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Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

June 2019
Annals of Oncology 30(8)

DOI:10.1093/annonc/mdz173

Authors:

Stella Kyriakides

Europa Donna Cyprus

Frédérique Penault-Llorca

Centre Jean Perrin

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Early breast cancer treatment algorithm. a Biology that requires ChT (TNBC, HER2-positive, luminal B-like), to assess response and prognosis and eventually decide on postoperative therapies, should preferentially receive preoperative ChT. b Aggressive phenotypes: TNBC or HER2-positive breast cancer. c If ChT is planned, it should all be given as neoadjuvant. d Concomitant postoperative RT, postoperative ET and anti-HER2 therapy. BCS, breast-conserving surgery; ChT, chemotherapy; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; RT, radiotherapy, TNBC, triple-negative breast cancer.

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(Neo)-adjuvant systemic treatment choice by marker expression and intrinsic phenotype. a With possible exception of selected cases with very low risk T1abN0. b Anti-HER2: trastuzumab 6 pertuzumab. c Adenoid cystic or apocrine, secretory carcinoma, low-grade metaplastic carcinoma. d Depending on level of ER and PgR expression, proliferation, genomically assessed risk, tumour burden and/or patient preference. e

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HER2-positive breast cancer treatment. a ESMO-MCBS v1.1 scores for new therapies/indications approved by the EMA since 1 January 2016. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee. b Not yet EMA-approved. ChT, chemotherapy; EMA, European Medicines Agency; ER, oestrogen receptor; ESMO-MCBS, ESMO-Magnitude of Clinical Benefit Scale; HER2, human epidermal growth factor receptor 2; N-positive, node-positive; pCR, pathological complete response; T-DM1, trastuzumab emtansine.

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Diagnostic work-up for early breast cancer

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Continued

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SPECIAL ARTICLE

Early breast cancer: ESMO Clinical Practice Guidelines

for diagnosis, treatment and follow-up

†

F. Cardoso

, S. Kyriakides

, S. Ohno

, F. Penault-Llorca

4,5

, P. Poortmans

6,7

, I. T. Rubio

, S. Zackrisson

E. Senkus

, on behalf of the ESMO Guidelines Committee*

Breast Unit, Champalimaud Clinical Center/Champalimaud Foundation, Lisbon, Portugal;

Europa Donna Cyprus, Nicosia, Cyprus;

Breast Oncology Center, Cancer

Institute Hospital, Tokyo, Japan;

Department of Pathology, Centre Jean Perrin, Clermont-Ferrand;

UMR INSERM 1240, IMoST Universite´ d’Auvergne, Clermont-

Ferrand;

Department of Radiation Oncology, Institut Curie, Paris;

Paris Sciences & Lettres – PSL University, Paris, France;

Breast Surgical Oncology Unit, Clinica

Universidad de Navarra, Madrid, Spain;

Department of Translational Medicine, Diagnostic Radiology, Lund University and Ska˚ne University Hospital Malmo¨, Malmo¨,

Sweden;

Department of Oncology and Radiotherapy, Medical University of Gda

nsk, Gda

nsk, Poland

*Correspondence to: ESMO Guidelines Committee, ESMO Head Ofﬁce, Via Ginevra 4, 6900 Lugano, Switzerland. E-mail: clinicalguidelines@esmo.org

†

Approved by the ESMO Guidelines Committee: August 2003, last update April 2019. This publication supersedes the previously published version—Ann Oncol

2015; 26(Suppl 5): v8–v30.

For the purpose of the ESMO guidelines, inoperable locally advanced breast cancer is considered part of advanced breast cancer (ABC) and is discussed in the ABC

guidelines; it will not be addressed in the present manuscript.

Key words:early breast cancer, diagnosis, treatment, follow-up

Incidence and epidemiology

In 2018, the predicted number of new breast cancers in 28

European Union (EU) countries was 404 920, with estimated

age-adjusted annual incidence of breast cancer of 144.9/100 000

and mortality of 32.9/100 000, with 98 755 predicted deaths [1].

Worldwide, there was about 2.1 million newly diagnosed female

breast cancer cases in 2018, accounting for almost one in four

cancer cases among women, and 630 000 died of it [2]. Breast

cancer incidence has increased since the introduction of mam-

mography screening and continues to grow with the ageing of the

population.

The most important risk factors include: genetic predispos-

ition, exposure to oestrogens [endogenous and exogenous,

including long-term hormone replacement therapy (HRT)], ion-

ising radiation, low parity, high breast density and a history of

atypical hyperplasia. The Western-style diet, obesity and the con-

sumption of alcohol also contribute to the rising incidence of

breast cancer [3].

There is a steep age gradient, with about a quarter of breast can-

cers occurring before age 50, and <5% before age 35.

The estimated 5-year prevalence of breast cancer (people with

a diagnosis within the last 5 years and still alive, with or without

disease) in Europe in 2012 was 1 814 572 cases [1]andastaggering

6 875 099 cases worldwide [2]. Prevalence is increasing, due to

increased incidence and improvements in treatment outcomes.

In most Western countries, the mortality rate has decreased in

recent years, especially in younger age groups, because of

improved treatment and earlier detection [4,5]. However, breast

cancer is still the leading cause of cancer-related deaths for

women in Europe and worldwide, although the mortality of lung

cancer in women is overcoming breast cancer mortality in some

countries.

Breast cancer in males is rare, contributing to 1% of cases.

The major risk factors include clinical disorders carrying hormonal

imbalances (especially gynaecomastia and cirrhosis), radiation ex-

posure, a positive family history and genetic predisposition [6].

Breast cancer screening

Out of the 28 member states of the EU, 25 were planning, piloting

or rolling out (ongoing or completed) national or regional

population-based mammography screening programmes, to de-

tect breast cancers at a pre-clinical stage [7]. The European

Guidelines for quality assurance in breast cancer screening and

diagnosis recommend performance parameters and indicators

that should be monitored in any screening programme [8]. The

CThe Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Annals of Oncology 30: 1194–1220, 2019

doi:10.1093/annonc/mdz173

Published online 4 June 2019

European Commission Initiative on Breast Cancer (ECIBC) has

produced evidence-based recommendations for mammography

screening, with the strongest recommendation for women aged

50–69 years and with conditional recommendations for women

in younger and older age groups [9]. The greatest mortality re-

duction beneﬁt has been shown in the 50- to 69-year-old age

group, while evidence for effectiveness of mammography screen-

ing in women aged 40–49 years is more limited, especially for

women aged between 40 and 44 years [10]. This was also the con-

clusion in the 2015 breast cancer screening report from the

International Agency for Research on Cancer (IARC) [11]. There

is no consensus about the exact effect of mammography screen-

ing on breast cancer mortality reduction, as the reported esti-

mates vary. In a UK review of the randomised controlled

mammography trials, a 20% relative breast cancer mortality re-

duction was estimated in women aged between 50 and 70 years

[12]. It must be noted that the review stresses the importance of

taking into account the risk of over-diagnosis and over-

treatment, as well as false-positive screening, when balancing the

beneﬁts and harms of screening. Screening programmes carry the

risk of false-negative results; consequently, a false feeling of secur-

ity among patients and doctors may be instilled. Nevertheless,

mammography screening and population-based awareness pro-

grammes, together with improved treatment, contribute to mor-

tality reduction in breast cancer. There is also controversy and no

consensus regarding the use of ultrasound (US) as a supplemen-

tary screening method. Risk-adapted screening is currently being

evaluated in clinical trials.

In women with familial breast cancer, with or without proven

BRCA mutations, annual screening with magnetic resonance

imaging (MRI) of the breast, in combination with mammog-

raphy, can detect the disease at a more favourable stage compared

with mammography screening alone (70% lower risk of being

diagnosed with breast cancer stage II or higher). However, it is

not known whether breast cancer mortality is lowered [13].

There is no consensus for the use of US.

Recommendations:

•Regular (annual or every 2 years) mammography is recom-

mended in women aged 50–69 years [I, A]. Regular mam-

mography may also be done for women aged 40–49 and 70–

74 years, although the evidence for beneﬁt is less well estab-

lished [II, B].

•In women with a strong familial history of breast cancer, with

or without proven BRCA mutations, annual MRI and annual

mammography (concomitant or alternating) are recom-

mended [III, A].

Diagnosis and pathology/molecular biology

The diagnosis of breast cancer is based on clinical examination in

combination with imaging and conﬁrmed by pathological assess-

ment (Table 1). Clinical examination includes bimanual palpa-

tion of the breasts and regional lymph nodes and assessment for

distant metastases (bones, liver and lungs; a neurological examin-

ation is only required when symptoms are present).

Imaging includes bilateral mammography and US of the breast

and regional lymph nodes [8]. An MRI of the breast is not rou-

tinely recommended, but should be considered in cases of:

•familial breast cancer associated with BRCA mutations [I, A];

•lobular cancers [I, A];

•dense breasts [II, B];

•suspicion of multifocality/multicentricity (particularly in lobular

breast cancer) [I, A];

•large discrepancies between conventional imaging and clinic-

al examination [III, B];

•before neoadjuvant systemic therapy, and to evaluate the re-

sponse to this therapy [II, A]; and

•when the ﬁndings of conventional imaging are inconclusive

(such as a positive axillary lymph node status with an occult

primary tumour in the breast) [III, A] [14].

•It may also be considered in case of breast implants.

Several new techniques are being tested for screening and diagnos-

tic imaging, such as three-dimensional (3D) mammography (digital

breast tomosynthesis), 3D US, shear wave elastography and contrast-

enhanced mammography/spectral mammography. None of these

are yet routinely implemented but they have the potential to increase

diagnostic accuracy, especially in women with dense breasts.

It is imperative to collect complete personal medical history,

family history relating to breast/ovarian and other cancers and

the menopausal status of the patient (if in doubt, measure serum

oestradiol and follicle-stimulating hormone levels), and to carry

out a full physical examination.

Table 1. Diagnostic work-up for early breast cancer

Assessment of

general health

status

History

Menopausal status

Physical examination

Full blood count

Liver, renal and cardiac (in patients planned for

anthracycline and/or trastuzumab treatment)

function tests, alkaline phosphatase and calcium

Assessment of

primary tumour

Physical examination

Mammography

Breast US

Breast MRI in selected cases

Core biopsy with pathology determination of hist-

ology, grade, ER, PgR, HER2 and Ki67

Assessment of

regional lymph

nodes

Physical examination

US-guided biopsy if suspicious

Assessment of

metastatic

disease

Physical examination

Other tests are not routinely recommended, un-

less high tumour burden, aggressive biology or

when symptoms suggestive of metastases are

present

ER, oestrogen receptor; HER2, human epidermal growth factor receptor

2; MRI, magnetic resonance imaging; PgR, progesterone receptor; US,

ultrasound.

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Volume 30 | Issue 8 | 2019 doi:10.1093/annonc/mdz173 | 1195

Apart from imaging, pretreatment disease evaluation includes

pathological examination of the primary tumour and cytology/

histology of the axillary nodes, if involvement is suspected.

Pathological diagnosis should be based on a core needle biopsy,

preferably obtained by US or stereotactic guidance. A core needle

biopsy (if this is not possible, at least a ﬁne-needle aspiration

indicating carcinoma) must be obtained before any type of treat-

ment is initiated. If preoperative systemic therapy is planned, a

core needle biopsy is mandatory to ensure a diagnosis of invasive

disease and assess biomarkers [I, A]. It is recommended that at

least 2–3 cores are obtained. In case of multifocal and multicen-

tric tumours, all lesions should be biopsied [I, A]. A marker (e.g.

surgical clip, carbon) should be placed into the tumour at biopsy,

to ensure resection of the correct site and to enable pathological

assessment of the surgical specimen [V, A]. As a minimum, US-

guided ﬁne-needle aspiration or core biopsy of suspicious lymph

nodes should be carried out, preferably followed by clip or carbon

marking of biopsied lymph nodes [III, A]. An excisional biopsy

should not be carried out, except in rare cases of repeated nega-

tive core biopsies.

Final pathological diagnosis should be made according to the

World Health Organization (WHO) classiﬁcation [15] and the

eighth edition of the American Joint Committee on Cancer

(AJCC) tumour, node, metastasis (TNM) staging system [16].

This staging system, apart from purely anatomical information,

includes also prognostic information related to tumour biology

[tumour grade, oestrogen receptor (ER), progesterone receptor

(PgR), human epidermal growth factor receptor 2 (HER2) and

gene expression data if available]. The two most frequent sub-

types are invasive carcinoma of the breast, not otherwise speciﬁed

(NOS, previously named ductal carcinoma) (70%–75%) and

lobular carcinoma (12%–15%). The other 18 subtypes exhibit

speciﬁc morphological traits and are rare (from 0.5% to 5%).

Each of these speciﬁc subtypes shows a particular prognosis. Of

note, a neuroendocrine differentiation can be observed in some

cases, without any prognostic or therapeutic consequences for

the patient [15]. The pathological report should include pres-

ence/absence of ductal carcinoma in situ (DCIS), the histological

type, grade, immunohistochemistry (IHC) evaluation of ER sta-

tus (using a standardised assessment methodology, e.g. Allred

score or H-score) and, for invasive cancer, IHC evaluation of PgR

and HER2 expression or HER2 gene ampliﬁcation. HER2 gene

ampliﬁcation status may be determined directly from all invasive

tumours using in situ hybridisation (ISH) (ﬂuorescent, chromo-

genic or silver), replacing IHC or only for tumours with an am-

biguous (2þ) IHC score [II, B] [17]. HER2 testing should be

carried out according to the American Society of Clinical

Oncology–College of American Pathologists (ASCO-CAP)

guidelines. HER2 is deﬁned as positive by IHC (3þ) when more

than 10% of the cells harbour a complete membrane staining,

and by ISH if the number of HER2 gene copies is 6, or the

HER2/chromosome 17 (CEP17) ratio is 2 and HER2 copies 4,

or HER2/CEP17 <2 and HER2 copies 6[18].

Proliferation markers such as the Ki67 labelling index may sup-

ply additional useful information, particularly if the assay can be

standardised [III, A] [19,20].

