care for breast cancer, using evidencebased medicine. Implementation of ESMO CPG and ESO-ESMO Consensus
Guidelines 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 or http://oncologypro.esmo.org to view the
full ESMO CPG.

628
PRIMARY BREAST CANCER
SCREENING..............................................................................................................6
DIAGNOSIS AND STAGING.......................................................................................6
TREATMENT...........................................................................................................14
Surgery...................................................................................................................14
Radiotherapy: Invasive carcinoma..........................................................................16
Radiotherapy: Non-invasive carcinoma...................................................................17
Adjuvant systemic therapy......................................................................................17
Endocrine therapy (ET)...........................................................................................18
Chemotherapy.........................................................................................................19
Human epidermal growth factor receptor 2 (HER2)-directed therapy.....................19
Adjuvant systemic therapy for ductal carcinoma in situ (DCIS)..............................20
Neoadjuvant systemic therapy................................................................................20
PERSONALISED MEDICINE....................................................................................20
FOLLOW-UP............................................................................................................21
SUMMARY RECOMMENDATIONS FOR PRIMARY BREAST CANCER................ 23
2943
ADVANCED BREAST CANCER (ABC)
GENERAL GUIDELINES...........................................................................................29
IMPORTANT ABC-RELATED DEFINITIONS..............................................................30
LOCALLY ADVANCED INOPERABLE, NON-INFLAMMATORY, BREAST CANCER.....30
LOCALLY ADVANCED INOPERABLE, INFLAMMATORY, BREAST CANCER.............32
SPECIFIC ABC POPULATIONS................................................................................32
SPECIFIC SITES OF METASTASES..........................................................................33
UPDATE ON ER POSITIVE/HER-2 NEGATIVE ABC..................................................34
UPDATE ON HER-2-POSITIVE ABC.........................................................................35
UPDATE ON HER-2-NEGATIVE ABC........................................................................36
UPDATE ON SURGERY OF THE PRIMARY TUMOUR
IN STAGE IV AT DIAGNOSIS...................................................................................36
ABC1 STATEMENTS................................................................................................37
LEVELS OF EVIDENCE GRADING SYSTEM.............................................................42

4447
BRCA IN BREAST CANCER
REFERRAL FOR BRCA TESTING.............................................................................44
MUTATION DETECTION..........................................................................................44
RISK REDUCTION: NON-SURGICAL PREVENTATIVE OPTIONS..............................44
Surveillance............................................................................................................44
Chemoprevention....................................................................................................44
RISK MODIFIERS....................................................................................................45
RISK REDUCTION: PROPHYLACTIC SURGICAL OPTIONS.....................................45
Prophylactic bilateral mastectomy (PBM)...............................................................45
Prophylactic bilateral salpingo-oophorectomy (PBSO)...........................................45
TREATMENT...........................................................................................................46
Surgery...................................................................................................................46
Systemic treatment.................................................................................................46
SUMMARY RECOMMENDATIONS FOR BRCA IN BREAST CANCER................. 47
4849
GLOSSARY

SCREENING

Biannual mammography screening has been shown to have the greatest effect
on breast cancer mortality reduction among women aged 5069 years and is
recommended by the European Union; the benefit of screening women aged
4049 years is currently disputed

Annual screening with magnetic resonance imaging (MRI) of the breast in

combination with mammography is recommended for women with familial breast

cancer with or without proven BRCA mutations

DIAGNOSIS AND STAGING

Diagnosis and treatment should be performed at specialised breast units that

care for a high volume of breast cancer patients

Care should be provided by a multidisciplinary team (MDT) including at least a

surgeon, radiation oncologist, medical oncologist, radiologist and pathologist

all specialised in breast cancer

Diagnostic assessments include:








Medical history, including family cancer history and menopausal status

Physical examination: Including bimanual palpation of the breasts and
locoregional lymph nodes and assessment for distant metastases
Performance status (PS)
Radiological examination: Including bilateral mammography and ultrasound
of the breast and regional lymph nodes
MRI is not routine; may be considered in certain cases (e.g. familial breast
cancer associated with BRCA mutations and cases where conventional
imaging results are inconclusive)
Pathological examination according to the World Health Organization (WHO)
classification (4th edition) and the American Joint Committee for Cancer
(AJCC)/Union for International Cancer Control (UICC) tumour node metastasis
(TNM) staging classification system (7th edition)
Core needle biopsy before any type of treatment, obtained preferably using
ultrasound or stereotactic guidance, or using manual guidance, providing
information on:
-- Histological type and grade
-- Oestrogen receptor (ER), progesterone receptor (PgR) and human
epidermal growth factor receptor 2 (HER2) status

-- Proliferation markers (e.g. Ki67)

For the purpose of prognostication and treatment decision-making, tumours

are grouped into surrogate intrinsic subtypes defined by routine histology

and immunohistochemistry (IHC) data (see table below)
If neoadjuvant systemic therapy is not planned, biological markers can be
assessed using the definitive surgical specimen
If core needle biopsy is not possible, carcinoma should at least be confirmed
by fine needle aspiration (FNA)
If pre-operative systemic therapy is planned, a core needle biopsy is
mandatory to ensure a diagnosis of invasive disease and assess biomarkers
Ultrasound-guided FNA or core biopsy of suspicious lymph nodes should
be performed
Laboratory assessments including full blood count, liver and renal function
tests, alkaline phosphatase and calcium should be carried out
Additional investigations, such as chest computed tomography (CT), abdominal
ultrasound or CT and bone scintigraphy, should be considered for patients
with clinically-positive axillary nodes, large tumours or signs, symptoms or
laboratory values suggesting the presence of metastases
Fluorodeoxyglucose positron emission tomography (FDG-PET)/CT may be
useful for detection of metastatic disease when conventional methods are
inconclusive, but is not recommended for staging local/regional disease





INTRINSIC SUBTYPES OF BREAST CANCER (ST GALLEN CONSENSUS

CONFERENCE, 2013)
CLINICOPATHOLOGIC

INTRINSIC SUBTYPE

SURROGATE DEFINITION

Luminal A-like
ER-positive
Luminal A
HER2-negative
Ki67 low*
PgR high*

Luminal B

NOTES
*Suggested values are 20% for
both PgR and Ki67, but laboratory
specific cut-off points can be used
to distinguish between low and high
values for Ki67 and PgR

Luminal B-like (HER2-negative)

ER-positive
HER2-negative
and either
 Ki67 high or
 PgR low

INTRINSIC SUBTYPE

CLINICOPATHOLOGIC
NOTES
SURROGATE DEFINITION
Luminal B-like (HER2-positive)
ER-positive
HER2-positive
any Ki67
any PgR

HER2 overexpression

Basal-like

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

Triple-negative (ductal)
ER and PgR absent
HER2-negative

~80% overlap between triple-negative

and intrinsic basal-like subtypes, but
triple-negative also includes some
special histological types such as
(typical) medullary and adenoid cystic
carcinoma with low risks of distant
recurrence

Post-operative pathological assessment of the surgical specimen should be

made according to the TNM system and include: Number, location and maximum
diameter of the tumours removed; histological type and grade of the tumour;
evaluation of the resection margins, including the location and minimum distance
of the margin, vascular and lymphovascular invasion and biomarker analysis
(evaluation of ER/PgR, HER2 receptor and proliferation markers expression);
number of positive lymph nodes and extent of metastases in the lymph nodes
(isolated tumour cells, micrometastases [0.22 mm], macrometastases)

The most important prognostic factors in early breast cancer are ER/PgR and

HER2 expression, proliferation markers, number of involved regional lymph

nodes, tumour histology, size, grade and presence of peritumoural vascular
invasion (PVI); additionally, in breast conserving therapy (BCT) patients, the
ipsilateral breast recurrence risk is related to the status of surgical margins and
presence of extensive intraductal component

Scoring systems integrating clinical parameters provide a relatively accurate

estimation of the probability of recurrence and death from breast cancer (e.g.
Nottingham Prognostic Index [NPI], Adjuvant! Online [www.adjuvantonline.com]
or PREDICT score) and can be used to assist with treatment decisions

Gene expression profiles (MammaPrint, Oncotype DX) may provide additional

prognostic and/or predictive information to complement pathological assessment

and to predict response to adjuvant chemotherapy, particularly in women with

ER-positive early breast cancer
AJCC/UICC TNM STAGING CLASSIFICATION SYSTEM (7TH EDITION) FOR
BREAST CANCER
PRIMARY TUMOUR (T)A,B,C,D
PRIMARY TUMOUR (T)a,b,c,d

TX

T0

Tis


Tis (DCIS)


Tis (LCIS)



Tis (Pagets)




T1

Primary tumour cannot be assessed

No evidence of primary tumour
Carcinoma in situ
Ductal carcinoma in situ
Lobular carcinoma in situ
Pagets disease (Paget disease) of the nipple NOT associated with invasive carcinoma
and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast parenchyma.
Carcinomas in the breast parenchyma associated with Pagets disease are categorised
based on the size and characteristics of the parenchymal disease, although the
presence of Pagets disease should still be noted
Tumour 20 mm in greatest dimension

T1mi

Tumour 1 mm in greatest dimension

T1a

Tumour >1 mm but 5 mm in greatest dimension

T1b

Tumour >5 mm but 10 mm in greatest dimension

T1c

Tumour >10 mm but 20 mm in greatest dimension

T2

Tumour >20 mm but 50 mm in greatest dimension

T3

Tumour >50 mm in greatest dimension

T4

Tumour of any size with direct extension to the chest wall and/or to the skin
(ulceration or skin nodules)e
T4a

Extension to the chest wall, not including only pectoralis muscle adherence/invasion

T4b

Ulceration and/or ipsilateral satellite nodules and/or oedema (including peau

dorange) of the skin, which do not meet the criteria for inflammatory carcinoma

T4c

Both T4a and T4b

T4d

Inflammatory carcinomaf


REGIONAL LYMPH NODES (N)
Clinical (cN)g,h,i,j,k

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

N0
No regional lymph node metastases

Metastases to movable ipsilateral level I, II axillary lymph node(s)
N1

Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or
N2
matted; or in clinically detectedk ipsilateral internal mammary nodes in the absence

of clinically evident axillary lymph node metastases


Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another
N2a

(matted) or to other structures


Metastases only in clinically detectedk ipsilateral internal mammary nodes and in
N2b

the absence of clinically evident level I, II axillary lymph node metastases


Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with

or without level I, II axillary lymph node involvement; or in clinically detectedk
N3
ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary

lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s)

with or without axillary or internal mammary lymph node involvement

N3a
Metastases in ipsilateral infraclavicular lymph node(s)

N3b

Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph

node(s)

N3c

Metastases in ipsilateral supraclavicular lymph node(s)

Pathological (pN)

h,i,j,k

10

pNX

Regional lymph nodes cannot be assessed (e.g. previously removed, or not

removed for pathological study)

pN0

No regional lymph node metastasis identified histologically

pN0(i)

No regional lymph node metastases histologically, negative IHC

pN0(i+)

Malignant cells in regional lymph node(s) no greater than 0.2 mm (detected by

haematoxylin and eosin [H&E] staining or IHC including isolated tumour cell
clusters (ITCs)

pN0(mol)

No regional lymph node metastases histologically, negative molecular findings

(RT-PCR)l

pN0(mol+)

Positive molecular findings (RT-PCR)l, but no regional lymph node metastases

detected by histology or IHC

pN1

Micrometastases; or metastases in 13 axillary lymph nodes; and/or in internal

mammary nodes with metastases detected by SLNB but not clinically detectedm
pN1mi

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

pN1a

Metastases in 13 axillary lymph nodes, at least one metastasis >2.0 mm

pN1b

Metastases in internal mammary nodes with micrometastases or macrometastases

detected by SLNB but not clinically detectedm

pN1c

Metastases in 13 axillary lymph nodes and in internal mammary lymph nodes

with micrometastases or macrometastases detected by SLNB but not clinically
detectedm
Metastases in 49 axillary lymph nodes; or in clinically detectedk internal
mammary lymph nodes in the absence of axillary lymph node metastases

pN2
pN2a

Metastases in 49 axillary lymph nodes (at least one tumour deposit >2.0 mm)

pN2b

Metastases in clinically detectedk internal mammary lymph nodes in the absence of

axillary lymph node metastases
Metastases in 10 axillary lymph nodes; or in infraclavicular (level III axillary)
lymph nodes; or in clinically detectedk ipsilateral internal mammary lymph nodes
in the presence of one or more positive level I, II axillary lymph nodes; or in
more than three axillary lymph nodes and in internal mammary lymph nodes
with micrometastases or macrometastases detected by SLNB but not clinically
detected;m or in ipsilateral supraclavicular lymph nodes

pN3

pN3a

Metastases in 10 axillary lymph nodes (at least one tumour deposit >2.0 mm);
or metastases to the infraclavicular (level III axillary lymph) nodes

pN3b

Metastases in clinically detectedk ipsilateral internal mammary lymph nodes in

the presence of one or more positive axillary lymph nodes; or in more than three
axillary lymph nodes and in internal mammary lymph nodes with micrometastases
or macrometastases detected by SLNB but not clinically detectedm

pN3c

Metastases in ipsilateral supraclavicular lymph nodes

11

Distant metastasis (M)

M0

No clinical or radiographic evidence of distant metastases

cM0(i+)

No clinical or radiographic evidence of distant metastases, but deposits of

molecularly or microscopically-detected tumour cells in circulating blood, bone
marrow or other non-regional nodal tissue that are no larger than 0.2 mm in a
patient without symptoms or signs of metastases

M1

Distant detectable metastases as determined by classic clinical and radiographic

means and/or histologically proven >0.2 mm

DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma in situ

Post-treatment ypT: The use of neoadjuvant therapy does not change the clinical (pre-treatment) stage. Clinical (pre-treatment) T will be
defined by clinical and radiographic findings, while y pathological (post-treatment) T will be determined by pathological size and extension.
The ypT will be measured as the largest single focus of invasive tumour, with the modifier m indicating multiple foci.
The measurement of the largest tumour focus should not include areas of fibrosis within the tumour bed
b
The T classification of the primary tumour is the same regardless of whether it is based on clinical or pathological criteria, or both.
Designation should be made with the subscript c or p modifier to indicate whether the T classification was determined by clinical (physical
examination or radiological) or pathological measurements, respectively. In general, pathological determination should take precedence over
clinical determination of T size
c
Size should be measured to the nearest millimetre
d
Multiple simultaneous ipsilateral primary carcinomas are defined as infiltrating carcinomas in the same breast, which are grossly or
macroscopically distinct and measurable. T stage is based only on the largest tumour. The presence and sizes of the smaller tumour(s) should
be recorded using the (m) modifier
e
Invasion of the dermis alone does not qualify as T4; dimpling of the skin, nipple retraction or any other skin change except those described
under T4b and T4d may occur in T1, T2 or T3 without changing the classification. The chest wall includes ribs, intercostal muscles and
serratus anterior muscle, but not the pectoralis muscles
f
Inflammatory carcinoma is a clinicalpathological entity characterised by diffuse erythema and oedema (peau dorange) involving a third or
more of the skin of the breast. These skin changes are due to lymphoedema caused by tumour emboli within dermal lymphatics. Although
dermal lymphatic involvement supports the diagnosis of inflammatory breast cancer, it is neither necessary nor sufficient, in the absence of
classical clinical findings, for the diagnosis of inflammatory breast cancer
g
Classification is based on axillary lymph node dissection (ALND) with or without sentinel lymph node biopsy (SLNB). Classification based
solely on SLNB without subsequent axillary lymph node dissection is designated (sn) for sentinel node, e.g. pN0(sn)
h
Isolated tumour cell clusters (ITCs) are defined as small clusters of cells not greater than 0.2 mm, single tumour cells or a cluster of <200
cells in a single histological cross-section. ITCs may be detected by routine histology or by IHC methods. Nodes containing only ITCs are
excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated
i
Post-treatment yp N should be evaluated as for pre-treatment N. The modifier sn is used if a sentinel node evaluation was performed.
If no subscript is attached, it is assumed that the axillary nodal evaluation was by axillary node dissection
j
ypN categories are the same as those for pN
k
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. Confirmation of clinically detected metastatic disease by FNA without excision biopsy is designated with an (f) suffix, e.g.
cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a clinical N,
e.g. cN1. Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine needle
aspiration, core biopsy or sentinel lymph node biopsy. Pathological classification (pN) is used for excision or SLNB only in conjunction
with a pathological T assignment
l
RT-PCR, reverse transcription polymerase chain reaction
m
Not clinically detected is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination
Edge SB, Byrd DR, Compton CC (eds). AJCC Cancer Staging Handbook, 7th ed. New York, NY.: Springer, 2010. Used with the permission
of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging
Handbook, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springer.com
a

12

AJCC/UICC TNM STAGE GROUPING SYSTEM (7TH EDITION) FOR BREAST

CANCER
STAGE

Tis

N0

M0*

IA

T1

N0

M0

T0

N1mi

M0

T1

N1mi

M0

T0

N1

M0

T1

N1

M0

T2

N0

M0

T2

N1

M0

T3

N0

M0

T0

N2

M0

T1

N2

M0

T2

N2

M0

T3

N1

M0

T3

N2

M0

T4

N0

M0

T4

N1

M0

T4

N2

M0

IIIC

Any T

N3

M0

IV

Any T

Any N

M1

IB

IIA

IIB

IIIA

IIIB

*M0 includes M0(i+). The designation pM0 is not valid; any M0 should be clinical. If a patient presents with M1 prior to neoadjuvant
systemic therapy, the stage is considered Stage IV and remains Stage IV regardless of response to neoadjuvant therapy. Stage designation
may be changed if post-surgical imaging studies reveal the presence of distant metastases, provided that the studies are carried out within
4 months of diagnosis in the absence of disease progression and that the patient has not received neoadjuvant therapy. Post-neoadjuvant
assessment is designated with a yc or yp prefix. Note: No stage group is assigned if there is a complete pathological response (pCR) to
neoadjuvant therapy, e.g. ypT0ypN0cM0

T1 includes T1mi

T0 and T1 tumours with nodal micrometastases only are excluded from Stage IIA and are classified as Stage IB
Edge SB, Byrd DR, Compton CC (eds). AJCC Cancer Staging Handbook, 7th ed. New York, NY.: Springer, 2010. Used with the permission
of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging
Handbook, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springer.com
13

TREATMENT

The treatment strategy should be based on tumour extent/location and biology

(pathology including biomarkers, gene expression) as well as on the age and

general health status of the patient as well as the patients preferences
 Age should be considered in conjunction with other factors and should not be
the sole reason for withholding or recommending a treatment
 Possible fertility issues, including fertility-preservation techniques, should be
discussed in premenopausal women prior to treatment initiation
 The possibility of hereditary cancer should be explored; if required, prophylactic
procedures should be discussed with the patient following adequate
counselling and genetic testing
Surgery
Breast conservation surgery (BCS)

Careful histological assessment of resection margins is essential

Marking the tumour bed with clips during surgery will facilitate accurate planning
of radiotherapy, where appropriate

Oncoplastic procedures can achieve better cosmetic outcomes, especially in

patients with large breasts, with a less favourable tumour/breast size ratio or
with a cosmetically difficult location of the tumour in the breast

Mastectomy

Breast reconstruction should be available for women requiring mastectomy,

but some women will be advised against immediate reconstruction for oncologic
reasons, particularly when post-mastectomy radiotherapy (PMRT) is anticipated

For women undergoing breast reconstruction (immediate or delayed), a range of

options are available:
Skin-sparing mastectomy (SSM) allows conservation of the skin envelope for
use in reconstruction
 Autologous tissue flaps can replace relatively large volumes of breast tissue
 Silicone gel implants are safe and acceptable


There is no evidence that reconstruction makes detection of local recurrence

more difficult or that women should wait for reconstruction for 1 to 2 years
following mastectomy

Advances in axillary staging

Sentinel lymph node biopsy (SLNB) is associated with less morbidity (shoulder

stiffness, arm swelling) and reduced hospital stay and is the standard of care (SoC)
unless axillary node involvement is suspected
14

 Routine IHC or PCR is not recommended for the evaluation of sentinel

lymph nodes

The presence of macrometastases in the sentinel nodes traditionally mandates

conventional axillary lymph node clearance

Further axillary treatment may be avoided in case of sentinel node

micrometastases (0.22 mm) and patients with clinical T1T2 cN0 invasive
breast cancer and 1 to 2 metastatic sentinel lymph nodes, treated with BCS
and tangential adjuvant radiotherapy

Surgery for in situ malignancy (intraepithelial neoplasia)

Ductal carcinoma in situ (DCIS) may be treated with total mastectomy or BCS,
provided that clear resection margins can be achieved (margins <2 mm are
considered inadequate)

Total mastectomy with clear margins in DCIS is curative

SLNB is not required for in situ malignancies but may be reasonable in the
context of large tumours requiring mastectomy