Alternatively, these biological markers can be assessed in the

deﬁnitive surgical specimen if primary systemic therapy (PST) is

not planned. However, ﬁxation is better controlled for core biop-

sies, allowing safer antigen preservation for IHC [21].

In case of negativity of ER/PgR and HER2 in the biopsy speci-

men, it is advisable to retest for them in the surgical specimen to

account for the putative tumour heterogeneity [III, A] [22]. In

case of discrepancy, the results from the surgical specimen are

considered deﬁnite. In case of a HER2-positive test on biopsy,

retesting for HER2 on the surgical specimen is mandatory for in-

vasive carcinoma NOS grade I, ER- and PgR-positive (including

special types such as tubular, mucinous, cribriform) or adenoid

cystic carcinoma or secretory carcinoma (both usually triple-

negative) [18].

For the purpose of prognostication and treatment decision

making, tumours should be grouped into surrogate intrinsic

subtypes, deﬁned by routine histology and IHC data [III, A]

(Table 2)[23,24]. Luminal A-like tumours are typically low

Table 2. Surrogate deﬁnitions of intrinsic subtypes of breast cancer [23]

Intrinsic subtype Clinicopathological surrogate definition

Luminal A ‘Luminal A-like’

ER-positive

HER2-negative

Ki67 low

PgR high

Low-risk molecular signature (if available)

Luminal B ‘Luminal B-like (HER2-negative)’

ER-positive

HER2-negative

and either

Ki67 high or

PgR low

High-risk molecular signature (if available)

‘Luminal B-like (HER2-positive)’

ER-positive

HER2-positive

Any Ki67

Any PgR

HER2 ‘HER2-positive (non-luminal)’

HER2-positive

ER and PgR absent

‘Basal-like’ ‘Triple-negative’

ER and PgR absent

HER2-negative

Adapted from the 2013 St Gallen Consensus Conference [23].

Ki-67 scores should be interpreted in light of local laboratory values: as

an example, if a laboratory has a median Ki-67 score in receptor-positive

disease of 20%, values of 30% or above could be considered clearly high;

those of 10% or less clearly low.

Suggested cut-off value is 20%; quality assurance programmes are es-

sential for laboratories reporting these results.

There is 80% overlap between ‘triple-negative’ and intrinsic ‘basal’ sub-

type, but ‘triple-negative’ also includes some special histological types such

as carcinoma with a rich lymphocytic stroma (former medullary), secretory

carcinoma, low-grade metaplastic carcinoma and adenoid cystic carcinoma.

ER, oestrogen receptor; HER2, human epidermal growth factor receptor

2; PgR, progesterone receptor.

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1196 | Cardoso et al. Volume 30 | Issue 8 | 2019

grade, strongly ER-positive/PgR-positive, HER2-negative

and have low proliferative fraction. Luminal B-like tumours

are ER-positive but may have variable degrees of ER/PgR

expression, are higher grade and have higher proliferative frac-

tion [23].

Tumour-inﬁltrating lymphocyte (TIL) scoring is demon-

stratedtohaveaprognosticvalueintriple-negativebreastcan-

cer (TNBC) and HER2-positive breast cancer. It has been

described as a predictor of pathological complete response

(pCR) to chemotherapy (ChT) in many prospective neoadju-

vant clinical trials and its increase appears linked to an

improved prognosis after adjuvant therapy. TIL scoring can be

used as a prognostic marker, as shown in a variety of clinical tri-

als (e.g. BIG-2-98, FinHER, Cleopatra), providing a typically

15%–20% relative improvement in survival per 10% increase in

TILs [25–27] and its use as a prognostic factor is endorsed by

the 2019 St Gallen Consensus. However, TIL scoring should not

be used to take treatment decisions nor to escalate or de-escalate

treatment.

Genetic counselling and testing for germline BRCA1 and

BRCA2 mutations should be offered to breast cancer patients in

high-risk groups, i.e. those with:

•strong family history of breast, ovarian, pancreatic and/or

high grade/metastatic prostate cancer;

•diagnosis of breast cancer before the age of 50;

•diagnosis of TNBC before the age of 60; and

•personal history of ovarian cancer or second breast cancer or

male sex [II, A] [28,29].

Other high-risk mutations may also be tested, if deemed ap-

propriate by the treating physician/genetic counsellor.

For details regarding genetic testing and management of BRCA

carriers, please refer to the appropriate ESMO Clinical Practice

Guidelines [29].

Recommendations:

•Breast imaging should involve bilateral mammogram and US

of breasts and axillae in all cases [I, A]; MRI is recommended

in case of uncertainties following standard imaging and in

special clinical situations [I, A].

•Pathological evaluation includes histology from the primary

tumour and cytology/histology of the axillary nodes (if in-

volvement is suspected) [I, A].

•Pathological report should include histological type, grade,

IHC evaluation of ER, PgR (for invasive cancer), HER2 (for

invasive cancer) and some form of proliferation markers (e.g.

Ki67 for invasive cancer) [I, A]. Tumours should be grouped

into surrogate intrinsic subtypes, deﬁned by routine histology

and IHC data [I, A].

•TIL scoring is of prognostic value and may be used to add on

information on patient’s prognosis. It should not, however,

be used to take treatment decisions nor to escalate or de-

escalate treatment.

•Genetic counselling and testing for germline BRCA1 and

BRCA2 mutations should be offered to breast cancer patients

in high-risk groups [II, A].

Staging and risk assessment

Disease stage should be assessed according to the eighth edition

of the AJCC TNM staging system [16]. In early breast cancer, rou-

tine staging evaluations are directed at locoregional disease.

Asymptomatic distant metastases are rare, and most patients do

not beneﬁt from comprehensive laboratory tests (including tu-

mour markers [30]) and radiological staging [III, D]. Minimum

blood work-up (a full blood count, liver and renal function tests,

alkaline phosphatase and calcium levels) is recommended before

surgery and systemic (neo)adjuvant therapy [V, A].

A computed tomography (CT) scan of the chest, abdominal

imaging (US, CT or MRI scan) and a bone scan can be considered

for patients with:

•clinically positive axillary nodes;

•large tumours (e.g. 5 cm);

•aggressive biology; and

•clinical signs, symptoms or laboratory values suggesting the

presence of metastases [III, A].

Dual imaging methods combining functional and anatomical

information such as ﬂuorodeoxyglucose (FDG) positron emis-

sion tomography (PET)-CT may be useful when conventional

methods are inconclusive [V, A]. PET-CT scanning can also re-

place traditional imaging for staging in high-risk patients [V, B]

[31], although in cases of lobular cancers and low-grade tumours,

PET-CT may be less sensitive. Current evidence does not support

the use of FDG-PET-CT in the staging of locoregional disease,

due to its limited sensitivity when compared with the gold stand-

ard, sentinel lymph node biopsy (SLNB) and axillary lymph node

dissection (ALND) [32].

In patients planned for (neo)adjuvant systemic treatment with

anthracyclines and/or trastuzumab, evaluation of cardiac func-

tion with a cardiac US or a multigated acquisition (MUGA) scan

is essential [I, A].

The postoperative pathological assessment of the surgical

specimens should be made according to the pathological TNM

system [16]. This assessment should include:

•the number, location and maximum diameter of the tumours

removed;

•the total number of removed and positive lymph nodes, as

well as the extent of metastases in the lymph nodes [isolated

tumour cells, micrometastases (0.2–2 mm), macrometastases];

•the histological type and grade of the tumour(s) using a

standard grading system;

•evaluation of the resection margins, including the location

and minimum distance of the margin;

•vascular invasion; and

•a biomarker analysis, as described above [I, A].

For small tumours diagnosed by core biopsy, measuring only

the residual tumour in the excision may result in understaging. It

is recommended to correlate imaging, clinical and gross ﬁndings

to microscopic observation if necessary [16].

The most important prognostic factors in early breast cancer

are the expression of ER/PgR, HER2 and proliferation markers

(e.g. Ki67), the number of involved regional lymph nodes, tu-

mour histology, the size, grade and the presence of peritumoral

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Volume 30 | Issue 8 | 2019 doi:10.1093/annonc/mdz173 | 1197

vascular invasion. Additionally, in patients undergoing breast-

conserving therapy (BCT), the ipsilateral breast recurrence risk is

related to the status of the surgical margins and the presence of

DCIS.

Immunohistochemically detected tumour markers known to

have great practical treatment importance are now incorporated

into the eighth edition of the AJCC TNM staging system to reﬁne

prognosis, which also uses genomic assays, when available, to

downstage some ER-positive, lymph node-negative tumours

[16]. Clinical parameters (age, tumour stage, ER, PgR and HER2

expression and histological grade) have also been integrated into

scoring systems, allowing a relatively accurate estimation of the

probability of recurrence and death from breast cancer; examples

include the Nottingham Prognostic Index (NPI), the PREDICT

score and Adjuvant! Online (currently temporarily unavailable)

[33–35].

UPA/PAI-1 (FEMTELLE; Sekisui Diagnostics, Lexington, MA)

is an enzyme-linked immunosorbent assay (ELISA) evaluating

the metastatic potential of a breast tumour. Despite its level [I, A]

of prognostic value in node-positive and node-negative breast

cancer patients, this test is not extensively used, probably due

to the requirement for a substantial amount of fresh-frozen tissue

[36].

Gene expression proﬁles, such as MammaPrint (Agendia,

Amsterdam, The Netherlands), Oncotype DX Recurrence Score

(Genomic Health, Redwood City, CA), Prosigna (PAM 50;

NanoString Technologies, Seattle, WA), Endopredict (Myriad

Genetics Salt Lake City, UT) and Breast Cancer Index

(Biotheranostics, Inc., San Diego, CA), may be used to gain add-

itional prognostic and/or predictive information to complement

pathology assessment and to predict the beneﬁt of adjuvant ChT

[19]. All tests except MammaPrint were designed for patients

with ER-positive early breast cancer only. The clinical utility of

MammaPrint and Oncotype DX has been or is still being pro-

spectively evaluated in large randomised clinical trials such as

MINDACT for MammaPrint, West German Study Group

(WSG) PLAN B trial, TAILORx and RxPONDER (SWOG 1007)

for Oncotype DX [37–39]. A level of evidence (LoE) and grade of

recommendation (GoR) of [I, A] have been achieved through the

prospective MINDACT trial for the prognostic value and clinical

utility (for ChT decision making) of MammaPrint (for clinical

high risk, low genomic score) and for Oncotype DX through the

TailorX and Plan B trials. A score of [I, B] according to biomarker

LoE guidelines [40] has been achieved from retrospective analy-

ses of data from prospective trials regarding the prognostic value

of Prosigna and Endopredict, in ER-positive breast cancers [36,

41]. In addition, the prognostic value of MammaPrint has been

validated in the RASTER trial, a prospective but non-

randomised, clinical trial [42]. The OPTIMA Prelim Trial has re-

cently shown that the use of molecular tests has an 86% probabil-

ity of being cost-effective [43], along with several other published

studies. Furthermore, both MammaPrint and Oncotype DX are

able to identify patients with an ultra-low risk of death from

breast cancer at 10 or 20 years [44,45].

ER/PgR and HER2 are the only validated predictive factors

allowing the selection of patients for endocrine therapy (ET) and

anti-HER2 therapies, respectively. High ER expression is usually

associated with lesser absolute beneﬁt of ChT [46]. It must be

stressed that IHC/ISH determination of intrinsic phenotype does

not have a 100% concordance with the molecular determination.

The prerequisite for using such a surrogate assessment is the use

of standardised assays and a meticulous quality control.

After neoadjuvant systemic treatment, the response to treat-

ment and the amount of residual disease are important prognos-

tic factors but need as much standardisation as any of the other

biological markers. A multidisciplinary international working

group developed practical recommendations for the systematic,

standardised evaluation of the post-neoadjuvant surgical breast

cancer specimen [47]. Systematic sampling of areas identiﬁed by

intelligent mapping of the specimen and close correlation with

radiological ﬁndings is preferable to overly exhaustive sampling

and permits the collection of tissue samples for translational re-

search. If a pCR was achieved (deﬁned as no invasive disease both

in the breast and axilla), this must be clearly stated [48]. In add-

ition, the presence or absence of residual DCIS must be described.

In case of residual invasive carcinoma, a comment must be made

as to the presence or absence of ChT effect in the breast and the

lymph nodes. The Residual Cancer Burden (RCB) is the preferred

method for quantifying residual disease in clinical trials; other

methods can be used according to regional preference [49]. Post-

treatment tumour staging, using the TNM system, should also be

included [16].

Recommendations:

•Disease stage should be assessed according to the AJCC TNM

staging system [I, A].

•Comprehensive laboratory testing including tumour markers

and radiological staging is not necessary for all patients [III, D].

•Minimum blood work-up (a full blood count, liver and renal

function tests, alkaline phosphatase and calcium levels) is rec-

ommended before surgery and systemic (neo)adjuvant ther-

apy [V, A].

•Imaging of chest, abdomen and bone is recommended for

higher-risk patients (high tumour burden, aggressive biology,

signs, symptoms or laboratory values suggesting the presence

of metastases) [III, A].

•FDG-PET-CT scanning may be useful when conventional

methods are inconclusive [V, A] and may replace traditional

imaging for staging in high-risk patients [V, B].

•Postoperative pathological assessment of the surgical speci-

mens should be made according to the pathological TNM

system [I, A].

•Validated gene expression proﬁles may be used to gain add-

itional prognostic and/or predictive information to comple-

ment pathology assessment and help in adjuvant ChT

decision making [I, A].

Treatment

General rules

Organisation of care. Treatment of breast cancer in the setting of

specialised breast units/centres deﬁned as specialised institu-

tions/departments that care for a high volume of breast cancer

patients (a minimum of 150 new early breast cancer cases per

year) leads to improved outcomes [both in terms of disease-free

Special article Annals of Oncology

1198 | Cardoso et al. Volume 30 | Issue 8 | 2019

survival (DFS) and overall survival (OS)], functional outcomes

and quality of life (QoL) of patients, and is highly recommended

[III, A]. The breast unit/centre should preferably be certiﬁed by

an accredited body [III, A]. Treatment of breast cancer patients

within specialised units is recommended by the European

Parliament and European Commission, reviewed in Ref. [50].

Recommendations:

•Treatment should be carried out in specialised breast units/

centres and provided by a multidisciplinary team specialised

in breast cancer, consisting of at least medical oncologists,

breast surgeons, radiation oncologists, breast radiologists,

breast pathologists and breast nurses (or similarly trained

and specialised health care practitioners) [III, A] [50,51].

•The breast unit/centre should have or be able to refer patients

to plastic/reconstructive surgeons, psychologists, physiothera-

pists and geneticists when appropriate [III, A].

•A breast nurse or a similarly trained and specialised health

care practitioner should be available to act as a patient navi-

gator [III, B] [50,51].

Patient information and involvement in decision making.

Following a diagnosis of breast cancer, a patient ﬁnds herself/

himself in a new and unfamiliar landscape. This creates

different levels of stress that vary from patient to patient and

needtobeaddressedindividuallyandtailoredtoeachpatient’s

needs. Most will remember the information provided to them

in a fragmented way. Patients need space, both physical and

timewise, to process and comprehend the information

about their diagnosis, so they can cope psychologically with the

treatment plan.

Recommendations:

•Information on diagnosis and treatment choice should be

given repeatedly (both verbally and in writing) in a compre-

hensive and easily understandable form [V, A].

•The use of reliable, patient-centred websites or similar sour-

ces of information is recommended [V, A].

•Patients should be actively involved in all management deci-

sions [V, A].

Treatment of early breast cancer is complex and involves com-

bination of local modalities [surgery, radiotherapy (RT)], sys-

temic anticancer treatments (ChT, ET, molecularly targeted

therapies) and supportive measures, delivered in diverse sequen-

ces. The use of predictive biomarkers such as ER, PgR, HER2 and

Ki67 and approved genomic signatures is well established to help

in determining the treatment of choice (see Figure 1).

Particular attention must be paid to treatment of early breast

cancer in special populations, e.g. very young or elderly patients.

However, age is a continuous variable and its cut-offs in clinical

trials are always arbitrarily chosen. ‘Younger’ patients should

not be overtreated because they are ‘young’, just as ‘older’

patients should not be undertreated solely based on their

calendar age.

In younger premenopausal patients, possible fertility issues

should be discussed and guidance about fertility-preservation

techniques should be provided, before the initiation of any

systemic treatment [52–56]. For details about fertility preserva-

tion, please refer to the appropriate ESMO Clinical Practice

Guidelines [56].

Recommendations:

•The choice of treatment strategy should be based on the tu-

mour burden/location (size and location of primary tumour,

number of lesions, extent of lymph node involvement) and

biology (pathology, including biomarkers and gene expres-

sion), as well as the age, menopausal status, general health

status and preferences of the patient [V, A].

•Age should be taken into consideration in conjunction with

other factors and should not be the sole determinant for

withholding or recommending a treatment [V, A].

•In younger premenopausal patients, fertility issues and, when

desired by the patient, fertility-preservation techniques

should be discussed, before the initiation of any systemic

treatment [V, A].

Local treatment

Surgery. The major change in the surgical treatment of primary

breast cancer has been a shift towards breast conservation techni-

ques, which started >30 years ago. Currently, in western Europe,

60%–80% of newly diagnosed cancers are amenable to breast

conservation (wide local excision and RT), at diagnosis or after

PST. A neoadjuvant approach should be preferred in subtypes

highly sensitive to ChT, such as triple-negative and HER2-

positive, in tumours >2 cm [II, A] and/or a positive axilla (see

Figure 1).

In some patients, mastectomy is still carried out due to:

•tumour size (relative to breast size);

•tumour multicentricity;

•inability to achieve negative surgical margins after multiple

resections;

•prior radiation to the chest wall/breast or other contraindica-

tions to RT;

•unsuitability for oncoplastic breast conservation; and

•patient choice [57].

Breast-conserving surgery: Breast-conserving surgery (BCS) is

the primary surgical choice for breast cancer. For patients

undergoing wide local excision, greater emphasis is now placed

on achieving acceptable cosmesis, and breast surgeons are

trained to undertake oncoplastic approaches to reduce the im-

pact of local tumour excision on cosmesis, often using tissue

displacement techniques. Oncoplastic procedures can result in

better cosmetic outcomes, especially in patients with large

breasts, a less favourable tumour/breast size ratio or a cosmetic-

ally challenging (central or inferior) location of the tumour

within the breast.

Despite the overall trend towards breast conservation,

increasing numbers of breast cancer patients are opting for bi-

lateral mastectomy (incorporating contralateral risk-reducing

surgery) rather than the preferred breast conservation and

mammographic surveillance of the irradiated breast [58]. This

must be confronted with data demonstrating that patients with

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early-stage breast cancer who opt for BCT might have an even

better survival compared with those who have a mastectomy

[59–62].

Margin status should be reported according to the recom-

mendations of the College of American Pathologists (CAP); for

example, a margin is positive and should be reported as such,

when there is ink touching invasive cancer or DCIS; the anatom-

ic location of the positive margin should be speciﬁed in oriented

specimens. For negative margins (i.e. ink not touching invasive

cancerorDCIS),thedistanceofinvasivecancerand/orDCIS

from the margin(s) should be reported. No tumour at the inked

margin is required and >2mm for in situ disease is preferred

[63–66].

Marking the tumour bed with clips in a standardised way facili-

tates accurate planning of the radiation boost if indicated.

Currently achievable low local recurrence rates [<0.5% per

year (with a target of <0.25%) and 10% overall at very long-

term follow-up] should be maintained.

Recommendations:

•BCS is the preferred local treatment option for the majority

of early breast cancer patients, with the use of oncoplastic

techniques, to maintain good cosmetic outcomes in technic-

ally challenging cases, when needed [I, A].

•Careful histological assessment of resection margins is essen-

tial. No tumour at the inked margin is required and >2mm

for in situ disease is preferred [I, A].

Mastectomy: Besides simple mastectomy and skin-sparing

mastectomy (SSM) that preserves the skin envelope, nipple-

sparing mastectomy (NSM) has been increasingly used in the last

decade. NSM has been shown to be safe from an oncological

point of view in selected patients and to improve cosmetic out-

comes for therapeutic and prophylactic surgeries [II, B] [67,68].

Because data on NSM cannot be achieved with randomised

Early Breast Cancer

Postoperative ChT ± anti-HER2

if applicable [I, A]

Postoperative RTd if applicable

(mandatory after BCS) [I, A]

Tumour ≤2 cm and/or optimal surgery feasiblea

with the exception of aggressive phenotypesb

No wish for breast conservation

or breast conservation not possible

with the exception of aggressive phenotypesb

Tumour >2 cm or optimal surgery not feasible

and wish for breast conservation

and breast conservation potentially feasible after downstaging

TNBC/HER2-positive tumours >2 cm

and/or with positive axilla

regardless of feasibility of optimal surgery

Unsatisfactory responseSatisfactory response

Mastectomy ± reconstruction [I, A]Breast-conserving surgery [I, A]

Postoperative ETd

if applicable [I, A]

Systemic induction therapyc [I, A]

Figure 1. Early breast cancer treatment algorithm.

Biology that requires ChT (TNBC, HER2-positive, luminal B-like), to assess response and prognosis and eventually decide on postoperative

therapies, should preferentially receive preoperative ChT.

Aggressive phenotypes: TNBC or HER2-positive breast cancer.

If ChT is planned, it should all be given as neoadjuvant.

Concomitant postoperative RT, postoperative ET and anti-HER2 therapy.

BCS, breast-conserving surgery; ChT, chemotherapy; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; RT, radiother-

apy, TNBC, triple-negative breast cancer.

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1200 | Cardoso et al. Volume 30 | Issue 8 | 2019

studies, the use of prospective data registries will further aid in

evaluation of the technique.

Immediate reconstruction in most women can make the pro-

spect of losing a breast easier to accept [51]. The only oncological

reason to advise against immediate reconstruction is the case of

inﬂammatory breast cancer. However, some women may decline

or defer reconstruction because of personal preferences. There is

no evidence that reconstruction makes detection of local recur-

rence more difﬁcult, and no basis for the outdated view that

patients should wait 1–2 years after mastectomy before being

offered reconstruction. The autologous tissue-based techniques

generally tolerate postoperative RT well. Implant-based recon-

struction may result in an unfavourable aesthetic outcome, fol-

lowing postoperative RT [69,70]. If post-mastectomy

radiotherapy (PMRT) is indicated, use of a temporary expander

before RT may facilitate RT planning in some cases.

For women undergoing breast reconstruction, whether imme-

diate or delayed, many surgical options are available. Silicone gel

implants are safe and acceptable components of the reconstruct-

ive armamentarium [III, A]. Advances in gel cross-linking have

reduced silicone bleed, and cohesive gel implants are likely to

have fewer problems relating to capsular rupture. When consid-

ering implant-based reconstruction, patients should be informed

about risk of anaplastic large cell lymphoma [71]. Autologous tis-

sue ﬂaps can replace relatively large volumes of breast tissue.

Tissue can be taken from the latissimus dorsi muscle, transverse

rectus abdominis muscle, or deep inferior epigastric perforator

ﬂap, among others.

Recommendations:

•Breast reconstruction should be available and proposed to all

women requiring mastectomy [V, A].

•Immediate breast reconstruction should be offered to the vast

majority of patients, except for those presenting with inﬂam-

matory cancer [V, A].

•The optimal reconstruction technique for each patient should

be discussed individually taking into account anatomic, treat-

ment- and patient-related factors and preferences [V, A].

Advances in axillary management: Regional lymph node status

remains one of the strongest predictors of long-term prognosis in

primary breast cancer. ALND is associated with lymphoedema

affecting the upper limb in up to 25% of women following sur-

gery (up to 15% following axillary RT without surgical clearance

and below 10% following SLNB) [72,73]. The incidence of lym-

phoedema rises signiﬁcantly (to 40%) when axillary clearance is

combined with RT to the axilla. SLNB delivers less morbidity in

terms of shoulder stiffness and arm swelling and allows for a

reduced hospital stay [I, A]. With appropriate training in the

dual radiocolloid/blue dye technique or others (indocyanine

green ﬂuorescence technique or superparamagnetic iron oxide),

high identiﬁcation rates (over 97%), low false-negative rates and

favourable axillary recurrence rates following SLNB are achiev-

able [74].

There is no deﬁnite consensus for the pathological assessment

of SLNB. The signiﬁcance of occult micrometastases in terms of

surgical management and patient outcome appears to be negli-

gible [75]. Thus, the authors do not recommend routine IHC or

polymerase chain reaction (PCR) for the evaluation of sentinel

lymph nodes (SLNs) in patients unexposed to preoperative sys-

temic therapy, in agreement with other guidelines [V, E] [76–79].

Micrometastatic spread and isolated tumour cells are prognos-

tically equivalent to N0 disease, with local as well as systemic

treatment options selected based on other tumour- and patient-

based parameters. Based on the results of the IBCSG 23–01 trial,

further axillary treatment is not required when an SLN has micro-

metastasis (0.2–2 mm) [79]. For cases with macrometastatic

spread in the SLN, the randomised controlled trial ACOSOG-

Z0011 (10 years of median follow-up) reported non-inferior rates

of OS, DFS and locoregional recurrence-free survival when

ALND was avoided, for patients with clinical T1–T2 cN0 invasive

breast cancer and 1–2 SLNs containing metastases (treated with

BCS, tangential adjuvant RT including part of the axilla and adju-

vant systemic therapy) [80,81]. Therefore, all patients with

micrometastatic spread and patients with limited involvement of

the SLN, who are undergoing tangential breast RT and adjuvant

systemic treatment and meet the criteria of the randomised trials,

do not need any further axillary surgery [II, A]. For patients who

do not meet those criteria, a level I/II ALND needs to be consid-

ered. Another option in patients with cN0 and SLN metastases

(irrespective of the risk factors) is axillary RT, as demonstrated by

the AMAROS study [72].

Recommendations:

•SLNB, rather than full nodal clearance, is the standard of care

for axillary staging in early, clinically node-negative breast

cancer [II, A].

•Further axillary surgery following positive SLNB is not

required in case of low axillary disease burden (micrometa-

stases or 1–2 SLNs containing metastases, treated with post-

operative tangential breast RT) [II, A].

•Axillary radiation is a valid alternative in patients with posi-

tive SLNB, irrespective of the type of breast surgery [II, A].

Surgery for in situ malignancy (intraepithelial neoplasia):

DCIS may be treated with total mastectomy or BCT, provided

that clear resection margins can be achieved. There is no general

agreement on what is considered an optimal margin; however, re-

cent consensus has determined that a 2-mm margin is adequate

in DCIS treated with whole-breast radiotherapy (WBRT) [64],

because it is associated with lower rates of ipsilateral local recur-

rences and improved cosmetic outcomes [II, B].

Axillary node evaluation with SLNB is not required with in situ

malignancy but may be reasonable in large and/or high-grade

tumours, especially when mastectomy is required (in case an inci-

dental invasive cancer is subsequently identiﬁed in the surgical

specimen). The risk of a positive SLN with pure DCIS is small

(7%–9%) and most of the metastases found are micrometastases

or isolated tumour cells, detected by IHC [82,83]. The decision

to carry out an SLNB procedure should be based on the underly-

ing risk of invasion. The invasive breast cancer underestimation

rate is reported to be 20%–38%, and increases with the presence

of:

•a palpable mass;

•an associated density on the mammogram;

•poorly differentiated DCIS in the biopsy;

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Volume 30 | Issue 8 | 2019 doi:10.1093/annonc/mdz173 | 1201

•younger age; and

•larger extent of microcalciﬁcations [84,85].

If invasive cancer appears in the specimen, SLNB after conser-

vative surgery is feasible and accurate for staging the axilla.