Lobular neoplasia (including atypical lobular hyperplasia [ALH] and lobular

carcinoma in situ [LCIS]), is considered a non-obligate precursor to invasive

cancer and does not require active treatment in case of ALH and classical LCIS
 The pleomorphic variant of LCIS and LCIS with comedo necrosis may behave
similarly to DCIS and should be treated accordingly
Risk-reducing mastectomy

Prophylactic bilateral mastectomy (PBM) reduces subsequent breast cancer

incidence and mortality by ~9095% and may be offered to women at very

high risk, such as those with previous chest wall irradiation or BRCA1 or BRCA2
mutations carriers; careful genetic assessment and psychological counselling
is mandatory before undertaking surgery

There is a lack of evidence for a significant survival advantage of contralateral

prophylactic mastectomy (CPM) as an alternative to breast conservation and
mammographic surveillance of the irradiated breast

Surgery after primary systemic therapy

Downsizing of a large unifocal primary tumour with neoadjuvant therapy will

allow BCS to be undertaken in some patients who, at presentation, would have

otherwise required mastectomy

Breast MRI is the most accurate modality for assessing the extent of residual
disease following neoadjuvant treatment

15

Radiotherapy: Invasive carcinoma

Radiotherapy after breast conservation surgery (BCS)

Whole breast radiotherapy (WBRT) reduces the risk of local recurrence by twothirds and is associated with a survival benefit

Boost irradiation gives a further 50% risk reduction and is indicated for patients
with unfavourable risk factors for local control (age <50 years, grade 3 tumour,
vascular invasion, non-radical tumour excision)

Accelerated partial breast irradiation (APBI)

APBI is an option for women aged 50 years with unicentric, unifocal, node-

negative, non-lobular breast cancer <3 cm in size without the presence of an

extensive intraductal component and lymphovascular invasion and with negative
margins 2 mm

Post-mastectomy radiotherapy (PMRT)

PMRT is recommended for women with positive deep margin, 4 positive axillary
nodes and for those with T3T4 tumours, independent of nodal status

PMRT should be considered in women with 13 positive axillary lymph nodes in

the presence of additional risk factors (young age, vessel invasion, low number
of examined axillary lymph nodes)

Regional radiotherapy

The role of regional radiotherapy has not been determined. Trials demonstrating

the benefit of post-mastectomy radiation therapy for node-positive disease used

locoregional radiotherapy. Therefore, it is indicated for patients with involved
lymph nodes undergoing breast or chest wall radiotherapy, and should be
considered for patients with pN0 with less than 10 nodes removed with ALND,
especially when other risk factors are present

After ALND, the resected part of the axilla should not be irradiated, except in
cases of residual disease after surgery

Radiotherapy doses and fractionation

Shorter fractionation schemes (e.g. 1516 fractions of 2.52.66 Gy) have similar
effectiveness and side effects and have largely replaced traditional fractionation
regimens

The typical boost dose is 1016 Gy in 2 Gy doses

Radiotherapy in patients with unresectable disease

If disease remains unresectable following induction systemic therapy,

radiotherapy should be considered to treat all sites of the original tumour

extension with a boost to residual disease

16

 Regular evaluation during the course of radiotherapy is advised to select patients

who may become amenable for resection after 4550 Gy

Radiotherapy: Non-invasive carcinoma

WBRT after BCS for DCIS decreases the risk of local recurrence, with survival
equal to that following mastectomy

A boost can be considered for women at higher risk for local failure
(e.g. young patients)

Omitting radiotherapy may be an option in some women with low-risk disease

(tumour size <10 mm, low/intermediate nuclear grade, adequate surgical
margins)

Adjuvant systemic therapy

The choice of systemic adjuvant therapies should be based on surrogate intrinsic

phenotype and must consider the predicted benefit, possible side effects and
patient preference

Adjuvant treatment should start within 26 weeks of surgery

Decision-making tools such as the NPI, Adjuvant! Online and the PREDICT score
can help in predicting recurrence risks and benefits from particular treatments

Gene expression assays, such as MammaPrint or Oncotype DX, may be

used where available to determine the individual recurrence risk and predict
the benefit from chemotherapy in case of uncertainty regarding indications
for adjuvant chemotherapy

Chemotherapy should not be used concomitantly with endocrine therapy

(ET); trastuzumab may routinely be combined with non-anthracycline-based

chemotherapy and ET; concomitant use with anthracyclines is not routinely
recommended; radiotherapy may be delivered safely during trastuzumab, ET and
non-anthracycline-based chemotherapy; if chemotherapy and radiotherapy are to
be used separately, chemotherapy usually precedes radiotherapy

When considering adjuvant therapy for older patients, biological age, general
health status and comorbidities should be considered rather than formal age

17

SYSTEMIC TREATMENT RECOMMENDATIONS FOR EARLY BREAST CANCER

SUBTYPES (ST GALLEN GUIDELINES, 2011 AND 2013)

SUBTYPE
RECOMMENDED THERAPY



Luminal A-like
ET alone in the majority of cases

Luminal B-like
(HER2-negative)

ET + CTh for the majority of cases

Luminal B-like
(HER2-positive)

CTh + anti-HER2 + ET for all patients

HER2-positive
(non-luminal)

CTh + anti-HER2

Triple-negative
(ductal)

CTh

COMMENTS
Consider CTh if
a) high tumour burden (4 or more positive LN,
T3 or higher)
b) grade 3

If contraindications for the use of CTh,

one may consider ET + anti-HER2 therapy,
although no randomised data exist

CTh, chemotherapy; LN, lymph nodes

Note: For special histological types, the St Gallen 2013 recommendations, which propose ET for endocrine responsive histologies (cribriform,
tubular, and mucinous) and CTh for endocrine nonresponsive (apocrine, medullary, adenoid cystic and metaplastic), should be followed

Endocrine therapy (ET)

ET is indicated in all patients with detectable ER expression (1% of invasive

cancer cells)

Premenopausal women






18

Tamoxifen alone (20 mg daily for 510 years) is SoC. Patients becoming
postmenopausal during the first 5 years may benefit from a switch to letrozole)
The value of the addition of ovarian suppression (by gonadotropin-releasing
hormone [GnRH] agonists or ovarian ablation) is not well defined, particularly
in chemotherapy-treated patients who frequently develop ovarian failure as a
consequence of cytotoxic treatment
For patients with contraindications to tamoxifen, a GnRH analogue, alone or in
combination with an aromatase inhibitor (AI), can be used
The role of GnRH agonists in preventing chemotherapy-related ovarian failure
is not well-established

 AIs (both non-steroidal and steroidal) and tamoxifen are valid options
AIs can be used upfront for 5 years, sequentially, after 23 years of tamoxifen
or following 5 years of tamoxifen (extended adjuvant therapy)
The optimal duration of adjuvant ET is currently unknown; extended adjuvant
therapy (10 years) should be discussed with all patients except those with very
low risk






Postmenopausal women

The use of tamoxifen is associated with increased risk of thromboembolic

complications and endometrial hyperplasia (including endometrial cancer)

Patients on tamoxifen should be advised to avoid the use of strong and moderate
cytochrome P450 2D6 (CYP2D6) inhibitors or, if such drugs cannot be avoided,
a switch to an alternative treatment should be considered

Patients undergoing ovarian suppression and AI users are at increased risk of

bone loss
These patients should be advised regarding the need for adequate calcium and
vitamin D3 intake and receive periodical bone mineral density assessments by
dual energy X-ray absorption (DEXA) scan
 In patients with treatment-related bone loss, bisphosphonates decrease the risk
of skeletal complications


Chemotherapy

The most frequently used regimens contain anthracyclines and/or taxanes

and reduce breast cancer mortality by about one-third. Sequential rather than
concomitant use of anthracyclines and taxanes is superior

Chemotherapy is usually administered for 1224 weeks (48 cycles). Four cycles
of doxorubicin/cyclophosphamide (AC) are considered equal to 6 cycles of
cyclophosphamide/methotrexate/fluorouracil (CMF), whereas 6 cycles of 3-drug
anthracycline-based regimens are superior

Non-anthracycline, taxane-based regimens may be used as an alternative in

selected patients (such as those at risk of cardiac complications)

The use of dose-dense schedules (with granulocyte colony-stimulating factor

[G-CSF] support) should be considered, particularly in highly proliferative
tumours

High-dose chemotherapy with stem cell support is not recommended

Human epidermal growth factor receptor 2 (HER2)-directed therapy

1 year of adjuvant trastuzumab should be considered for the majority of patients

with HER2-positive tumours

19

 Due to its cardiotoxicity (usually reversible), trastuzumab should not be routinely

administered concomitantly with anthracyclines; selection of patients based on
the baseline cardiac function and periodic monitoring during treatment
are necessary

Adjuvant systemic therapy for ductal carcinoma in situ (DCIS)

Tamoxifen reduces the risk of invasive and non-invasive recurrences after BCS of
ER-positive DCIS and decreases the incidence of second primary (contralateral)
breast cancer, but does not affect survival
 The use of tamoxifen in these cases is optional

AIs should not be routinely used

Neoadjuvant systemic therapy

In locally advanced and large tumours, neoadjuvant systemic therapy may

allow for reducing tumour size and achieving operability or decreasing the
extent of surgery

All modalities (chemotherapy, ET and targeted therapy) used in adjuvant

treatment may also be used pre-operatively

In operable cases, the timing of treatment (pre- versus post-operative) has
no effect on long term outcomes

Neoadjuvant systemic therapy should be delivered without unnecessary breaks

(e.g. dividing it between the pre- and post-operative period)

Chemotherapy regimens are the same as those used in the adjuvant setting;
a sequential regimen of anthracyclines and taxanes is recommended

Neoadjuvant ET may be considered for patients with ER-positive and HER2-

negative tumours and is usually given for 46 months before surgery and
continued post-operatively; for postmenopausal women, AIs are more effective
than tamoxifen

Dual anti-HER2 blockade is not recommended outside of clinical trials

PERSONALISED MEDICINE

Surrogate intrinsic tumour phenotypes, based on biomarker expression

(ER, PgR, HER2 and Ki67), are the basis for treatment individualisation

Urokinase plasminogen activator-plasminogen activator inhibitor 1 (uPA-PAI1)

and molecular signatures such MammaPrint or Oncotype DX can be used,

in conjunction with other clinicopathological factors, to aid treatment decisionmaking in early breast cancer