Lobular neoplasia [formerly called lobular carcinoma in situ

(LCIS)], unlike DCIS, is considered a non-obligate precursor

to invasive cancer. It is regarded as a risk factor for future

development of invasive cancer in both breasts [relative

risk (RR): 5.4–12] and does not require active treatment. The

pleomorphic variant of lobular neoplasia may behave similarly

to DCIS and should be treated accordingly, after multidisciplin-

ary discussion.

Recommendations:

•BCS followed by WBRT or total mastectomy are acceptable

treatment options for DCIS [I, A].

•When treated with BCS, a 2-mm margin is adequate in DCIS

treated with WBRT [II, B].

•SLNB should not be routinely carried out in DCIS, apart

from patients with large and/or high-grade tumours, especial-

ly when mastectomy is required [V, D].

Management of occult breast cancer: Occult breast cancer is a

tumour presenting as lymph node metastases without identiﬁable

primary lesion within the breast. It constitutes <0.5% of all new

diagnosed breast cancer cases [86]. Routine diagnosis, apart from

standard breast and axillary imaging, requires breast MRI and

PET-CT (to exclude another primary tumour site). Management

includes ALND, although axillary RT in the case of a low axillary

disease burden might be an option. Local treatment options in-

clude WBRT and/or mastectomy, but there is no beneﬁt in doing

both [IV, B] [86,87].

Recommendation:

•The preferred locoregional management of occult breast can-

cer is ALND and WBRT [IV, B].

Risk-reducing mastectomy: Thelifetimeriskofbreastcancer

in a BRCA1 mutation carrier varies between 65% and 90%, with

a 10-year actuarial risk of contralateral breast cancer ranging

from 25% to 31% [88]. With bilateral mastectomy, the risk for

subsequent breast cancer is reduced by 90%–95%, whereas

improved survival has not yet been demonstrated in healthy

BRCA1 and BRCA2 mutation carriers [III, A] [89], although

signiﬁcant improvement in survival was observed among

BRCA1/2 mutation carriers with a history of unilateral breast

cancer [90].

Recommendations:

•Risk-reducing surgery (with prophylactic bilateral mastec-

tomy and reconstruction) may be offered to women at very

high risk, such as BRCA1 or BRCA2 mutation carriers or

those who have had previous chest RT at young age. Careful

genetic assessment and psychological counselling are manda-

tory before undertaking such surgery, and the option of in-

tense surveillance should also be discussed [III, A].

•Non-high-risk patients who opt for bilateral mastectomy

(incorporating contralateral risk-reducing surgery) rather

than the preferred breast conservation should be counselled

that survival outcomes in patients with early-stage breast can-

cer treated with BCS might be even better (and certainly not

worse) than those treated with mastectomy [V, A].

Surgery after PST: PST should be followed by surgery accord-

ing to the principles outlined above. Patients need to be evaluated

considering the baseline tumour characteristics as well as the

post-treatment outcomes to decide on surgical treatment.

Downsizing of a large unifocal primary tumour with PST will

allow BCS to be undertaken in a substantial proportion of

patients, even in tumours that were unresectable at diagnosis.

With multifocal disease or where reduction of the primary tu-

mour size is more limited, patients may still be eligible for BCS or

oncoplastic conservative surgery, and if not, mastectomy will be

required. Breast MRI is the most accurate modality for assessing

the extent of residual disease following PST. Breast MRI should

also be carried out before the start of PST for proper comparative

evaluation. When BCS is anticipated, it is necessary to mark the

primary site (using a marker clip or carbon localisation, under

US guidance) to facilitate accurate surgery [V, A].

In patients with clinically and imaging-negative axilla, al-

though SLNB can be carried out before or after preoperative sys-

temic therapy [91,92], a post-systemic therapy SLNB is

preferable [II, A] as it obviates the need for two separate surgeries

and facilitates the ﬁnal deﬁnition of pCR of the axilla. In patients

with limited initial (biopsy proven) nodal involvement (cN1)

who convert to negative, results from the SENTINA and

ACOSOG Z1071 studies have shown that SLNB can be carried

out in selected cases. In these studies, false-negative rates of SLN

post-systemic therapy range from 8% to 14.2% [93,94]. False-

negative rates can be improved by marking the biopsied positive

node(s) to verify their removal, as well as using dual tracer and

removing 3 SLNs [II, B] [95–97]. It should be stressed that any

tumour deposits in SLNs prompt ALND in these patients.

Available data do not support the routine use of SLNB in patients

with initial bulky nodal involvement (cN2–3) [II, E].

Recommendations:

•Surgery following PST should be carried out according to

general rules for early breast cancer and considering the base-

line tumour characteristics as well as the post-treatment out-

comes [II, A].

•If BCS is anticipated, marking of the tumour site must be car-

ried out [V, A] and pre- and post-treatment breast MRI

should be carried out [II, A].

•In clinically negative axilla, although SLNB may be carried

out either pre- or post-PST, post-PST SLNB is preferred [II, A].

•In patients with baseline axillary involvement converting to

negative, SLNB may be carried out in selected cases, and, if

negative, further axillary surgery may be avoided [II, B].

•Identiﬁcation of any tumour deposits in post-PST SLNB

prompts ALND [II, B].

Radiotherapy.

Whole-breast RT after BCS: Postoperative RT is strongly rec-

ommended after BCS [I, A]. WBRT alone reduces the 10-year

risk of any ﬁrst recurrence (including locoregional and distant)

Special article Annals of Oncology

1202 | Cardoso et al. Volume 30 | Issue 8 | 2019

by 15% and the 15-year risk of breast cancer-related mortality by

4% [98]. Boost RT gives a further 50% RR reduction and is indi-

cated for most patients who have unfavourable risk factors for

local control such as age <50 years, grade 3 tumours, presence of

vascular invasion or extensive intraductal component and non-

radical tumour excision (focally—otherwise further surgery

should be advocated) [I, A] [99,100].

Recommendations:

•Postoperative RT is strongly recommended after BCS [I, A].

•Boost RT is recommended to reduce the risk of in-breast re-

lapse in patients at higher risk of local recurrence [I, A].

Accelerated partial-breast RT after BCS: The concept of accel-

erated partial-breast irradiation (APBI) is an appealing ap-

proach to substantially shorten the overall treatment time.

The rationale for APBI is that the majority of local failures

occur in the vicinity of the primary tumour site, while so-called

‘elsewhere’ in-breast failures may represent a new primary tu-

mour. Excellent results with low local recurrence rates equiva-

lent to WBRT are reported for partial-breast irradiation

(accelerated and conventionally fractionated) using external

beam techniques [101,102] and brachytherapy [103].

However, for intraoperative RT, as used in the ELIOT (single

dose with electrons) and TARGIT (single dose with 50-kV X-

rays) randomised trials, the ipsilateral breast cancer recurrence

rate was signiﬁcantly higher in the APBI groups, compared

with the WBRT [104,105]. Based on these results, APBI might

be considered an acceptable treatment option in patients with a

low risk for local recurrence, for example those who are at least

50 years old, with unicentric, unifocal, node-negative, non-

lobular breast cancer, up to 3 cm without the presence of exten-

sive intraductal components or vascular invasion and with

negative margins, especially if they will receive adjuvant endo-

crine treatment [III, C] [106]. APBI may also be considered

for low-grade DCIS [III, C]. More and long-term results of

several past and ongoing prospective randomised APBI trials

are awaited.

Recommendation:

•APBI is an acceptable treatment option in patients with a low

risk for local recurrence [III, C].

Post-mastectomy RT: PMRT in node-positive patients reduces

the 10-year risk of any recurrence (including locoregional and

distant) by 10% and the 20-year risk of breast cancer-related

mortality by 8% [107]. The beneﬁts of PMRT are independent

from the number of involved axillary lymph nodes and the ad-

ministration of adjuvant systemic treatment. Therefore, although

PMRT is always recommended for high-risk patients, including

those with involved resection margins, 4 involved axillary

lymph nodes [I, A] and T3–T4 tumours independent of the nodal

status [II, B], it should also be considered for routine use in

patients with 1–3 positive axillary lymph nodes [I, A] [107].

Recommendation:

•PMRT is recommended for high-risk patients, including

those with involved resection margins, involved axillary

lymph nodes and T3–T4 tumours [I, A]; it should also be

considered in patients with 1–3 positive axillary lymph nodes

[I, A].

Regional RT: Older randomised trials have used extended

comprehensive locoregional RT encompassing the chest wall and

all lymph nodes. Recently presented results support this ap-

proach, especially for patients with involved axillary lymph nodes

[108–110]. Therefore, although clinically apparent lymph node

relapses (especially axillary and internal mammary) are rare,

nodal RT remains indicated for patients with involved lymph

nodes [I, B] [111]. The authors cannot discriminate which part of

the regional lymph nodes is most important to irradiate. The re-

cent Danish population-based study, in which left-sided node-

positive breast cancer patients received medial supraclavicular

RT and right-sided patients received the same treatment includ-

ing the internal mammary nodes, points to the importance of

including the internal mammary lymph nodes in the regional tar-

get volume. Regarding the supraclavicular part of the target vol-

ume, the authors agree with the European Society for

Radiotherapy and Oncology (ESTRO) guidelines for target vol-

ume delineation in breast cancer that advise to include only the

most caudal lymph nodes surrounding the subclavicular arch

and the base of the jugular vein [112]. After ALND, the resected

part of the axilla should not be irradiated, except in cases of clear

residual disease after surgery. After a positive SLNB without sub-

sequent ALND, regional RT is advised. Which axillary lymph

node levels should be irradiated can be deﬁned based on the pres-

ence of other risk factors including extent of nodal involvement,

tumour diameter, tumour grade, vascular invasion and tumour

site (i.e. in the lowest-risk cases, no RT; in the intermediate-risk

cases, exclusive level 1–2 RT; in the highest-risk cases, full level 1–

4 treatment, including the internal mammary nodes) [98,107].

Recommendations:

•Comprehensive nodal RT is recommended for patients with

involved lymph nodes (the role of irradiating particular nodal

volumes is poorly deﬁned; see details in text) [I, B].

•After ALND, routine axillary irradiation should not be done

to the operated part of the axilla [I, E].

RT and breast reconstruction: Many patients who have a clin-

ical indication for mastectomy are eligible for PMRT. In the case

of breast reconstruction, either immediate or delayed, a close col-

laboration between reconstructive surgeons and radiation oncol-

ogists is an absolute requirement to deﬁne the most appropriate

timing, type of reconstruction and RT target volumes. Based on

several patient- and treatment-related factors, individualisation

of the approach towards the combination of RT and reconstruc-

tion is required to obtain satisfactory results, irrespective of the

sequence and the reconstructive method used. Better outcomes

in patients with an indication for PMRT, both in terms of cosme-

sis and complication risks, are usually obtained with autologous

tissue reconstruction [113–115].

Recommendations:

•Postoperative RT, if indicated, can be administered after im-

mediate breast reconstruction [III, A].

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Volume 30 | Issue 8 | 2019 doi:10.1093/annonc/mdz173 | 1203

•An intensive multidisciplinary and interactive patient-

involving approach is required to individualise the best com-

bination of the sequence and type of breast reconstruction

and RT [V, A].

RT doses and fractionation: Doses used for local and/or re-

gional adjuvant irradiat ion have traditionally been 45–50 Gy in

25–28 fractions of 1.8–2.0 Gy with a typical boost dose of 10–

16 Gy in 2 Gy single doses. Shorter fractionation schemes (e.g.

15–16 fractions with 2.5–2.67 Gy single dose) have shown similar

effectiveness and comparable side-effects [I, A] [116–118]. These

data are not separately validated in young patients and in patients

with mastectomy and/or additional regional RT, as these patients

were either not included or underrepresented in the relevant tri-

als. As hypofractionation in many places is being introduced for

all patient subgroups, the authors advise to carefully monitor,

evaluate and compare outcomes in patients treated with hypo-

fractionation outside of the inclusion criteria of the published

studies. Further hypofractionation (up to ﬁve fractions in 1

week) is currently the subject of an ongoing prospective clinical

trial.

Recommendation:

•Moderate hypofractionation schedules (15–16 fractions of

3 Gy/fraction) are recommended for routine postoperative

RT of breast cancer [I, A].

RT for in situ malignancy (intraepithelial neoplasia):WBRT

after BCS for DCIS decreases the risk of local recurrence, with

survival equal to that after mastectomy [I, A] [119]. The de-

crease in the risk of local recurrence by RT is evident in all sub-

types of DCIS. WBRT is recommended in the majority of

women with DCIS, on the basis of the substantial reduction in

diseaserecurrenceleadingtoahigher rate of long-term breast

conservation and the inability to deﬁne subsets of women who

do not beneﬁt from RT [120–122]. However, in some patients

with low-risk DCIS (tumour size <10 mm, low/intermediate

nuclear grade, adequate surgical margins), the risk of local re-

currence following excision only is low and omitting radiation

can be an option. Tumour bed boost can be considered for

patients at higher risk for local failure [III, B]. APBI should only

be considered for highly selected low-risk patients, provided

that patients are monitored [123]. Total mastectomy with clear

margins in DCIS is curative, and PMRT is not recommended.

RT is not warranted for lobular intraepithelial neoplasia, with

the exception of the pleomorphic subtype that should be con-

sidered from a treatment-perspective point of view as high-

grade DCIS.

Recommendations:

•WBRT is recommended for the majority of women with

DCIS treated with BCS [I, A].

•In patients with low-risk DCIS, omitting radiation is an op-

tion [V, B].

•Tumour bed boost can be considered for patients at higher

risk for local failure [III, B].

•PMRT is not recommended for DCIS [I, E].

(Neo)Adjuvant systemic treatment

General recommendations. The decision on (neo)adjuvant sys-

temic treatment should be based on the predicted sensitivity to

particular treatment types, the beneﬁt from their use and an indi-

vidual’s risk of relapse (Tables 2–4, Figure 2) [V, A]. The ﬁnal de-

cision should also incorporate the predicted treatment short- and

long-term toxicities, the patient’s biological age, general health

status, comorbidities and preferences [V, A]. Adjuvant systemic

therapy should be started without undue delays, as data show an

important decrease in efﬁcacy when it is administered >12 weeks

after surgery [I, A] [124].

ET should be used in all luminal-like cancers [I, A]. Indications

for ChT within this subtype depend on the individual’s risk of re-

lapse, taking into account the tumour burden and features sug-

gestive of biological aggressiveness (grade, proliferation, vascular

invasion), presumed responsiveness to ET and patient preferen-

ces [I, A]. Features associated with lower endocrine responsive-

ness include low steroid receptor expression, lack of PgR

expression, high tumour grade and high expression of prolifer-

ation markers.

The majority of luminal A-like cancers do not require ChT, ex-

cept those with high disease burden [I, A]. Data from neoadju-

vant studies have demonstrated that ChT sensitivity depends on

the intrinsic phenotype, the highest being for HER2-positive

(when combined with anti-HER2 therapy) and TNBC. However,

even assuming the relative beneﬁt would be similar, the absolute

beneﬁt derived from adjuvant ChT varies substantially, depend-

ing on the individual risk of relapse, which is determined by both

the biology and the burden of the disease. For example, the abso-

lute beneﬁt of adjuvant ChT for a low-burden, luminal A-like

breast cancer is extremely small. When balanced against

the known short- and long-term side-effects, ChT is not recom-

mended in this setting.

Several decision-making tools such as PREDICT Plus, NPI and

Adjuvant! Online (the last is currently temporarily unavailable)

exist to help predict recurrence risk and potential beneﬁt from

systemic treatments [33–35]. In cases of uncertainty regarding

indications for adjuvant ChT, urokinase plasminogen activator–

plasminogen activator inhibitor 1 (uPA-PAI1) [I, A] [125]or

gene expression assays, such as MammaPrint, Oncotype DX,

Prosigna, Endopredict or Breast Cancer Index, may be used (see

LoE/GoR recommendations in ‘Diagnosis and pathology/mo-

lecular biology’ section and in Table 4). These assays can help de-

termine the individual’s recurrence risk and potentially predict

the beneﬁt of ChT in general [I, A] [19,126], albeit not for specif-

ic cytotoxic agents. Genomic tests are not recommended for

patients with:

•clinicopathological low-risk tumours (pT1a, pT1b, G1, ER

high, pN0); and/or

•patients with comorbid health conditions who are not candi-

dates for adjuvant ChT; and/or

•special types of luminal-like breast cancer such as low-grade

encapsulated papillary carcinoma and solid papillary carcin-

oma (which should be considered as DCIS for the sake of

treatment decisions [127]), and invasive tubular carcinoma

may be treated with locoregional treatment only, as the prog-

nosis is excellent; or

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•1–3 involved nodes coexisting with many other high-risk fac-

tors, or with 4 positive nodes for whom adjuvant ChT is

indicated [126].

Recommendations:

•Adjuvant systemic treatment should preferably start within

3–6 weeks after surgery [I, A] and neoadjuvant systemic ther-

apy should start as soon as diagnosis and staging is completed

(ideally within 2–4 weeks) [V, A].

•The decision on adjuvant systemic therapies should be based on

an individual’s risk of relapse (which depends on tumour bur-

den and tumour biology), the predicted sensitivity to particular

types of treatment, the beneﬁt from their use and their associ-

ated short- and long-term toxicities, the patient’s biological age,

general health status, comorbidities and preferences [V, A].

•All luminal-like cancers should be treated with ET [I, A].

•Most luminal A-like tumours do not require ChT, except

those with high disease burden [I, A].

•ChT use in luminal B-like HER2-negative patients depends

on individual risk of recurrence, presumed responsiveness to

ET and patient preferences [V, A].

•In cases of uncertainty regarding indications for adjuvant

ChT (after consideration of all clinical and pathological fac-

tors), expression of uPA-PAI1 [I, A] or gene expression

assays, such as MammaPrint [I, A], Oncotype DX [I, A],

Prosigna, Endopredict or Breast Cancer Index, can be used.

•Luminal B-like HER2-positive tumours should be treated

with ChT, ET and anti-HER2 therapy [I, A]. In selected low-

risk patients (T1abN0), the combination of anti-HER2 ther-

apy and ET alone may be used [III, B].

•Patients with TNBC should receive ChT, with the possible

exception of low-risk ‘special histological subtypes’ such as

secretory or adenoid cystic carcinomas or very early (T1aN0)

tumours [I, A].

•HER2-positive cancers should be treated with ChT plus anti-

HER2 therapy, with the possible exception of selected cases

with very low risk, such as T1aN0 tumours [I, A].

•ChT should not be used concomitantly with ET [II, D], with

the exception of gonadotropin-releasing hormone (GnRH)

analogues used for ovarian protection [I, A] [128].

•Anti-HER2 therapy may routinely be combined with non-

anthracycline-based ChT, ET and RT [I, A].

•RT may be delivered safely during anti-HER2 therapy, ET

and non-anthracycline, non-taxane-based ChT [III, B].

•If ChT and RT are to be used, ChT should usually precede

RT [V, A].

Recommendations:

•For premenopausal women, tamoxifen for 5–10 years is a

standard of care [I, A].

•In patients becoming postmenopausal during the ﬁrst 5 years

of tamoxifen, a switch to letrozole should be considered, de-

pending on predicted risk of late recurrence [II, A].

•In patients requiring ChT and who recover menses (in par-

ticular in the ﬁrst year but acceptable within the ﬁrst 2 years),

addition of OFS to ET should be strongly considered [I, A].

•The role of replacing tamoxifen with an AI can be considered

in high-risk patients; if used, it mandates effective OFS, with

regular biochemical control of oestrogen levels [I, A].

•The role of OFS in patients <35 years not requiring ChT is

not clear, but inferior outcomes of young luminal early breast

cancer patients suggest the use of the most effective ET (i.e.

combination with OFS) [III, A].

•OFS during ChT provides some protection of ovarian func-

tion and has no negative impact on oncological outcomes;

thus, it should be proposed to patients [I, A]. It should not,

however, be the sole fertility preservation method used, in

case of desired pregnancy [I, A].

Postmenopausal patients: AIs compared with tamoxifen allow

for about 4% absolute beneﬁt in DFS, with no signiﬁcant impact

on OS (1%–2%, depending on the choice of an upfront or se-

quential strategy) [139–141]. DFS beneﬁt was demonstrated for

their use upfront (non-steroidal AI and exemestane), after 2–

Table 3. Systemic treatment recommendations for early breast cancer subtypes

Subtype Recommended therapy Comments

Luminal A-like ET alone in the majority of cases Consider ChT if high tumour burden (4 LNs, T3

or higher)

Luminal B-like (HER2-negative) ChT followed by ET for the majority of cases

Luminal B-like (HER2-positive) ChT þanti-HER2 followed by ET for all patients If contraindications for the use of ChT, one may

consider ET þanti-HER2 therapy, although no

randomised data exist

HER2-positive (non-luminal) ChT þanti-HER2

Triple-negative (ductal) ChT

For special histological types, the authors recommend following the St Gallen recommendations [23] that propose ET for endocrine-responsive histologies

(cribriform, tubular and mucinous), ChT for high-risk endocrine-nonresponsive histologies (medullary, metaplastic) and no systemic therapy for low-risk

endocrine nonresponsive histologies (adenoid cystic and apocrine).

ChT, chemotherapy; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; LN, lymph node.

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Table 4. Summary of biomarkers used in treatment decision making

Biomarker Method Use LoE GoR

ER IHC

Positive if 1%

Essential to the characterisation of

the IHC luminal-like group

Poor prognostic marker if negative

Predictive marker for ET

Mandatory for ET prescription

PgR IHC

Positive if 1%

If negative tumour classiﬁed as IHC

luminal B-like

Strong poor prognostic marker if

negative

Predictive marker for ET

HER2 IHC

Positive if >10% complete mem-

brane staining (3þ)

ISH

Single probe

if HER2 6 copies

Dual probe

Positive if HER2/CEP17 2 and

HER2 copies 4

Or HER2/CEP17 <2 and HER2

copies 6

Essential to the characterisation of:

HER2-enriched (ER-negative)

Luminal B-like, HER2-positive

Prognostic marker

Predictive marker for anti-HER2

treatment

Mandatory for anti-HER2 therapy re-

gardless of treatment line

Ki67 IHC

No ﬁnal consensus on cut-off but val-

ues <10% are considered low and

>30% are considered high

Absence of international consensus

for scoring and threshold

Prognostic value in ER-positive,

HER2-negative tumours (primary

tumours and post-neoadjuvant

residual tumour)

Absence of prognostic value in

HER2-positive or triple-negative

tumours

Predictive of response to

neoadjuvant ET

Predictive of response to

neoadjuvant ChT

Expert opinion A

If elevated, ChT is often prescribed in

ER-positive, HER2-negative

tumours

Expert opinion A

Part of the IHC deﬁnition of luminal-

like tumours

Ki67 low, luminal A-like

Ki67 high, luminal B-like

II B

Intrinsic subtypes Gene expression proﬁle, N-Counter

technology

Prognostic II and III B

Predictive: Different responses to

neoadjuvant ChT and anti-HER2

therapy according to the subtype

First-generation signatures

(Mamma Print, Oncotype

DX)

Gene expression proﬁle, RT-PCR For ER-positive, HER2-negative

tumours

Prognostic

(Neo)Adjuvant ChT is indicated if

high risk or high score

Continued

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3 years of tamoxifen (non-steroidal AI and exemestane) or as

extended adjuvant therapy, after 5 years of tamoxifen (letrozole

and anastrozole) [142–144]. Numerous studies demonstrated an

advantage of 10 years rather than 5years of ET, although the opti-

mal duration and regimen of adjuvant ET are currently unknown

and there is a minimal beneﬁt for the use of AIs for more than

5 years [I, C] [142,145].

The use of tamoxifen is associated with an increased risk of

thromboembolic complications and endometrial hyperplasia

(including a small risk of endometrial cancer). Caution should be

exercised in patients with risk factors for these conditions, and

appropriate diagnostic tests should be carried out in the presence

of symptoms suggestive of these complications. Patients on tam-

oxifen should be advised to avoid the use of strong and moderate

CYP2D6 inhibitors (although there are no unequivocal data on

their detrimental effects). If such drugs cannot be replaced, a

switch to alternative treatment, i.e. AIs, should be considered [IV,

B] [146,147]. The study of CYP2D6 polymorphisms as a decision

aid regarding the use of adjuvant tamoxifen is not proven and

should not be done outside a clinical trial.

Patients undergoing OFS and those taking AIs are at an

increased risk of bone loss and musculoskeletal pain often affect-

ing their treatment compliance.

Recommendations:

•For postmenopausal women, AIs (both non-steroidal and ster-

oidal) and tamoxifen are considered standard treatments [I, A].

•AIs can be used upfront (non-steroidal AI and exemestane),

after 2–3 years of tamoxifen (non-steroidal AI and exemes-

tane) or as extended adjuvant therapy, after 5 years of tam-

oxifen (letrozole and anastrozole) [I, A].

•Extended adjuvant therapy should be discussed with all

patients, except those with a very low risk of relapse [I, A],

but the optimal duration and regimen of adjuvant ET are cur-

rently unknown. There is only a minimal beneﬁt for the use

of AIs for more than 5 years [I, C].

•Patients undergoing OFS and those taking AIs should be

advised to have adequate calcium and vitamin D3 intake and

undergo periodic assessment of bone mineral density [by

dual energy X-ray absorption (DEXA) scan] [I, A].

•The study of CYP2D6 polymorphisms as a decision aid

regarding the use of adjuvant tamoxifen is not proven and

should not be done [I, E].

Chemotherapy. ChT is recommended in the vast majority of

triple-negative, HER2-positive breast cancers and in high-risk lu-

minal-like HER2-negative tumours [I, A]. The absolute beneﬁt of

ChT is more pronounced in ER-negative tumours [148,149].

The most frequently used regimens contain anthracyclines and/

or taxanes, although in selected patients cyclophosphamide/

methotrexate/5-ﬂuorouracil (CMF) may still be used. Four cycles

of doxorubicin and cyclophosphamide (AC) are considered to

have equal efﬁcacy to 6 cycles of CMF. There is no place for rou-

tine use of 6 cycles of three-drug anthracycline-based regimens,

possibly except in patients with strong contraindications to tax-

anes [I, D] [150,151]. Randomised phase III data have shown

that 5-ﬂuorouracil (5-FU) can be dropped from anthracycline-

based regimens because it does not add efﬁcacy and it increases

toxicity; therefore, the standard anthracycline-based regimens

are AC or epirubicin plus cyclophosphamide (EC) [I, A] [152].

The addition of taxanes slightly improves the efﬁcacy of ChT,

independently of age, nodal status, tumour size or grade, steroid

receptor expression or tamoxifen use, but at the cost of increased

non-cardiac toxicity; most importantly it allows for the use of a

lower total dose of anthracyclines through the use of sequential

regimens [I, A] [150,153]. Sequential use of anthracyclines and

taxanes is superior to concomitant use [154] and is also much less

toxic [I, A]. Some data suggest that a taxane/anthracycline se-

quence may be slightly more effective than the traditionally used

anthracycline/taxane order [155] but both are acceptable [I, A].

Overall, ChT regimens based on anthracyclines and taxanes re-

duce breast cancer mortality by about one-third [129,150]. Non-

Table 4. Continued

Biomarker Method Use LoE GoR

Can be carried out in biopsy or surgi-

cal specimen

Second-generation signa-

tures (Prosigna

Endopredict

)

N-Counter

technology, RT-PCR For ER-positive, HER2-negative

tumours, include T size and N status

in their ﬁnal score

Prognostic

(Neo)Adjuvant ChT is indicated if

high risk or high score

Can be carried out in biopsy or surgi-

cal specimen

According to the International Ki67 Working Group Guidelines [215].

A decrease in Ki67 expression during neoadjuvant ET is highly predictive of response.