20

BIOMARKERS FOR TREATMENT DECISION MAKING IN PRIMARY BREAST

CANCER
BIOMARKER PROGNOSTIC

PREDICTIVE

TEST AND SCORING PATIENT

RECOMMENDATIONS SELECTION

ER

++

+++

IHC

Hormonal
treatment

PgR

+++

IHC

If negative,
chemotherapy
in some cases

HER2

++

+++

IHC 10% cell +

Anti-HER2
treatment

Ki67
++
+
IHC no consensus




Intrinsic
Gene expression profile (not

++
++
subtypes
for IHC surrogates)

Chemotherapy
if elevated
Different
response to
neoadjuvant
chemotherapy
according to
subtype

1st generation
signatures
(MammaPrint,
Oncotype Dx)

+++

Gene expression profile,

RT-PCR

Chemotherapy
if high risk or
high score

2nd generation
signatures

Gene expression profile

None yet

ER, oestrogen receptor; PgR, progesterone receptor; HER-2, human epidermal growth factor receptor 2; IHC, immunohistochemistry;
RT-PCR, reverse transcription polymerase chain reaction

FOLLOW-UP

In the first years, the risk of recurrence is higher in patients with ER-negative
tumours than in those with ER-positive tumours, but the annual risk of
recurrence drops below the level for ER-positive tumours ~58 years
after diagnosis



The aims of follow-up are:

To detect early local recurrences or contralateral breast cancer
21




To evaluate and treat therapy-related complications (such as menopausal

symptoms, osteoporosis and second cancers)
To motivate patients continuing ET
To provide psychological support and information in order to enable a return
to normal life after breast cancer


There is no evidence from randomised trials to support any particular follow-up

protocol

Follow-up visits including history and physical examination are recommended

every 34 months in the first 2 years, every 6 months from years 35 and
annually thereafter
 Mammography (ipsilateral after BCS, and contralateral) is recommended every
12 years
 Breast MRI may be indicated for young patients, especially in the case of dense
breast tissue and genetic or familial predisposition
 In asymptomatic patients, there are no data to indicate that other laboratory
or imaging tests are associated with a survival benefit

Routine lipid profile assessment is indicated to follow-up patients on ET; for

patients on tamoxifen, an annual gynaecological examination by an experienced

gynaecologist is recommended; for patients on AIs, regular bone density
evaluation is recommended

In symptomatic patients or in the case of abnormal findings on examination,

appropriate tests should be carried out immediately

Regular exercise provides functional and psychological benefits, possibly

reducing the risk of recurrence, and should be recommended to all suitable

patients after treatment

Weight gain and obesity are likely to negatively affect prognosis; nutritional
counselling should be recommended for obese patients

The use of hormone replacement therapy increases the risk of recurrence and
should be discouraged

Patients should have unlimited access to specialised rehabilitation facilities and

services to decrease the physical, psychological and social sequelae of breast
cancer treatment; there are no data indicating that any type of physiotherapy
may increase the risk of recurrence

Follow-up clinics should focus not only on late side effects but also on issues that
deal with the long-term implications of living with breast cancer and assessing
the various quality of life (QoL) issues

22

SCREENING
Biannual mammography screening is recommended for women aged 5069 years
Annual screening with MRI of the breast in combination with mammography is
recommended for women with familial breast cancer with or without proven BRCA
mutations
DIAGNOSIS AND STAGING
Diagnosis and treatment should be performed at specialised breast units by an
MDT who specialise in breast cancer
Diagnostic assessments include:
 Medical history
 Physical examination
 PS
 Radiological examination
 Pathological examination according to the WHO classification (4th edition) and
the AJCC)/UICC TNM staging classification system (7th edition)
 Laboratory assessments, including full blood count, liver and renal function
tests, alkaline phosphatase and calcium
 Additional investigations, such as chest CT, abdominal ultrasound or CT and
bone scintigraphy, should be considered for patients with clinically-positive
axillary nodes, large tumours or signs, symptoms or laboratory values
suggesting the presence of metastases
 FDG-PET/CT may be useful for detection of metastatic disease when
conventional methods are inconclusive
For the purpose of prognostication and treatment decision-making, tumours are
grouped into surrogate intrinsic subtypes defined by routine histology and IHC data
according to the St Gallen Consensus Conference guidance (2013)
Post-operative pathological assessment of the surgical specimen should be made
according to the TNM system
Scoring systems such as the NPI, Adjuvant! Online or PREDICT scores can be used
to assist treatment decisions
Gene expression profiles (MammaPrint, Oncotype DX Recurrence Score)
may provide additional prognostic and/or predictive information to complement
23

pathological assessment and to predict response to adjuvant chemotherapy,

particularly in women with ER-positive early breast cancer
TREATMENT
The treatment strategy should be based on tumour extent/location and biology
(pathology including biomarkers, gene expression) as well as on the age and
general health status of the patient as well as the patients preferences
Surgery
BCS
Careful histological assessment of resection margins is essential
Mastectomy
Breast reconstruction should be available for women requiring mastectomy
SSM allows conservation of the skin envelope for use in reconstruction
Autologous tissue flaps can replace relatively large volumes of breast tissue
Silicone gel implants are safe and acceptable
Advances in axillary staging
SLNB is the SoC unless axillary node involvement is suspected
The presence of macrometastases in the sentinel nodes traditionally mandates
conventional axillary lymph node clearance
Further axillary treatment may be avoided in case of sentinel node micrometastases
(0.22 mm) and patients with clinical T1T2 cN0 invasive breast cancer and
12 metastatic sentinel lymph nodes, treated with BCS and tangential adjuvant
radiotherapy
Surgery for in situ malignancy
DCIS may be treated with total mastectomy or BCS provided that clear resections
margins can be achieved; margins <2mm are considered inadequate
Lobular neoplasia (including ALH and LCIS), is considered a non-obligate
precursor to invasive cancer and does not require active treatment in case of ALH
and classical LCIS
Risk-reducing mastectomy
PBM may be offered to women at very high risk,such as those with previous chest
wall irradiation or BRCA1 or BRCA2 mutations carriers
24

Surgery after primary systemic therapy

Downsizing of a large unifocal primary tumour with neoadjuvant therapy will allow
BCS in some patients who would have otherwise required mastectomy
Breast MRI is the most accurate modality for assessing the extent of residual
disease following neoadjuvant treatment
Radiotherapy: Invasive carcinoma
Radiotherapy after BCS
WBRT reduces the risk of local recurrence by two-thirds and is associated with a
survival benefit
APBI
APBI is an option for women aged 50 years with unicentric, unifocal, nodenegative, non-lobular breast cancer <3 cm in size without the presence of an
extensive intraductal component and lymphovascular invasion and with negative
margins 2 mm
PMRT
PMRT is recommended for women with positive deep margin, 4 positive axillary
nodes and for those with T3T4 tumours, independent of nodal status
PMRT should be considered in women with 13 positive axillary lymph nodes
in the presence of additional risk factors (young age, vessel invasion, low number
of examined axillary lymph nodes)
Regional radiotherapy
Regional radiotherapy is indicated for patients with involved lymph nodes
undergoing breast or chest wall radiotherapy, and should be considered for
patients with pN0 with less than 10 nodes removed with ALND
Radiotherapy doses and fractionation
Shorter fractionation schemes (e.g. 1516 fractions of 2.52.66 Gy) have similar
effectiveness and side effects and have largely replaced traditional fractionation
regimens
The typical boost dose is 1016 Gy in 2 Gy doses

25

Radiotherapy in patients with unresectable disease

If disease remains unresectable following induction systemic therapy, radiotherapy
should be considered to treat all sites of the original tumour extension with a boost
to residual disease
Radiotherapy: Non-invasive carcinoma
WBRT after BCS for DCIS decreases the risk of local recurrence; a boost can be
considered for women at higher risk for local failure (e.g. young patients)
Omitting radiotherapy may be an option in some women with low-risk disease
Adjuvant systemic therapy
The choice of systemic adjuvant therapies should be based on surrogate intrinsic
phenotype and must consider the predicted benefit, possible side effects and
patient preference
Adjuvant treatment should start within 26 weeks of surgery
Decision-making tools such as the NPI, Adjuvant! Online and the PREDICT score
can help in predicting recurrence risks and benefits from particular treatments
Gene expression assays, such as MammaPrint or Oncotype DX, may be used to
determine the individual recurrence risk and predict the benefit from chemotherapy
Chemotherapy should not be used concomitantly with ET but trastuzumab may be
combined with non-anthracycline-based chemotherapy and ET
Endocrine therapy
ET is indicated in all patients with detectable ER expression (1% of invasive
cancer cells)
Premenopausal women:
Tamoxifen alone (20 mg daily for 510 years) is the SoC. Patients becoming
postmenopausal during the first 5 years may benefit from a switch to letrozole
The value of the addition of ovarian suppression (by GnRH agonists or ovarian
ablation) is not well defined
For patients with contraindications to tamoxifen, a GnRH analogue, alone or in
combination with an AI, can be used
Postmenopausal women:
AIs (both non-steroidal and steroidal) and tamoxifen are valid options
26

 AIs can be used upfront for 5 years, sequentially, after 23 years of tamoxifen or
following 5 years of tamoxifen (extended adjuvant therapy)
The optimal duration of adjuvant ET is currently unknown; extended adjuvant
therapy (10 years) should be discussed with all patients except those with very
low risk
Patients undergoing ovarian suppression and AI users are at increased risk of
bone loss
These patients should be advised regarding the need for adequate calcium and
vitamin D3 intake and receive periodical bone mineral density assessments by
DEXA scan
Chemotherapy
The most frequently used regimens contain anthracyclines and/or taxanes
Chemotherapy is usually administered for 1224 weeks (48 cycles). The use of
dose-dense schedules (with G-CSF support) should be considered particularly in
highly proliferative tumours
HER2-directed therapy
1 year of trastuzumab should be considered for the majority patients with HER2positive tumours (eligibility based on the baseline cardiac function)
Due to its cardiotoxicity, trastuzumab should not be routinely administered
concomitantly with anthracyclines
Adjuvant systemic therapy for DCIS
Tamoxifen may be considered since it reduces the risk of invasive and non-invasive
recurrences after BCS of ER-positive DCIS, and decreases the incidence of second
primary (contralateral) breast cancer, but does not affect survival
Neoadjuvant systemic therapy
In locally advanced and large tumours, neoadjuvant systemic therapy may allow for
reducing tumour size and achieving operability or decreasing the extent of surgery
Should be delivered without unnecessary breaks (e.g. dividing it between the preand post-operative period)
Chemotherapy regimens are the same as those used in the adjuvant setting;
a sequential regimen of anthracyclines and taxanes is recommended
Neoadjuvant ET may be considered for patients with ER-positive and HER2negative tumours
27