ChT, chemotherapy; ER, oestrogen receptor; ET, endocrine therapy; GoR, grade of recommendation; HER2, human epidermal growth factor receptor 2; IHC,

immunohistochemistry; ISH, in situ hybridisation; LoE, level of evidence; PgR, progesterone receptor; RT-PCR, reverse transcription polymerase chain

reaction.

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anthracycline, taxane-based regimens, such as 4 cycles of doce-

taxel and cyclophosphamide (TC), may be used as an alternative

to 4 cycles of anthracycline-based ChT [I, A] [156], although

such an approach has proven inferior to a combination of anthra-

cyclines and taxanes [157]. No robust, prospective randomised data

exist on the use of platinum compounds in the adjuvant setting, ei-

ther in unselected triple-negative tumours or in BRCA1/2 mutation

carriers and they cannot therefore be recommended [V, E].

The advantages and potential complications of the use of

implanted devices (like Port-a-Cath) providing venous access for

administration of systemic therapy should be discussed with all

patients (for detail, please refer to the ESMO Clinical Practice

Guidelines on central venous access in oncology [158]).

High-dose ChT with stem cell support should not be used

[I, E].

Recommendations:

•ChT should be administered for 12–24 weeks (4–8 cycles)

[I, A].

•Sequential anthracycline/taxane-based regimen is the stand-

ard for the majority of patients [I, A].

•In selected lower-risk patients, 4 cycles of anthracycline- or

taxane-based ChT or CMF may be used [II, B].

•Non-anthracycline regimens may be used in patients at risk

of cardiac complications [I, A].

•Anthracycline-based regimens should not include 5-FU (EC

or AC is standard) [I, A].

•Platinum compounds should not be used routinely in the ad-

juvant setting [V, E].

•The use of dose-dense schedules [with granulocyte colony-

stimulating factor (G-CSF) support] should be considered,

particularly in highly proliferative tumours [I, A] [159,160].

Anti-HER2 therapy. Trastuzumab combined with ChT in

patients with HER2 overexpression/ampliﬁcation approximately

halves the recurrence and mortality risk, compared with ChT

alone, translating into a 10% absolute improvement in long-term

DFS and 9% increase in 10-year OS [I, A] [161–163] (see

Figure 3). Trastuzumab is approved in patients with node-

positive disease and in N0 patients with tumours >1 cm. Due to

the relatively high relapse risk, even in patients with N0 tumours

<1 cm, it should also be considered in this patient group, particu-

larly in ER-negative disease [IV, B] [164]. If a HER2 test result is

ultimately deemed to be equivocal, even after reﬂex testing with

an alternative assay, HER2-targeted therapy may also be consid-

ered, although the true beneﬁt from trastuzumab in those

patients is still unknown [V, B].

In most studies, trastuzumab was administered for 1 year, al-

though in the FinHER trial a similar improvement was obtained

with only 9 weeks of treatment [II, A] [165]. No additional bene-

ﬁt was demonstrated for 2-year trastuzumab administration in

the HERA trial [166]. A few studies compared shorter versus

standard 12-month administration of trastuzumab, but only the

largest Persephone trial was able to show the non-inferiority of

Early Breast Cancer

ER-negative ER-positive

HER2-positive HER2-positive

TNBC HER2-negative

Ductal Luminal BL

uminal B

Special histological typesc, N0,

no other risk factors Luminal A

Observation or ChT

[III, B]

ChT only in selected

cases with high-

disease burden

[I, A]

ChT

[I, A]

ET ± ChTd

[I, A]

ChTa + anti-HER2b

[I, A]

ChTe + anti-HER2b

+ ET [I, A]

Figure 2. (Neo)-adjuvant systemic treatment choice by marker expression and intrinsic phenotype.

With possible exception of selected cases with very low risk T1abN0.

Anti-HER2: trastuzumab 6pertuzumab.

Adenoid cystic or apocrine, secretory carcinoma, low-grade metaplastic carcinoma.

Depending on level of ER and PgR expression, proliferation, genomically assessed risk, tumour burden and/or patient preference.

Except for very low-risk patients T1abN0 for whom ET/anti-HER2 therapy alone can be considered.

ChT, chemotherapy; ER, oestrogen receptor; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; N0, node-negative;

PgR, progesterone receptor; TNBC, triple-negative breast cancer.

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the shorter 6-month regimen, although this could not be demon-

strated in the other studies [167–170]. Therefore, a duration of 1

year remains the standard, although in highly selected low-risk

patients, who receive anthracycline/taxane-based ChT, shorten-

ing trastuzumab duration to 6 months may be discussed [I, B].

Further data and longer follow-up are needed and several ques-

tions are still open regarding de-escalation of anti-HER2 therapy,

ChT or both in HER2-positive early breast cancer. Trastuzumab

is usually well-tolerated, although cardiac dysfunction may

occur, usually reversible. Baseline cardiac function (expressed by

the left ventricular ejection fraction) is indispensable before the

start of treatment and periodic monitoring of cardiac function

(usually every 3–4 months) during treatment is necessary.

Due to its cardiotoxicity, trastuzumab should not be routinely

administered concomitantly with anthracyclines [I, D]. Combination

with taxanes is safe and has been demonstrated to be more effective

than sequential treatment [I, A] [162]. Trastuzumab may also be safe-

ly combined with RT and ET.

In the neoadjuvant setting, dual anti-HER2 blockade associ-

ated with ChT (trastuzumab/lapatinib, trastuzumab/pertuzu-

mab) has led to improvements in the pCR rate when compared

with ChT associated with one anti-HER2 agent [171–173].

However, this did not translate into statistically signiﬁcant im-

provement in long-term outcomes for the combination of trastu-

zumab/lapatinib, and such a treatment cannot be recommended

[I, E] [174]. For the trastuzumab/pertuzumab combination, after

reviewing potential risks and beneﬁts (including the ﬁnancial im-

pact), in selected higher-risk cases it is an acceptable option as

PST [II, B]. In the adjuvant setting, the addition of pertuzumab

resulted in a very small (0.9%) improvement in invasive DFS

[175] in the intention-to-treat (ITT) population and a higher

beneﬁt (2.5%) in the high-risk population (deﬁned as N-positive

or ER-negative), leading to its approval in the latter setting by the

European Medicines Agency (EMA) and the United States Food

and Drug Administration (FDA). This combination can there-

fore be considered in high-risk patients (as per above deﬁnition)

[I, A; ESMO-Magnitude of Clinical Beneﬁt Scale (ESMO-MCBS)

v1.1 score: B] (see Table 5). It is currently unknown if dual block-

ade in the neoadjuvant setting should be continued for a total of

1 year in patients for whom a pCR is achieved or if this treatment

should be stopped at surgery. For this reason, and until new trials

are concluded, it is recommended to decide on the administration

of 1 year of trastuzumab/pertuzumab based on the risk assessment

at diagnosis; the treatment may start before or after the surgery, in

accordance with the approval wording by the regulators.

For patients with HER2-positive early breast cancer who had

residual invasive disease after completion of neoadjuvant ChT

combined with anti-HER2 therapy, substitution of adjuvant tras-

tuzumab with trastuzumab emtansine (T-DM1) decreases the

risk of recurrence of invasive breast cancer or death by 50% and is

recommended, once approved and where available [176].

Extended adjuvant anti-HER2 therapy with neratinib in

patients who completed 1 year of trastuzumab demonstrated

additional improvement in DFS, in particular in the ER-positive/

HER2-positive subgroup, albeit at the cost of signiﬁcant toxicity,

mostly diarrhoea [177]. It can be considered in some selected

high-risk patients, with appropriate diarrhoea prophylaxis and

management [I, B; ESMO-MCBS v1.1 score: A]. It is unknown,

however, if this beneﬁt is maintained for patients who have previ-

ously received dual blockade with trastuzumab/pertuzumab.

In small, node-negative, mostly ER-positive, HER2-positive

tumours with no other risk factors, the combination of single-

agent paclitaxel and trastuzumab provided excellent outcomes in

a single-arm phase II study [178]. No randomised data exist to

support omission of ChT in this group. However, in cases of con-

traindications for ChT or patient refusal, it is acceptable to offer the

combination of targeted agents (ET and trastuzumab) [V, A].

Recommendations:

•(Neo)Adjuvant trastuzumab is highly effective and should be

given to all HER2-positive early breast cancer patients who

do not have contraindications for its use, with the possible

exception of selected cases with very low risk, such as T1aN0

tumours [I, A].

•If a HER2 test result is ultimately deemed to be equivocal,

even after reﬂex testing with an alternative assay, HER2-

targeted therapy may also be considered [V, B].

•One year of (neo)adjuvant trastuzumab remains a standard

for the vast majority of HER2-positive patients [I, A].

•In highly selected, low-risk patients who receive

anthracycline/taxane-based ChT, shortening trastuzumab

duration to 6 months may be discussed [I, A].

•Trastuzumab should usually not be given concomitantly with

anthracycline-based ChT [I, D]; it can be safely combined

with non-anthracycline-based ChT (i.e. taxanes) and its con-

comitant use is more effective than sequential treatment [I, A].

•Regular cardiac monitoring is mandatory before starting and

during trastuzumab treatment [I, A].

•Dual blockade with trastuzumab/lapatinib has not led to

improved long-term outcomes and cannot therefore be rec-

ommended [I, E].

•Dual blockade with trastuzumab/pertuzumab can be consid-

ered in high-risk patients, deﬁned as N-positive or ER-

negative, for the duration of 1 year, starting before or after

surgery [I, A; ESMO-MCBS v1.1 score: B].

•In cases of residual invasive disease after completion of neo-

adjuvant ChT combined with anti-HER2 therapy, adjuvant

trastuzumab should be replaced by adjuvant T-DM1, once

approved and where available [I, A].

•Extended anti-HER2 therapy with neratinib may be consid-

ered in selected high-risk patients, not previously treated with

dual blockade, and with appropriate diarrhoea prophylaxis

and management [I, B; ESMO-MCBS v1.1 score: A].

Primary (neoadjuvant) systemic therapy. In locally advanced and

large ‘operable’ cancers, in particular when mastectomy is

required due to tumour size, PST is recommended to decrease

the extent of surgery needed [I, A]. In operable cases, the timing of

treatment (pre- versus postoperative) has no effect on long-term

outcomes, except a possible small increase in locoregional recur-

rences in the PST group, but without impact on survival [II, A]

[153,179–181]. Additionally, PST allows for assessment of therapy

response, which is of well-established prognostic value and may

guide choice of postoperative treatment. Thus, in subtypes highly

sensitive to ChT, such as triple-negative and HER2-positive, a

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neoadjuvant approach should be preferred, in tumours >2cm[II,

A] (see Figure 1).

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

treatment may also be used preoperatively. If ChT is used, it is

recommended to deliver all planned treatment without unneces-

sary breaks, i.e. without dividing it into preoperative and postop-

erative periods, irrespective of the magnitude of tumour response

[II, A]. This will increase the probability of achieving a pCR,

which is a proven factor for a good prognosis. Unfortunately,

there are no validated predictive markers to allow the tailoring of

the regimen to the individual patient. The addition of a platinum

compound (usually carboplatin) to preoperative ChT allows for

an increase in the pCR rate in triple-negative tumours. Data on

the effect of those compounds on long-term outcomes are con-

ﬂicting, in particular in patients with deleterious BRCA1/2 muta-

tions [I, C] [182–185], thus strong recommendations regarding

selection of patients who may beneﬁt from addition of carbopla-

tin cannot be given (see Figure 2).

After delivery of the standard 4–8 cycles of anthracyclines and

taxanes, in the absence of pCR, addition of 6–8 cycles of capecita-

bine resulted in improvement of DFS and OS (in particular in

triple-negative tumours) in one trial run in Asian patients [186].

Although more data are necessary in non-Asian patients, this

option may be offered to triple-negative patients who do not

achieve a pCR after optimal neoadjuvant ChT [I, B]. The value of

adjuvant capecitabine after the use of a platinum compound in

the neoadjuvant setting is currently unknown.

ER-positive/HER2-negative carcinomas, especially of the lobu-

lar histology and luminal A-like subtype, are generally less re-

sponsive to primary ChT and may beneﬁt more from primary ET

[187]. In postmenopausal patients, primary (neoadjuvant) ET is

usually given for 4–8 months before surgery or until maximum

response and continued postoperatively. AIs are more effective

than tamoxifen in decreasing the tumour size and facilitating less

extensive surgery [I, A] [188–190]. Good response to preopera-

tive ET, expressed by Ki67 drop or preoperative endocrine prog-

nostic index (PEPI) score, may, in combination with other

clinical factors, guide in selecting patients with favourable prog-

nosis not requiring adjuvant ChT [191–193].

Due to paucity of data from randomised trials, preoperative

ET is not routinely recommended in premenopausal patients,

outside clinical trials. However, in highly selected patients with

luminal A-like tumours and no indication for ChT, who are not

candidates for optimal surgery, preoperative ET consisting of

OFS plus an aromatase inhibitor can be considered [II, C]

[194].

HER2-positive

Breast Cancer

pCR

Initially N-positive

or ER-negative Other cases

No pCR

Pre-operative ChT + trastuzumab ± pertuzumab

Complete 1 year of dual blockade

[I, A; MCBS B]a

Complete 1 year of trastuzumab

[I, A]

Complete 1 year of trastuzumab

[I, A] T-DM1 [I, A]b

Figure 3. HER2-positive breast cancer treatment.

ESMO-MCBS v1.1 scores for new therapies/indications approved by the EMA since 1 January 2016. The scores have been calculated by the

ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee.

Not yet EMA-approved.

ChT, chemotherapy; EMA, European Medicines Agency; ER, oestrogen receptor; ESMO-MCBS, ESMO-Magnitude of Clinical Beneﬁt Scale; HER2,

human epidermal growth factor receptor 2; N-positive, node-positive; pCR, pathological complete response; T-DM1, trastuzumab emtansine.