Personalised medicine
Surrogate intrinsic tumour phenotypes, based on biomarker expression
(ER, PgR, HER2 and Ki67), are the basis for treatment individualisation
uPA-PAI1 and molecular signatures such MammaPrint or Oncotype DX can
be used, in conjunction with other clinicopathological factors, to aid treatment
decision-making in early breast cancer
FOLLOW-UP
Follow-up visits including history and physical examination are recommended
every 34 months in the first 2 years, every 6 months from years 35 and annually
thereafter
Mammography (ipsilateral after BCS, and contralateral) is recommended every
12 years
Breast MRI may be indicated for young patients, especially in the case of dense
breast tissue and genetic or familial predisposition
Routine lipid profile assessment is indicated to follow-up patients on ET
In symptomatic patients or in the case of abnormal findings on examination,
appropriate tests should be carried out immediately
Patients should have unlimited access to specialised rehabilitation facilities and
services to decrease the physical, psychological and social sequelae of breast
cancer treatment
Follow-up clinics should focus not only on late side effects but also on issues that
deal with the long-term implications of living with breast cancer and assessing the
various QoL issues

28

GENERAL GUIDELINES
GUIDELINE STATEMENT

LoE

CONSENSUS

All ABC patients should be offered comprehensive, culturally sensitive,

up-to-date and easy to understand information about their disease and its
management

IB

97,2% (36) Yes

0% (0) Abstain
(37 voters)

Specialised oncology nurses (if possible specialised breast nurses) should

be part of the multidisciplinary team managing ABC patients. In some
countries, this role may be played by a physician assistant or other trained
and specialised health care practitioner

Expert
opinion

92,1% (35) Yes

7,8% (3) Abstain
(38 voters)

Strong consideration should be given to the use of validated instruments

for patients to report the symptoms of disease and side effects of treatment
they experience as a regular part of their clinical care. These PRO (patientreported outcomes) instruments should be simple and user-friendly to
IC
facilitate their use in clinical practice. This systematic monitoring will serve
to facilitate communication between patients and their treatment teams,
allow optimal quality of life, and may better characterise the toxicities of all
anticancer therapies

89,4% (34) Yes

5,2% (2) Abstain
(38 voters)

The age of the patient should not be the sole reason to withhold effective
therapy (in elderly patients) nor to overtreat (in young patients). Age alone
should not determine the type and intensity of treatment

100% (38) Yes

0% (0) Abstain
(38 voters)

IB

LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the statement

29

IMPORTANT ABC-RELATED DEFINITIONS

GUIDELINE STATEMENT

LoE

CONSENSUS

VISCERAL CRISIS is defined as severe organ dysfunction as assessed

by signs and symptoms, laboratory studies, and rapid progression of
disease. Visceral crisis is not the mere presence of visceral metastases but Expert
implies important visceral compromise leading to a clinical indication for a opinion
more rapidly efficacious therapy, particularly since another treatment option
at progression will probably not be possible

95,0% (38) Yes

5,0% (2) Abstain
(40 voters)

PRIMARY ENDOCRINE RESISTANCE is defined as: relapse while on

the first 2 years of adjuvant ET, or PD within first 6 months of 1st line ET
for MBC, while on ET
SECONDARY (ACQUIRED) ENDOCRINE RESISTANCE is defined as:
relapse while on adjuvant ET but after the first 2 years, or relapse within 12
months of completing adjuvant ET, or PD 6 months after initiating ET for
MBC, while on ET

66,6% (22) Yes

21,2% (7)
Abstain
(33 voters)

Expert
opinion

LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the statement; ET, endocrine therapy; PD,
progressive disease; MBC, metastatic breast cancer.

LOCALLY ADVANCED INOPERABLE, NON-INFLAMMATORY, BREAST CANCER

GUIDELINE STATEMENT

30

LoE

CONSENSUS

Before starting any therapy, a core biopsy providing histology and

biomarker (ER, PR, HER-2, proliferation/grade) expression is indispensable I B
to guide treatment decisions

97,2% (36) Yes

2,7% (1) Abstain
(37 voters)

Since LABC patients have a significant risk of metastatic disease, a full

staging workup, including a complete history, physical examination, lab
tests and imaging of chest and abdomen (preferably CT scans) and bone,
prior to initiation of systemic therapy is highly recommended

IB

100% (37) Yes

0% (0) Abstain
(37 voters)

PET-CT, if available, may be used (instead of and not on top of CT scans

and bone scan)

II B

100% (37) Yes

0% (0) Abstain
(37 voters)

Systemic therapy (not surgery or radiotherapy) should be the initial

treatment. If LABC remains inoperable after systemic therapy and eventual
radiation, palliative mastectomy should not be done, unless the surgery
is likely to result in an overall improvement in quality of life

Expert
opinion

100% (40) Yes

0% (0) Abstain
(40 voters)

A combined treatment modality based on a multidisciplinary approach

(systemic therapy, surgery and radiotherapy) is strongly indicated in the
vast majority of cases

IA

100% (39) Yes

0% (0) Abstain
(39 voters)

For TRIPLE NEGATIVE LABC, anthracycline- and-taxane-based

chemotherapy is recommended as initial treatment

IA

85,3% (35) Yes

9,7% (4) Abstain
(41 voters)

For HER-2-POSITIVE LABC, concurrent taxane and anti-HER-2 therapy

is recommended since it increases the rate of pathological complete
response (pCR)

IA

91,8% (34) Yes

5,4% (2) Abstain
(37 voters)

For HER-2-POSITIVE LABC, anthracycline-based chemotherapy should

be incorporated in the treatment regimen

IA

71,7% (28) Yes

12,8% (5)
Abstain
(39 voters)

In HER-2-POSITIVE LABC, when an anthracycline is given, it should be

administered sequentially with the anti-HER-2 therapy

IA

86,8% (33) Yes

10,5% (4)
Abstain
(38 voters)

Options for HORMONAL RECEPTOR POSITIVE LABC include an

anthracycline- and taxane-based chemotherapy regimen, or endocrine
therapy.
The choice of chemotherapy versus endocrine therapy, as initial treatment,
will depend on tumour (grade, biomarker expression) and patient
(menopausal status, performance status, comorbidities, preference)
considerations

IA

85,3% (35) Yes

9,7% (4) Abstain
(41 voters)

Following effective neoadjuvant systemic therapy with or without

radiotherapy, surgery will be possible in many patients. This will consist
of mastectomy with axillary dissection in the vast majority of cases, but
in selected patients with a good response, breast conserving surgery may
be possible

II B

97,5% (39) Yes

0% Abstain
(40 voters)

CT, computed tomography; LABC, locally advanced breast cancer; LoE, Available level of evidence; Consensus, Percentage of panel
members in agreement with the statement; ER, estrogen receptor; HER-2, human epidermal growth factor receptor 2; PET, positron emission
tomography; PR, progesterone receptor

31

LOCALLY ADVANCED INOPERABLE, INFLAMMATORY, BREAST CANCER

GUIDELINE STATEMENT

LoE

CONSENSUS

For inflammatory LABC, overall treatment recommendations are similar to

those for non-inflammatory LABC, with systemic therapy as first treatment

IB

92,6% (38) Yes

4,8% (2) Abstain
(41 voters)

Mastectomy with axillary dissection is recommended in almost all cases,

even when there is good response to primary systemic therapy

IB

95,1% (39) Yes

4,8% (2) Abstain
(41 voters)

Immediate reconstruction is generally not recommended in patients with

inflammatory LABC

Expert
opinion

94,7% (36) Yes

2,6% (1) Abstain
(38 voters)

Loco-regional radiotherapy (chest wall and lymph nodes) is required, even

when a pCR is achieved with systemic therapy

IB

97,5% (39) Yes

2,5% (1) Abstain
(40 voters)

LABC, locally-advanced breast cancer; LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the
statement; pCR, pathological complete remission

SPECIFIC ABC POPULATIONS

GUIDELINE STATEMENT

LoE

CONSENSUS

In patients with BRCA-ASSOCIATED TRIPLE NEGATIVE OR

ENDOCRINE-RESISTANT MBC previously treated with an anthracycline
and a taxane (in the adjuvant or metastatic setting), a platinum regimen
may be considered, if the patient is not included in a clinical trial.
All other treatment recommendations are similar to sporadic MBC

IC

82,5% (33) Yes

12,5% (5)
Abstain
(40 voters)

For MALE PATIENTS WITH ABC who need to receive an aromatase

inhibitor, a concomitant LHRH agonist or orchiectomy is the preferred
option. Aromatase inhibitor monotherapy may also be considered, with
close monitoring of response.
Clinical trials are needed in this patient population

Expert
opinion

86,1% (31) Yes

11,1% (4)
Abstain
(36 voters)

LHRH, luteinising hormone-releasing hormone; MBC, metastatic breast cancer; LoE, Available level of evidence; Consensus, Percentage of
panel members in agreement with the statement

32

SPECIFIC SITES OF METASTASES

GUIDELINE STATEMENT

LoE

CONSENSUS

Prospective randomised clinical trials of local therapy for breast cancer

LIVER METASTASES are urgently needed, since available evidence
comes only from series in highly selected patients. Since there are no
randomised data supporting the effect of local therapy on survival, every
patient must be informed of this when discussing a potential local therapy Expert
technique. Local therapy should only be proposed in very selected cases of opinion
good performance status, with limited liver involvement, no extra-hepatic
lesions, after adequate systemic therapy has demonstrated control of the
disease. Currently, there are no data to select the best technique for the
individual patient (surgery, stereotactic RT, intra-hepatic CTh or other)

83,3% (25) Yes

16,6% (5)
Abstain
(30 voters)

MALIGNANT PLEURAL EFFUSIONS require systemic treatment

with/without local management. Thoracentesis for diagnosis should be
performed if it is likely that this will change clinical management. False
negative results are common. Drainage is recommended in patients with
symptomatic, clinically significant pleural effusion. Use of an intrapleural
catheter or intrapleural administration of talc or drugs (e.g. bleomycin,
biological response modifiers) can be helpful.
Clinical trials evaluating the best technique are needed

II B

86,4% (32) Yes

10,8% (4)
Abstain
(37 voters)

Due to the high risk of concomitant distant metastases, patients with

chest wall or regional (nodal) recurrence should undergo full restaging,
including assessment of chest, abdomen and bone

Expert
opinion

100% (38) Yes

0% (0) Abstain
(38 voters)

Chest wall and regional recurrences should be treated with surgical

excision when feasible with limited risk of morbidity.

IB

97,3% (37) Yes

2,6% (1) Abstain
(38 voters)

Locoregional radiotherapy is indicated for patients not previously irradiated I B

97,3% (37) Yes

2,6% (1) Abstain
(38 voters)

For patients previously irradiated, re-irradiation of all or part of the chest

wall may be considered in selected cases

97,3% (37) Yes

2,6% (1) Abstain
(38 voters)

Chest wall and regional (nodal) recurrences

Expert
opinion

33

In addition to local therapy (surgery and/or RT), in the absence of distant

metastases, the use of systemic therapy (CTh, ET and/or anti-HER-2
therapy) should be considered.
CTh after first local or regional recurrence improves long-term outcomes
primarily in ER negative disease.
ET in this setting improves long-term outcomes for ER positive disease.
The choice of systemic treatment depends on tumour biology, previous
treatments, length of disease free interval, and patient-related factors (comorbidities, preferences, etc)

IB

94,8% (37) Yes

5,1% (2) Abstain
(39 voters)

In patients with disease not amenable to radical local treatment, the choice
of palliative systemic therapy should be made according to principles
previously defined for MBC. These patients may still be considered for
palliative local therapy

Expert
opinion

97,3% (37) Yes

2,6% (1) Abstain
(38 voters)

MBC, metastatic breast cancer; LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the statement;
CTh, chemotherapy; RT, radiotherapy; ET, endocrine therapy; HER-2, human epidermal growth factor receptor 2; ER, oestrogen receptor

UPDATE ON ER POSITIVE/HER-2 NEGATIVE ABC

GUIDELINE STATEMENT

LoE

CONSENSUS

The preferred 1st line ET for postmenopausal patients is an aromatase

inhibitor or tamoxifen, depending on type and duration of adjuvant ET

IA

83,3% (30) Yes

16,6% (6)
Abstain
(36 voters)

Fulvestrant HD is also an option

IB

83,3% (30) Yes

16,6% (6)
Abstain
(36 voters)

The addition of everolimus to an aromatase inhibitor is a valid option

for some post-menopausal patients with disease progression after a
non-steroidal aromatase inhibitor, since it significantly prolongs PFS
by a median interval of 5 months. There is a survival prolongation of
similar magnitude (4.4 months) although this difference is not statistically
significant. The decision to treat must take into account the relevant
toxicities associated with this combination and should be made on a case
by case basis.
At present, no predictive biomarker exists to identify those patients who
will benefit from this approach

IB

100% Yes
(30 voters)

LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the statement; ER, oestrogen receptor;
ET, endocrine therapy; HD, high-dose; HER-2, human epidermal growth factor receptor 2; PFS, progression-free survival

34

UPDATE ON HER-2-POSITIVE ABC

GUIDELINE STATEMENT

LoE

CONSENSUS

In the 1st line setting, for HER-2+ MBC previously treated (in the adjuvant
setting) or untreated with trastuzumab, combinations of CTh + trastuzumab
are superior to combinations of CTh + lapatinib in terms of PFS and OS

IA

84,6% (33) Yes

10,2% (4)
Abstain
(39 voters)

In 1st line therapy, the combination of CTh + trastuzumab and pertuzumab

is superior to CTh + trastuzumab, primarily for previously untreated HER2+ MBC, making it the preferred treatment option since it is associated
with OS benefit.
It is currently unknown how this treatment compares to other anti-HER-2
options such as T-DM1

IA

89,7% (35) Yes

10,2% (4)
Abstain
(39 voters)

There are currently no data supporting the use of dual blockade with
trastuzumab + pertuzumab associated with CTh beyond 1st line, after
treatment with trastuzumab + pertuzumab + CTh in 1st line (i.e. continuing
dual blockade beyond progression) and therefore this 3 drug regimen
should not be given beyond 1st line outside clinical trials

85,0% (34) Yes

12,5% (5)
Abstain
(40 voters)

In a HER-2+ MBC patient previously untreated with pertuzumab, it is

acceptable to use pertuzumab beyond 1st line

II C

43,7% (14) Yes

21,8% (7)
Abstain
(32 voters)

After 1st line trastuzumab-based therapy, T-DM1 provides superior efficacy

relative to other HER-2-based therapies in the 2nd line (vs. lapatinib +
capecitabine) and beyond (vs. treatment of physicians choice).
T-DM1 should be preferred in patients who have progressed through at
least 1 line of trastuzumab-based therapy, since it provides an OS benefit

IA

89,7% (35) Yes

10,2% (4)
Abstain
(39 voters)

All patients with HER-2+ MBC who relapse after adjuvant anti-HER-2
therapy should be considered for further anti-HER-2 therapy, except in the
presence of contraindications.
The choice of the anti-HER-2 agent will depend on country-specific
availability, the specific anti-HER-2 therapy previously administered, and
the relapse free interval.
The optimal sequence of all available anti-HER-2 therapies is currently
unknown

IB

87,5% (35) Yes

12,5% (5)
Abstain
(40 voters)

Because patients with HER-2-positive MBC and brain metastases can

live for several years, consideration of long-term toxicity is important and
less toxic local therapy options (e.g. stereotactic RT) should be preferred
to whole brain RT, when available and appropriate (e.g. in the setting of a
limited number of brain metastases)

IC

89,1% (33) Yes

10,8% (4)
Abstain
(37 voters)

MBC, metastatic breast cancer; LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the statement;
CTh, chemotherapy, HER-2, human epidermal growth factor receptor 2; RT, radiotherapy; OS, overall survival; PFS, progression-free survival;
T-DM1, Trastuzumab Emtansine
35

UPDATE ON HER-2-NEGATIVE ABC

GUIDELINE STATEMENT

LoE

CONSENSUS

Sequential monotherapy is the preferred choice for MBC. Combination

CTh should be reserved for patients with rapid clinical progression,
life-threatening visceral metastases, or need for rapid symptom and/or
disease control

IA

96% (25) Yes

4% (1) Abstain
(26 voters)

In patients pre-treated (in the adjuvant or metastatic setting) with

an anthracycline and a taxane, and who do not need combination
chemotherapy, single agent capecitabine, vinorelbine or eribulin are the
preferred choices.
Additional choices include gemcitabine, platinum agents, taxanes, and
liposomal anthracyclines.
The decision should be individualised and take into account different
toxicity profiles, previous exposure, patient preferences, and country
availability

IB

77,1% (27) Yes

20,0% (7)
Abstain
(35 voters)

LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the statement; CTh, chemotherapy;
MBC, metastatic breast cancer

UPDATE ON SURGERY OF THE PRIMARY TUMOUR IN STAGE IV AT DIAGNOSIS

GUIDELINE STATEMENT

LoE

The true value of the removal of the primary tumour in patients with de
novo stage IV breast cancer is currently unknown. However, it can be
considered in selected patients. Of note, some studies suggest that surgery
II B
is only valuable if performed with the same attention to detail (e.g. attaining
clear margins and addressing disease in the axilla) as in patients with early
stage disease
LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the statement

36

CONSENSUS
100% (29) Yes
0% (0) Abstain
(29 voters)

ABC1 STATEMENTS
GUIDELINE STATEMENT

LoE

CONSENSUS

The management of ABC is complex and, therefore, involvement of all

appropriate specialties in a multidisciplinary team (including but not
restricted to medical, radiation, surgical oncologists, imaging experts,
pathologists, gynaecologists, psycho-oncologists, social workers, nurses
and palliative care specialists), is crucial

Expert
opinion

100% (29) Yes

0% (0) Abstain
(29 voters)

From the time of diagnosis of ABC, patients should be offered appropriate

psychosocial care, supportive care, and symptom-related interventions as
a routine part of their care. The approach must be personalised to meet the
needs of the individual patient

Expert
opinion

100% (30) Yes

0% (0) Abstain
(30 voters)

Following a thorough assessment and confirmation of MBC, the potential

treatment goals of care should be discussed. Patients should be told that
MBC is incurable but treatable, and that some patients can live with MBC
for extended periods of time (many years in some circumstances).
This conversation should be conducted in accessible language, respecting
patient privacy and cultural differences, and whenever possible, written
information should be provided

Expert
opinion

97% (29) Yes

3% (1) Abstain
(30 voters)

Patients (and their families, caregivers or support network, if the patient

agrees) should be invited to participate in the decision-making process
at all times. When possible, patients should be encouraged to be
accompanied by persons who can support them and share treatment
decisions (e.g. family members, caregivers, support network)

Expert
opinion

100% (30) Yes

0% (0) Abstain
(30 voters)

There are few proven standards of care in ABC management. After

appropriate informed consent, inclusion of patients in well-designed,
prospective, randomised independent trials must be a priority whenever
such trials are available and the patient is willing to participate

Expert
opinion

100% (30) Yes

0% (0) Abstain
(30 voters)

The medical community is aware of the problems raised by the cost of ABC
Expert
treatment. Balanced decisions should be made in all instances; patients
opinion
well being, length of life and preferences should always guide decisions

100% (32) Yes

0% (0) Abstain
(32 voters)

Assessment guidelines
Minimal staging workup for MBC includes a history and physical
examination, haematology and biochemistry tests, and imaging of chest,
abdomen and bone

2C

Brain imaging should not be routinely performed in asymptomatic patients.