Special article Annals of Oncology

1210 | Cardoso et al. Volume 30 | Issue 8 | 2019

Table 5. ESMO-MCBS table for new therapies/indications in early breast cancer

Therapy Disease setting Trial Control Absolute sur-

vival gain

HR (95%CI) QoL/toxicity ESMO-MCBS

score

Pertuzumab þstandard

adjuvant ChT þ1 year

of treatment with

trastuzumab

Early breast cancer

adjuvant

Adjuvant pertuzumab and

trastuzumab in early HER2-

positive breast cancer

(APHINITY: a randomised

placebo-controlled phase III

study) [174]

Phase III

NCT01358877

Placebo þstandard

adjuvant ChT þ1

year of treatment

with trastuzumab

OS not yet

reported; 0.9%

improvement in

3-year iDFS

(94.1% versus

93.2%) in the

ITT population

iDFS HR: 0.81 (0.66–

1.00) in the ITT

population

Increased grade 3

diarrhoea (9.8% ver-

sus 3.7%)

B (Form 1)

Neratinib (1 year of oral

therapy, 240 mg/day)

Early breast cancer

adjuvant

Neratinib after trastuzumab-

based adjuvant therapy in

HER2-positive breast cancer

(ExteNET): 5-year analysis of

a randomised, double-blind,

placebo-controlled, phase III

trial [176]

Phase III

NCT00878709

1 year of oral placebo OS not yet

reported; 2.5%

improvement in

5-year iDFS

(90.2% versus

87.7%) in the

ITT population

iDFS HR: 0.73 (0.57–

0.92) in the ITT

population

Increased grade 3

diarrhoea (40% ver-

sus 2%)

A (Form 1)

EMA approvals since January 2016.

ESMO-MCBS version 1.1 [214]. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee.

High-risk population deﬁned as N-positive or ER-negative; corresponds to the regulatory approval setting (by the EMA and the FDA).

ChT, chemotherapy; CI, conﬁdence interval; EMA, European Medicines Agency; ER, oestrogen receptor; ESMO-MCBS, ESMO-Magnitude of Clinical Beneﬁt Scale; FDA, Food and Drug Administration; HER2,

human epidermal growth factor receptor 2; HR, hazard ratio; iDFS, invasive disease-free survival; ITT, intention to treat; N-positive, node-positive; OS, overall survival; QoL, quality of life.

Annals of Oncology Special article

Volume 30 | Issue 8 | 2019 doi:10.1093/annonc/mdz173 | 1211

Recommendations:

•PST should be used to reduce the extent of surgery in locally

advanced and large operable cancers, in particular when

mastectomy is required due to tumour size [I, A]. It should

also be considered in all patients with tumours >2 cm for

which ChT is deemed necessary, in particular with triple-

negative and HER2-positive subtypes [I, B].

•Drugs and drug regimens used in the preoperative setting

should be selected according to rules identical to those in the

postoperative setting [I, A]. A sequential regimen of anthra-

cyclines and taxanes is recommended for the vast majority of

patients [I, B].

•The addition of a platinum compound may be considered in

triple-negative tumours and/or in patients with deleterious

BRCA1/2 mutations [I, C].

•If PST is used, all ChT should be delivered preoperatively

[I, B].

•In high-risk, triple-negative patients not achieving pCR after

standard neoadjuvant ChT, the addition of 6–8 cycles of

capecitabine postoperatively may be considered [I, C].

•In postmenopausal patients with ER-positive/HER2-negative

cancers requiring PST and without a clear indication for ChT,

preoperative ET (4–8 months or until maximum response)

should be considered and continued postoperatively [I, A].

Bisphosphonates for early breast cancer. Prophylactic use of

bisphosphonates in women with a low-oestrogen status (postme-

nopausal or undergoing OFS) leads to prolongation of DFS and

breast cancer-speciﬁc survival [135,195–197]. In patients with

treatment-related bone loss, bisphosphonates decrease the risk of

skeletal complications [I, A] [198,199].

Recommendations:

•Bisphosphonates for early breast cancer are recommended in

women with low-oestrogen status (undergoing OFS or post-

menopausal), especially if at high risk of relapse [I, A].

•Bisphosphonates are also recommended in patients with

treatment-related bone loss [I, A].

Treatment of elderly patients. Due to the limited data from rand-

omised studies, strong recommendations cannot be made regard-

ing the use of (neo)adjuvant systemic therapies in this

population. Full doses of drugs should be used, whenever feasible

[V, A]. In patients suitable for standard ChT, single-agent capeci-

tabine or docetaxel has been demonstrated to be inferior to the

standard multidrug regimen (AC or CMF) [II, D] [200,201]. In

frail elderly patients, the use of a single-agent pegylated liposomal

doxorubicin and metronomic cyclophosphamide plus metho-

trexate is feasible and demonstrates similar activity, although

their efﬁcacy in comparison to standard ChT remains unknown

[II, B] [202].

A geriatric assessment should be carried out before treatment

decisions; the G8 tool can be used as a screening tool to select

patients needing a full geriatric assessment [II, A] [203].

Recommendations:

•Treatment of elderly early breast cancer patients should be

adapted to biological (not chronological) age, with

consideration of less aggressive regimens in frail patients. In

patients suitable for standard ChT, a standard multidrug regi-

men should be used [II, B].

•A geriatric assessment should be carried out before making

treatment decisions [II, A].

Treatment of male breast cancer. The vast majority of breast can-

cer cases in male patients are ductal invasive carcinomas of the

luminal-like type. Tamoxifen is the standard adjuvant systemic

therapy [IV, A]; AIs should not be used alone in this setting,

due to lower efﬁcacy [IV, E] [189,190]. ChT and anti-HER2 ther-

apy indications and regimens should follow the same recommen-

dations as those for breast cancer in female patients [IV, A] [190–

191].

Recommendations:

•Tamoxifen is the standard adjuvant ET for male breast cancer

patients [IV, A].

•If a strong contraindication exists for the use of tamoxifen, a

combination of an AI plus a luteinizing hormone-releasing

hormone (LHRH) agonist may be considered, but its higher

toxicity must be discussed with the patient to avoid compli-

ance issues [IV, B].

•An AI alone should not be used as adjuvant ET in male breast

cancer patients [IV, E].

•ChT and anti-HER2 therapy indications and regimens should

follow the same recommendations as those for breast cancer

in female patients [IV, A].

Systemic adjuvant therapy for DCIS. In patients treated conser-

vatively for ER-positive DCIS, both tamoxifen and AIs decrease

the risk of invasive and non-invasive recurrences and reduce the

incidence of second primary (contralateral) breast cancer, albeit

without an effect on OS [204–206].

Recommendations:

•Both tamoxifen and AIs may be used after conservative local

treatment of DCIS to prevent local recurrence and to de-

crease the risk of development of a second primary breast

cancer [I, B].

•Following mastectomy for DCIS, tamoxifen or AIs might

be considered to decrease the risk of contralateral breast can-

cer in patients who are at a high risk of new breast tumours

[II, B].

Personalised medicine

Breast cancer was the pioneer of personalised medicine in oncol-

ogy. ER, PgR and HER2 status have been used for many years as

predictive factors to select patients for targeted ET or anti-HER2

treatment [I, A]. In recent years, surrogate intrinsic tumour phe-

notypes, based on biomarker expression, have also been used for

treatment individualisation [I, A]. Additionally, uPA-PAI1, a

marker of tumour invasiveness, has been validated in prospective

clinical trials as a prognostic marker for both node-negative and

node-positive breast cancer [I, A] and can be used in treatment

decision making for early breast cancer [125]. Molecular signa-

tures for ER-positive breast cancer such as MammaPrint,

Special article Annals of Oncology

1212 | Cardoso et al. Volume 30 | Issue 8 | 2019

Oncotype DX, EndoPredict, Prosigna and Breast Cancer Index

are commercially available and may help with (neo)adjuvant

ChT decision making, in conjunction with all clinicopathological

factors, in cases where decisions are challenging, such as luminal

B-like/HER2-negative and node-negative/nodes 1–3-positive breast

cancer [126,192]. Results from large phase III prospective clinical

trials, such as MINDACT [37], TAILORx [39]andPlanB[38]have

identiﬁed molecularly deﬁned groups of patients where adjuvant

CT can be safely spared. Results from the phase III adjuvant

RxPONDER trial in N-positive patients are awaited. A biomarker

summary is shown in Table 4.

Recommendations:

•ER, PgR and HER2 status should guide all systemic treatment

decisions [I, A].

•Surrogate intrinsic tumour phenotypes, based on expression

of ER, PgR, HER2 and Ki67, should be used to deﬁne subpo-

pulations of breast cancers [I, A].

•Expression of uPA-PAI1 or multigene panels, such as

MammaPrint, Oncotype DX, EndoPredict, Prosigna or

Breast Cancer Index, may be used in conjunction with all

clinicopathological factors to guide systemic treatment deci-

sions in patients where these decisions are challenging, such as

luminal B-like/HER2-negative and node-negative/nodes 1–3-

positive breast cancer [I, A].

Follow-up, long-term implications and

survivorship

The aims of follow-up are:

•to detect early local recurrences or contralateral breast cancer;

•to evaluate and treat therapy-related complications (such as

menopausal symptoms, osteoporosis and second cancers);

•to motivate patients continuing adjuvant ET; and

•to provide psychological support and information in order to

enable a return to normal life after breast cancer.

Ten-year survival of breast cancer exceeds 70% in most

European regions, with 89% survival for local and 62% for re-

gional disease [207]. The annual hazard of recurrence peaks in

the second year after diagnosis but remains at 2%–5% in years 5–

20 [208]. Patients with node-positive disease tend to have higher

annual hazards of recurrence than patients with node-negative

cancers. In the ﬁrst years the risk of recurrence is higher in

patients with ER-negative cancers, but 5–8 years after diagnosis

their annual hazard of recurrence drops below the level of ER-

positive tumours [III, B] [209]. Relapse of breast cancer may

occur as late as >20 years after the initial diagnosis, particularly

in patients with ER/PgR-positive disease [208].

Despite the fact that no randomised data exist to support any

particular follow-up sequence or protocol, balancing patient

needs, follow-up costs and burden is necessary [V, A]. Every visit

should include a thorough history, eliciting of symptoms and a

physical examination. Apart from routine mammography 6

breast US, an MRI of the breast may be indicated for young

patients, especially in cases of dense breast tissue and genetic or

familial predispositions. US can also be considered in the follow-

up of lobular invasive carcinomas [III, B]. In asymptomatic

patients, there are no data to indicate that other laboratory or

imaging tests (e.g. blood counts, routine chemistry tests, chest X-

rays, bone scans, liver US exams, CT scans, FDG-PET-CT) or any

tumour markers such as cancer antigen 15-3 (CA15-3) or carci-

noembryonic antigen (CEA) produce a survival beneﬁt [I, A].

However, routine blood tests may be indicated as follow-up for

patients on ET due to the potential side-effects of these drugs,

namely in the lipid proﬁle, although the impact of these changes

on the risk of cardiovascular complications has not been fully

demonstrated [V, B]. For patients on tamoxifen, an annual gy-

naecological examination by an experienced gynaecologist is rec-

ommended [V, B]. Routine transvaginal US is not recommended,

as it leads to unacceptably high numbers of false-positive ﬁndings

[210].

Very importantly, most available data for follow-up recom-

mendations come from an era of less sophisticated diagnostic

procedures and less efﬁcacious treatment of advanced disease,

and new trials are urgently needed to reassess this question. In

symptomatic patients or in the case of abnormal ﬁndings on

examination, appropriate tests should be carried out immediately

[V, A].

In addition to adequate local and systemic treatments, epi-

demiological evidence points towards lifestyle factors having an

effect on the prognosis of patients with breast cancer. For ex-

ample, regular exercise provides functional and psychological

beneﬁts [II, B] [211] and possibly reduces the risk of recurrence.

Regular exercise is therefore a relatively simple and effective rec-

ommendation that should be made to all suitable patients after

treatment of breast cancer [II, B] [211]. Weight gain and obesity

are likely to adversely affect the prognosis of breast cancer [212].

Nutritional counselling should be recommended as part of the

survivor care for all obese patients [III, B]. The use of HRT

increases the risk of recurrence and is usually contraindicated

[I, D] [213].

Specialised rehabilitation facilities and services are indispens-

able to decrease the physical, psychological and social sequelae of

breast cancer treatment. The main aims of physiotherapy should

include the prevention and treatment of lymphoedema, assuring

full range of movements of arm and shoulder, and prevention or

correction of postural defects resulting from mastectomy. There

are no data indicating that any type of physiotherapy may in-

crease the risk of recurrence. When indicated, patients should not

be denied access to rehabilitation services [I, A].

Available data, albeit with some limitations, conﬁrm the safety

of pregnancy after treatment of breast cancer. Pregnancy may be

considered after completion of ChT, RT and anti-HER2 therapy;

for ER-positive disease, it is also recommended to complete at

least 18 months of ET. Women desiring pregnancy should be

encouraged to join prospective clinical trials/registries, such as

the POSITIVE trial.

There are no data to support advising patients who have

undergone axillary clearance to avoid cannulation, venesection

and blood pressure monitoring in the ipsilateral arm [V, D].

Prompt initiation of antibiotic treatment of potentially infected

wounds on the ipsilateral arm is advised, in particular after

ALND [I, A].

Follow-up cannot and should not be seen exclusively from the

physical perspective. Patients often have increased levels of anx-

iety after the completion of treatment, when close contact with

Annals of Oncology Special article

Volume 30 | Issue 8 | 2019 doi:10.1093/annonc/mdz173 | 1213

the treatment team decreases. Depression and intense fatigue fre-

quently occur in the months following the end of adjuvant ChT

and/or RT. This is also aggravated by long-term survivorship

issues involving work, family and sexuality, which are often not

closely addressed during follow-up and result in some patients

not being able to cope effectively. Long-term survivorship needs

to be addressed as a different set of challenges and realities, to en-

compass the psychosocial needs of patients once treatment ends

[V, A]. Follow-up clinics should focus not only on late side-

effects but also on issues that deal with the long-term implica-

tions of living with breast cancer. Assessing the various QoL

issues, particularly for patients under long-term ET, is an import-

ant aspect of follow-up care. The role of a specialised breast nurse

(or equivalent dedicated health professional acting as a patient

navigator) throughout a patient’s diagnosis, treatment and

follow-up is crucial [V, A]. All countries should develop the ne-

cessary educational structure and infrastructure required to pro-

vide the help of specialised breast nurses within the

multidisciplinary team to all breast cancer patients [V, A].