Expert
This approach is applicable to all patients with MBC including those
opinion
patients with HER-2+ and/or TNBC MBC

67% (20) Yes

3% (1) Abstain
(30 voters)
94% (30) Yes
0% Abstain
(32 voters)

37

The clinical value of tumour markers is not well established for diagnosis
or follow-up after adjuvant therapy, but their use is reasonable (if elevated)
as an aid to evaluate response to treatment, particularly in patients with
non-measurable metastatic disease. A change in tumour markers alone
should not be used to initiate a change in treatment

2C

89% (24) Yes

4% (1) Abstain
(27 voters)

Evaluation of response to therapy should generally occur every 2 to 4

months for ET or after 2 to 4 cycles for CTh, depending on the dynamics
of the disease, the location and extent of metastatic involvement, and type
of treatment.
Imaging of a target lesion may be sufficient in many patients. In certain
patients, such as those with indolent disease, less frequent monitoring is
acceptable.
Additional testing should be performed in a timely manner, irrespective
of the planned intervals, if PD is suspected or new symptoms appear.
Thorough history and physical examination must always be performed

Expert
opinion

81% (25) Yes

10% (3) Abstain
(31 voters)

A biopsy (preferably providing histology) of a metastatic lesion should

be performed, if easily accessible, to confirm diagnosis particularly when
metastasis is diagnosed for the first time

1 C*

96% (27) Yes

0% (0) Abstain
(28 voters)

Biological markers (especially HR and HER-2) should be reassessed at

least once in the metastatic setting, if clinically feasible

2C

90% (26) Yes

7% (2) Abstain
(29 voters)

If the results of tumour biology in the metastatic lesion differ from the
primary tumour, it is currently unknown which result should be used for
treatment-decision making. Since a clinical trial addressing this issue
is difficult to undertake, we recommend considering the use of targeted
therapy (ET and/or anti-HER-2 therapy) when receptors are positive in at
least one biopsy, regardless of timing

Expert
opinion

87% (27) Yes

3% (1) Abstain
(31 voters)

Treatment choice should take into account at least these factors: HR and
HER-2 status, previous therapies and toxicities, disease-free interval,
tumour burden (defined as number and site of metastases), biological
age, performance status, co-morbidities (including organ dysfunctions),
menopausal status (for ET), need for a rapid disease/symptom control,
socio-economic and psychological factors, available therapies in the
patients country and patient preference

Expert
opinion

100% (30) Yes

0% (0) Abstain
(30 voters)

A small but very important subset of patients with MBC, for example those
with oligo-metastatic disease, can achieve complete remission and a long
survival. A multimodal approach should be considered for these selected
patients.
A prospective clinical trial addressing this specific situation is needed

Expert
opinion

96% (25) Yes

0% Abstain
(26 voters)

Treatment general guidelines

38

Endocrine therapy (ET) is the preferred option for hormone receptor

positive disease, even in the presence of visceral disease, unless
there is concern or proof of endocrine resistance, or there is disease
needing a fast response

IA

100% (29) Yes

0% (0) Abstain
(29 voters)

For pre-menopausal women, ovarian suppression/ablation combined with

additional endocrine therapy is the first choice

IA

97% (29) Yes

0% (0) Abstain
(30 voters)

The additional endocrine agent should be tamoxifen unless tamoxifen

resistance is proven.
An aromatase inhibitor is also a viable option, but absolutely mandates the
use of ovarian suppression/ablation.
Fulvestrant has not been adequately studied in premenopausal women

IB

97% (29) Yes

0% (0) Abstain
(30 voters)

Optimal post-aromatase inhibitor treatment is uncertain.

Available options include, but are not limited to, tamoxifen, another
aromatase inhibitor (with a different mechanism of action), fulvestrant HD,
megestrol acetate and everolimus + aromatase inhibitor

IA

97% (30) Yes

3% (1) Abstain
(31 voters)

Endocrine treatment after CTh (maintenance ET) to maintain benefit is

a reasonable option, although this approach has not been assessed in
randomised trials

IC

88% (28) Yes

9% (3) Abstain
(32 voters)

Concomitant CTh + ET has not shown a survival benefit and should not be
administered outside of a clinical trial

IB

100% (30) Yes

0% (0) Abstain
(30 voters)

Anti-HER-2 therapy should be offered early to all patients with HER-2+

MBC, except in the presence of contra-indications to the use of such
therapy

IA

91% (30) Yes

3% (1) Abstain
(33 voters)

For patients with ER+/HER-2+ MBC for whom ET was chosen over CTh,
anti-HER-2 therapy + ET should be considered with the initiation of
endocrine therapy (provided that further anti-HER-2 therapy is available)
since anti-HER-2 therapy (either trastuzumab or lapatinib) in combination
with ET has shown substantial PFS benefit (i.e. time without CTh)
compared to ET alone. The addition of anti-HER-2 therapy in this setting
has not led to a survival benefit

IA

90% (27) Yes

10% (3) Abstain
(30 voters)

Patients whose tumours progress on an anti-HER-2 therapy combined with

a cytotoxic or endocrine agent should be offered additional anti-HER-2
therapy with subsequent treatment since it is beneficial to continue
suppression of the HER-2 pathway.
The optimal duration of anti-HER-2 therapy for MBC (i.e. when to stop
these agents) is currently unknown

IB

97% (29) Yes

0% (0) Abstain
(30 voters)

HER-2-POSITIVE ABC

39

Patients who have received any type of (neo)adjuvant anti-HER-2 therapy

should not be excluded from clinical trials for HER-2+ MBC

IB

100% (23) Yes

0% (0) Abstain
(27 voters)

In case of progression on trastuzumab, the combination of trastuzumab +

lapatinib is also a reasonable treatment option in the course of the disease

IB

83% (24) Yes

10% (3) Abstain
(29 voters)

In the absence of medical contraindications or patient concerns,

anthracycline or taxane based regimens, preferably as single agents, would
usually be considered as first line CTh for HER-2 negative MBC, in those
patients who have not received these regimens as adjuvant treatment
and for whom chemotherapy is appropriate. Other options are, however,
available and effective, such as capecitabine and vinorelbine, particularly if
avoiding alopecia is a priority for the patient

IA

71% (17) Yes

4% (1) Abstain
(24 voters)

In patients with taxane-naive and anthracycline-resistant MBC or with

anthracycline cumulative dose or toxicity (i.e. cardiac) who are being
considered for further CTh, taxane-based therapy, preferably as single
agents, would usually be considered as treatment of choice. Other options
are, however, available and effective, such as capecitabine and vinorelbine,
particularly if avoiding alopecia is a priority for the patient

IA

59% (14) Yes

8% (2) Abstain
(24 voters)

If given in the adjuvant setting, a taxane can be re-used in the metastatic

setting, particularly if there has been at least one year of disease-free
survival

IA

92% (22) Yes

8% (2) Abstain
(24 voters)

Chemotherapy and biological therapy

Duration of each regimen and the number of regimens should be tailored to Expert
each individual patient
opinion

96% (26) Yes

0% (0) Abstain
(27 voters)

Usually each regimen (except anthracyclines) should be given until

progression of disease or unacceptable toxicity.
What is considered unacceptable should be defined together with the patient

IB

72% (21) Yes

7% (2) Abstain
(29 voters)

Bevacizumab combined with a chemotherapy as 1st or 2nd line therapy

for MBC provides only a moderate benefit in PFS and no benefit in OS.
The absence of known predictive factors for bevacizumab efficacy renders
recommendations on its use difficult. Bevacizumab can only therefore
be considered as an option in selected cases in these settings and is not
recommended after 1st/2nd line

IA

74% (17) Yes

17% (4) Abstain
(23 voters)

IA

96% (26) Yes

4% (1) Abstain
(27 voters)

Specific sites of metastases: bone and brain

A bone modifying agent (bisphosphonate or denosumab) should be
routinely used in combination with other systemic therapy in patients with
MBC and bone metastases

40

Radiological assessments are required in patients with persistent and

localised pain due to bone metastases to determine whether there are
impending or actual pathological fractures. If a fracture of a long bone
is likely or has occurred, an orthopaedic assessment is required as the
treatment of choice may be surgical stabilisation, which is generally
followed by RT. In the absence of a clear fracture risk, RT is the treatment
of choice

IA

96% (23) Yes

4% (1) Abstain
(24 voters)

Neurological symptoms and signs which suggest the possibility of spinal

cord compression must be investigated as a matter of urgency. This
requires a full radiological assessment of potentially affected area as well
as adjacent areas of the spine. MRI is the method of choice. An emergency
surgical opinion (neurosurgical or orthopaedic) may be required for
surgical decompression. If no decompression/stabilisation is feasible,
emergency radiotherapy is the treatment of choice and vertebroplasty is
also an option

IB

100% (24) Yes

0% (0) Abstain
(24 voters)

Patients with a single or small number of potentially resectable brain

metastases should be treated with surgery or radiosurgery. Radiosurgery is
an option for some unresectable brain metastases

IB

92% (22) Yes

4% (1) Abstain
(24 voters)

If surgery/radiosurgery is performed it may be followed by whole brain

radiotherapy but this should be discussed in detail with the patient,
balancing the longer duration of intracranial disease control against the
risk of neurocognitive effects

IB

72% (18) Yes

16% (4) Abstain
(25 voters)

Supportive care allowing safer and more tolerable delivery of appropriate

treatments should always be part of the treatment plan

IA

100% (26) Yes

0% (0) Abstain
(26 voters)

Early introduction of expert palliative care, including effective control of

pain and other symptoms, should be a priority

IA

100% (26) Yes

0% (0) Abstain
(26 voters)

Access to effective pain treatment (including morphine, which is

inexpensive) is necessary for all patients in need of pain relief

IA

100% (27) Yes

0% (0) Abstain
(27 voters)

Optimally, discussions about patient preferences at the end of life should

begin early in the course of metastatic disease. However, when active
treatment no longer is able to control widespread and life-threatening
disease, and the toxicities of remaining options outweigh benefits,
physicians and other members of the healthcare team should initiate
discussions with the patient (and family members/friends, if the patient
agrees) about end-of-life care

Expert
opinion

96% (25) Yes

0% (0) Abstain
(26 voters)

Supportive and palliative care

41

Metastatic male breast cancer

For ER+ Male MBC, which represents the majority of cases, ET is the
preferred option, unless there is concern or proof of endocrine resistance
or rapidly progressive disease needing a fast response

Expert
opinion

100% (25) Yes

0% (0) Abstain
(25 voters)

For ER+ Male MBC, tamoxifen is the preferred option

Expert
opinion

83% (15) Yes

6% (1) Abstain
(18 voters)

ABC, advanced breast cancer; MBC, metastatic breast cancer; TNBC, triple-negative breast cancer; ET, endocrine therapy; CTh, chemotherapy;
PD, progressive disease; HD, high-dose; PFS, progression-free survival; OS, overall survival; MRI, magnetic resonance imaging;
ER, oestrogen receptor; HER-2, human epidermal growth factor receptor 2; HR, hormone receptor; RT, radiotherapy
*= LoE changed since ABC1 from 2 C to 1 C based on new published data (Thompson_2010, Amir_2012, Foukakis_2012).

LEVELS OF EVIDENCE GRADING SYSTEM

GRADE OF
RECOMMENDATION/
DESCRIPTION

BENEFIT VS.
RISK AND
BURDENS

Benefits clearly
1A/ Strong recommendation,
outweigh risk and
high quality evidence
burdens, or vice versa

RCTs without important

limitations or
overwhelming evidence
from observational
studies

Strong
recommendation,
can apply to most
patients in most
circumstances
without reservation

Benefits clearly
1B/ Strong recommendation,
outweigh risk and
moderate quality evidence
burdens, or vice versa

RCTs with important

limitations (inconsistent
results, methodological
flaws, indirect,
or imprecise) or
exceptionally strong
evidence from
observational studies

Strong
recommendation,
can apply to most
patients in most
circumstances
without reservation

Observational studies or
case series

Strong
recommendation,
but may change
when higher quality
evidence becomes
available

1C/ Strong
Benefits clearly
recommendation, low quality outweigh risk and
evidence
burdens, or vice versa

42

METHODOLOGICAL
QUALITY OF
IMPLICATIONS
SUPPORTING
EVIDENCE

2A/ Weak recommendation,

high quality evidence

RCTs without important

Benefits closely
limitations or
balanced with risks and overwhelming evidence
burden
from observational
studies

Weak
recommendation,
best action may
differ depending on
circumstances or
patients or societal
values

2B/ Weak recommendation,

moderate quality evidence

RCTs with important

limitations (inconsistent
results, methodological
Benefits closely
flaws, indirect,
balanced with risks and
or imprecise) or
burden
exceptionally strong
evidence from
observational studies

Weak
recommendation,
best action may
differ depending on
circumstances or
patients or societal
values

2C/ Weak recommendation,

low quality evidence

Benefits closely
Observational studies or
balanced with risks and
case series
burden

Very weak
recommendation,
other alternatives
may be equally
reasonable

RCT, randomised controlled trial

43

 Mutations in the high-penetrance breast cancer predisposition genes BRCA1

and BRCA2 explain ~20% of the familial clustering of breast cancer

REFERRAL FOR BRCA TESTING

Widely accepted clinical criteria for referral include: 3 breast and/or ovarian

cancer cases with at least one patient aged <50 years, two breast cancer cases
in patients aged <40 years, women of Ashkenazi Jewish descent aged <60 years
with breast cancer, male breast cancer and ovarian cancer or early onset female
breast cancer, early onset bilateral breast cancer, and breast and ovarian cancer
in the same patient

Genetic testing should be performed in adults who have received genetic

counselling and provided informed consent

Those carrying mutations should be encouraged to advise close family members

to get genetic counselling

MUTATION DETECTION

Direct DNA sequencing is the gold standard for mutation detection, although
several techniques are available

Specific techniques to detect duplications or deletions of 1 exons, such as

multiplex ligation-dependent probe amplification (MLPA), are required as 212%

of high-risk families harbour a large genomic alteration

RISK REDUCTION: NON-SURGICAL PREVENTATIVE OPTIONS

Surveillance

Surveillance of breast cancer in women carrying BRCA mutations includes

monthly self-examinations, clinical breast examinations twice a year, yearly

mammograms and yearly magnetic resonance imaging (MRI) scans of the
breasts, starting at age 2530 years

Chemoprevention

The benefit of tamoxifen for primary prevention of breast cancer in women

carrying BRCA mutations has not been demonstrated

Adjuvant tamoxifen reduces the risk of contralateral breast cancer in women

with BRCA mutations and breast cancer

44

RISK MODIFIERS

Parity appears to confer protection from breast cancer in women carrying BRCA
mutations, as in the general population

RISK REDUCTION: PROPHYLACTIC SURGICAL OPTIONS

There are no randomised controlled trials to support recommendations on

prophylactic surgery; prospective cohort studies have shown a consistent
risk reduction

Risk reduction options include prophylactic bilateral mastectomy (PBM),

prophylactic bilateral salpingo-oophorectomy (PBSO) or both

Prophylactic bilateral mastectomy (PBM)

PBM is the most effective strategy for risk reduction in women carrying BRCA
mutations (risk reduction 90%)
Survival benefits have not been demonstrated



In addition to total mastectomy, other surgical techniques are available, but no

randomised trials have compared them

Skin-sparing mastectomy (SSM)
Several large series have reported the oncologic safety of SSM with a similar
rate of local failures to total mastectomy
Has a cosmetic advantage, but total loss of all nipple sensation makes it
less satisfactory
 Nipple-sparing mastectomy (NSM)
Preliminary reports indicate similar failure rates with superior cosmetic
results compared with the other mastectomy techniques


Types of prophylactic mastectomy and immediate breast reconstruction should

be discussed with the patient, addressing the potential risks and benefits

Routine sentinel lymph node biopsy (SLNB) is not recommended

Contralateral prophylactic mastectomy (CPM) is an option for women carrying
BRCA mutations with early breast cancer who have undergone unilateral
mastectomy
 CPM decreases the risk of contralateral breast cancer; however, there are
limited data to suggest that it is associated with decreased mortality
Prophylactic bilateral salpingo-oophorectomy (PBSO)


Recommended in women aged >35 years who have completed childbearing

PBSO is associated with a risk reduction for breast cancer and ovarian cancer
and there is evidence of a reduction in overall mortality in premenopausal
women
45

The significantly reduced risk of breast cancer with PBSO appears to be

higher in women carrying BRCA2 mutations than those carrying BRCA1

mutations

Short-term hormonal replacement therapy after PBSO appears not to decrease

the overall benefit of PBSO in terms of breast cancer risk reduction

TREATMENT
Surgery

Surgical treatment of breast cancer in women carrying BRCA mutations should

be based on the same parameters as sporadic cancer, while considering the

higher risk of contralateral breast cancer
 Women carrying BRCA1/2 mutations treated with breast conservation surgery
(BCS) or mastectomy have similar breast cancer-specific and overall survival
Chemotherapy was the only independent predictor of local failure in those
treated with BCS

It is not known whether PBSO is associated with a significantly decreased risk

of breast cancer in women carrying BRCA1 mutations who have previously had
breast cancer

Systemic treatment

BRCA deficiency seems to be predictive of chemosensitivity, particularly to DNAdamaging agents

There is no definitive chemotherapy regimen for women carrying BRCA

mutations with breast cancer; standard prognostic features should be used

to decide treatment

46

REFERRAL FOR BRCA TESTING

Widely accepted clinical criteria for referral include: 3 breast and/or ovarian cancer
cases with at least one patient aged <50 years, two breast cancer cases in patients
aged <40 years, women of Ashkenazi Jewish descent aged <60 years with breast
cancer, male breast cancer and ovarian cancer or early onset female breast cancer,
early onset bilateral breast cancer, and breast and ovarian cancer in the same patient
Women should receive genetic counselling and provide informed consent
MUTATION DETECTION
Direct DNA sequencing is the gold standard
RISK REDUCTION
Non-surgical options
Surveillance: Includes monthly self-examinations, clinical breast examinations
twice a year, yearly mammograms and yearly MRI scans of the breasts, starting
at age 2530 years
Chemoprevention: The benefit of tamoxifen for primary prevention has not been
demonstrated; adjuvant tamoxifen reduces the risk of contralateral breast cancer
in women with BRCA mutations and breast cancer
Surgical options
PBM: The most effective strategy for risk reduction (no effect on survival); surgical
techniques (total mastectomy, SSM, NSM) and reconstruction should be discussed
with the patient
CPM: An option for women carrying BRCA mutations with early breast cancer who
have undergone unilateral mastectomy
PBSO: Recommended in women aged >35 years who have completed childbearing
BREAST CANCER TREATMENT IN WOMEN WITH BRCA MUTATIONS
Surgery
Should be based on the same parameters as for sporadic cancer, while considering
the higher risk of contralateral breast cancer
Systemic treatment
No definitive chemotherapy regimen for these patients; standard prognostic
features should be used to decide treatment; BRCA deficiency seems to be
predictive of chemosensitivity
47

ABC, advanced breast cancer

AC, doxorubicin/cyclophosphamide
AI, aromatase inhibitor
AJCC, American Joint Committee for Cancer
ALH, atypical lobular hyperplasia
ALND, axillary lymph node dissection
APBI, accelerated partial breast irradiation
BCS, breast conservation surgery
BCT, breast conserving therapy
CMF, cyclophosphamide/methotrexate/fluorouracil
CPG, clinical practice guidelines
CPM, contralateral prophylactic mastectomy
CT, computed tomography
CTh, chemotherapy
CYP2D6, cytochrome P450 2D6
DCIS, ductal carcinoma in situ
DEXA, dual energy X-ray absorption
ER, oestrogen receptor
ESMO, European Society for Medical Oncology
ESO, European School of Oncology
ET, endocrine therapy
FDG-PET, fluorodeoxyglucose positron emission tomography
FNA, fine needle aspiration
G-CSF, granulocyte colony-stimulating factor
GnRH, gonadotropin-releasing hormone
HD, high-dose
H&E, haematoxylin and eosin
HER2, human epidermal growth factor receptor 2
HR, hormone receptor
IHC, immunohistochemistry
ITCs, isolated tumour cell clusters
LABC, locally advanced breast cancer
LCIS, lobular carcinoma in situ (lobular neoplasia)
LHRH, luteinizing hormone-releasing hormone
LN, lymph nodes
LoE, Available level of evidence
MBC, metastatic breast cancer
MDT, multidisciplinary team
MLPA, multiplex ligation-dependent probe amplification
MRI, magnetic resonance imaging
NPI, Nottingham Prognostic Index
NSM, nipple-sparing mastectomy
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OS, overall survival

PBM, prophylactic bilateral mastectomy
PBSO, prophylactic bilateral salpingo-oophorectomy
pCR, pathological complete remission
PD, progressive disease
PET, positron emission tomography
PFS, progression-free survival
PgR, progesterone receptor
PMRT, post-mastectomy radiotherapy
PR, progesterone receptor
PRO, patient reported outcomes
PS, performance status
PVI, peritumoural vascular invasion
QoL, quality of life
RCT, randomised controlled trial
RT, radiotherapy
RT-PCR, reverse transcription polymerase chain reaction
SoC, standard of care
SLNB, sentinel lymph node biopsy
SSM, skin-sparing mastectomy
T-DM1, Trastuzumab Emtansine
TNBC, triple-negative breast cancer
TNM, tumour node metastasis
UICC, Union for International Cancer Control
uPA-PAI1, urokinase plasminogen activatorplasminogen activator inhibitor 1
WBRT, whole breast radiotherapy
WHO, World Health Organization

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Access the full ESMO Clinical Practice Guidelines

2014 European Society for Medical Oncology

All rights reserved. No part of this booklet may be reprinted, reproduced, transmitted or utilised in any form by any electronic, mechanical or
other means, now known or hereafter invented, including photocopying and microfilming, or in any information storage or retrieval system,
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trademarks or registered trademarks and are used only for identification and explanation without intent to infringe.
This booklet contains information obtained from authentic and highly regarded sources (http://www.esmo.org). Although every effort has been
made to ensure that treatment and other information are presented accurately in this publication, the ultimate responsibility rests with the
prescribing physician. Neither the publisher or the Guidelines Working Groups can be held responsible for errors or for any consequences
arising from the use of information contained herein. For detailed prescribing information on the use of any product or procedure discussed
herein, please consult the prescribing information or instructional material issued by the manufacturer.
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