Recommendations:

•Regular follow-up visits are recommended every 3–4 months

in the ﬁrst 2 years (every 6 months for low-risk and DCIS

patients), every 6–8 months from years 3 to 5 and annually

thereafter. The interval of visits should be adapted to the risk

of relapse and patients’ needs [V, A].

•Annual bilateral (after BCT) and/or a contralateral mammog-

raphy (after mastectomy), with US and breast MRI when

needed (see ‘Diagnosis and pathology/molecular biology’ sec-

tion), is recommended [II, A].

•In asymptomatic patients, other laboratory or imaging tests

(e.g. blood counts, routine chemistry tests, chest X-rays, bone

scans, liver US exams, CT scans, FDG-PET-CT) or any tumour

markers such as CA15-3 or CEA are not recommended [I, D].

•Regular bone density evaluation is recommended for patients

on AIs or undergoing OFS [I, A].

•Patients should be encouraged towards adopting a healthy

lifestyle, including diet modiﬁcation and exercise [II, A].

•HRT should usually not be used [I, D].

•Patients should have unlimited access to specialised rehabili-

tation facilities and services [V, A].

•Long-term survivorship problems including psychological

needs and issues related to work, family and sexuality should

be addressed [V, A].

Methodology

These Clinical Practice Guidelines were developed in accordance

with the ESMO standard operating procedures for Clinical

Practice Guidelines development (http://www.esmo.org/

Guidelines/ESMO-Guidelines-Methodology). The relevant lit-

erature has been selected by the expert authors. An ESMO-MCBS

table with MCBS scores is included in Table 5. ESMO-MCBS v1.1

[214] was used to calculate scores for new therapies/indications

approved by the EMA since 1 January 2016. The scores have been

calculated by the ESMO-MCBS Working Group and validated by

the ESMO Guidelines Committee. Levels of evidence and grades

of recommendation have been applied using the system shown in

Table 6. Statements without grading were considered justiﬁed

standard clinical practice by the experts and the ESMO Faculty.

This manuscript has been subjected to an anonymous peer review

process.

Acknowledgements

The ESMO Guidelines Committee would like to thank the

ESMO Faculty and other experts who provided critical reviews

of these ESMO Clinical Practice Guidelines.

Funding

No external funding has been received for the preparation of

these guidelines. Production costs have been covered by ESMO

from central funds.

Disclosure

FC has reported consultancy/research grants from Amgen,

Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo,

Eisai, GE Oncology, Genentech, GlaxoSmithKline, Medscape,

MacroGenics, Merck Sharp & Dohme, Merus BV, Mylan,

Mundipharma, Novartis, Pﬁzer, Pierre-Fabre, prIME, Roche,

Sanoﬁ, Seattle Genetics and Teva; SO has reported honoraria

from AstraZeneca, Chugai, Eisai, Novartis, Pﬁzer, Eli Lilly,

Taiho and Kyowa Hakko Kirin and research grants from Daiichi

Sankyo, Eisai and Taiho; FP-L has reported consultancy/hono-

raria from Roche, Pﬁzer, Novartis, AstraZeneca, Genomic

Table 6. Levels of evidence and grades of recommendation (adapted from

the Infectious Diseases Society of America–United States Public Health

Service Grading System

)

Levels of evidence

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

methodological quality (low potential for bias) or meta-analyses of

well-conducted randomised trials without heterogeneity

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

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

or of trials with demonstrated heterogeneity

III Prospective cohort studies

IV Retrospective cohort studies or case–control studies

V Studies without control group, case reports, expert opinions

Grades of recommendation

A Strong evidence for efﬁcacy with a substantial clinical beneﬁt, strong-

ly recommended

B Strong or moderate evidence for efﬁcacy but with a limited clinical

beneﬁt, generally recommended

C Insufﬁcient evidence for efﬁcacy or beneﬁt does not outweigh the

risk or the disadvantages (adverse events, costs, etc.), optional

D Moderate evidence against efﬁcacy or for adverse outcome, generally

not recommended

E Strong evidence against efﬁcacy or for adverse outcome, never

recommended

By permission of the Infectious Diseases Society of America [216].

Special article Annals of Oncology

1214 | Cardoso et al. Volume 30 | Issue 8 | 2019

Health, Agendia, Myriad and NanoString; ITR has reported

honoraria from Roche; SZ has reported travel support from

Siemens AG and speaker’s fees from Siemens AG and

AstraZeneca; ES has reported honoraria from Amgen, Astellas,

AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Clinigen,

EGIS Pharmaceuticals, Eli Lilly, Janssen, Novartis, Pﬁzer, Pierre

Fabre, prIME, Roche, Sandoz and Teva, travel support from

Amgen, AstraZeneca, EGIS Pharmaceuticals, Novartis, Pﬁzer

and Roche and clinical research fees from Amgen, Astellas,

AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer, Eli Lilly,

Janssen, Merck, Novartis, Pﬁzer, Roche and Samsung; SK and

PP have declared no potential conﬂicts of interest.

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Special article Annals of Oncology

1220 | Cardoso et al. Volume 30 | Issue 8 | 2019

Association of HER2-low with clinicopathological features in patients with early invasive lobular breast cancer: an international multicentric study

Article

Full-text available

Jun 2025

Purpose The antibody–drug conjugate trastuzumab deruxtecan has proven to be not only efficient in patients with HER2+ breast cancers (BC), but also in those patients with so-called HER2-low BC. HER2-low tumors are well described in the general BC population, but not in patients with invasive lobular carcinoma (ILC). Here, we aimed at analyzing the association of HER2-low with clinicopathological features and survival outcomes in patients with early-stage pure ILC. Methods A multicentric retrospective cohort of patients diagnosed with stage I-III estrogen receptor positive (ER+) HER2 negative (HER2-) ILC between 01/01/2000 and 12/31/2020 was assembled. HER2- disease was categorized further by immunohistochemical (IHC) score into HER2 0, HER2 1+ and HER2 2+ following time appropriate ASCO/CAP guidelines from 2007 onward and by local guidelines prior to 2007. The association of HER2-low (HER2 1+ and 2+) with clinicopathological variables was assessed using multinomial logistic regression. Survival analyses were performed to evaluate the association of HER2-low with disease-free (DFS), distant recurrence-free (DRFS) and overall survival (OS). Results The data of 2098 patients with ER+ HER2- ILC was collected of which 1103 (52.6%) had a HER2-low tumor. Of these 716 (34.1%) had an IHC score of HER2 1+ and 387 (18.4%) of HER2 2+. In multivariable analysis, both tumor size of ≥ 2cm (OR: 1.37; 95%CI 1.01 – 1.87; p-value 0.042) and multifocality (OR: 1.55; 95%CI 1.11 – 2.15; p-value 0.009) were associated with HER2-low. HER2-low was associated with worse DFS (HR: 1.32; 95%CI 1.06 − 1.66; p-value 0.015) and OS (HR: 1.42; 95%CI 1.12 − 1.81; p-value 0.004) as compared to HER2 0. No association of HER2-low with DRFS was observed. Conclusions HER2-low is present in more than half of the patients with early ER+ HER2- pure ILCs and is associated with larger tumor size and multifocality. HER2-low is associated with a worse DFS and OS as compared to HER2 0.

Circulating chemokines and leukocytes and their impact on breast cancer prognosis

Article

Full-text available

Jun 2025

Tumor staging (TNM) and immunohistochemistry (IHC) are established predictors of breast cancer (BC) prognosis, but there are modulations by the tumor microenvironment and serum factors. This study aims to evaluate circulating chemokines, cytokines and leukocytes in the blood of patients with BC. A prospective study involving 200 women with infiltrative breast carcinoma was conducted. Patients were stratified by TNM stage and IHC subtype for survival analysis and correlations with the Neutrophil-to-Lymphocyte Ratio (NLR) and the expression of 13 chemokines and 3 cytokines. Survival was significantly higher in women with early-stage tumors (I/II) and in Luminal A and HER2 + subtypes. No significant differences in NLR were observed across TNM stages or IH subtypes. Among the 172 non-metastatic patients, those with NLR > 2 had shorter disease-free survival (DFS) (multivariate analysis). In the Luminal B subgroup, patients with NLR > 2 exhibited worse progression-free survival (PFS) (multivariate analysis), while in the triple-negative (TN) subgroup NLR > 3 was associated with poorer overall survival (OS) (univariate analysis). NLR was prognostic during follow-up, with lower OS observed in patients with NLR > 3 at 12 months post-diagnosis. Significant correlations were identified among 8 CC/CXC chemokines. Furthermore, leukocyte count was significantly correlated with IL-6, RANTES/CCL5, and GRO-Alpha/CXCL1; lymphocytes with MCP1/CCL2; and monocytes with IP10/CXCL10. NLR was significantly correlated with RANTES/CCL5. Risk stratification in BC patients is grounded in tumor staging and immunohistochemistry. However, systemic inflammatory responses, including cytokine- and chemokine-mediated signaling of neutrophils and lymphocytes, play a critical role in modulating prognosis.

Risk Stratification of Breast Cancer Metastasis: A Predictive Modelling Framework Using Clinical and Hormonal Receptor Data in a Ghanaian Cohort

Preprint

Full-text available

May 2025

Breast cancer remains the most diagnosed cancer among women globally. It is a leading cause of cancer-related deaths, with disproportionately high mortality rates in sub-Saharan Africa due to late-stage presentation and limited access to diagnostic and treatment services. In Ghana, nearly 70% of breast cancer cases are diagnosed at advanced or metastatic stages, underscoring the urgent need for accurate and context-specific prognostic tools. Here, we assembled clinical, molecular and demographic data from 558 breast cancer patients at Korle-Bu Teaching Hospital in Ghana to develop and compare five supervised machine‐learning model logistic regression, random forest, support vector machine, XGBoost and naïve Bayes for metastasis prediction. Using standardized preprocessing and repeated 10-fold stratified cross-validation, logistic regression achieved the most balanced performance (96% cross-validated accuracy; 93% test‐set accuracy) and facilitated interpretability via SHAP analysis, which identified lymph node involvement, tumour size and stage as top predictors. We further refined prognostic utility by stratifying patients into low, intermediate and high metastatic risk groups, revealing distinct clinical and biological profiles high‐risk individuals exhibited aggressive subtypes (triple-negative, HER2-positive) and advanced staging, whereas low-risk patients showed favourable receptor status and earlier disease. These findings demonstrate that tailored, interpretable machine-learning tools can support accurate, resource-appropriate metastasis risk assessment in low-resource settings.

Tumor Ki67 after a 2-week aromatase inhibitor run-in in patients with ER+ early breast cancer proposed for up-front surgery

Article

Jun 2025

Impact of Digital Breast Tomosynthesis on Extra Views and Concomitant Ultrasound Examinations in One Year Post Breast‐Conserving Surgery Patients

Article

Full-text available

Jun 2025

Introduction Imaging surveillance of patients post breast surgery for breast cancer is routinely performed with mammography. In practice, a large number of patients receive a concomitant ultrasound. The latter has not been established as routine practice and varies across imaging departments and referrers. This study aims to determine if the use of digital breast tomosynthesis (DBT) has decreased the need for concomitant ultrasound and extra mammographic views compared to digital mammography (DM). Methods Data was retrospectively reviewed for patients undergoing surveillance mammography for two periods: 2015–2016 (DM) and 2018–2019 (DBT). Patients identified as first‐year post breast‐conserving surgery (BCS) were included in the study. Comparison of proportions of concomitant ultrasound use between the two periods, with subgroup analysis for breast density categories, was performed using Chi‐squared tests. Results The study included 499 patients, of which 245 and 254 represented the DM and DBT periods, respectively, with a mean age of 60.1 years (SD 13.1) for the entire cohort. During DBT period, the percentage of patients having concomitant ultrasounds decreased by 15 percentage points (95% CI 8.9%–21.1%) (p < 0.0001) when compared to the DM period. During DBT period, the percentage of patients having extra views decreased by 44 percentage points (95% CI 36.1%–51.1%) (p < 0.0001). Conclusion The introduction of DBT resulted in fewer concomitant ultrasound examinations and extra mammographic views performed in the first‐year post breast cancer treatment. The role of ultrasound in cancer surveillance post‐treatment is debatable and large prospective studies investigating its value are warranted.

Reducing unnecessary biopsies of BI-RADS 4 lesions based on a deep learning model for mammography

Article

Full-text available

Jun 2025

Objective In this study, we aimed to explore the diagnostic value of a deep learning (DL) model based on mammography for Breast Imaging Reporting and Data System (BI-RADS) 4 lesions and to reduce unnecessary breast biopsies. Methods We retrospectively collected clinical and imaging data of 557 BI-RADS 4 lesions (304 benign lesions, 195 malignant lesions, and 58 high-risk lesions which have risk of developing malignancy) obtained by mammography at Shenzhen People’s Hospital and Luohu People’s Hospital from January 2020 to June 2022. The DL model was constructed to predict the pathological classifications of these lesions, calculated its sensitivity, specificity, and accuracy, and evaluated its diagnostic performance using receiver operating characteristic curve and area under the curve (AUC). Results This study included 557 patients with BI-RADS 4 lesions, including 381 patients (68.40%) with BI-RADS 4A, 106 patients (19.03%) with BI-RADS 4B, and 70 patients (12.57%) with BI-RADS 4C. For BI-RADS categories 4A, 4B, and 4C lesions, 70.9%, 27.4%, and 7.1% were respectively confirmed as benign through biopsy, surgical pathology, or follow-up. The DL model demonstrated high diagnostic performance in identifying BI-RADS 4 lesions, achieving a sensitivity of 81.0%, specificity of 76.9%, accuracy of 78.8%, and an AUC of 0.790. We found that our DL model could avoid unnecessary biopsies for BI-RADS 4 lesions by 40.6% in our included patients, reducing unnecessary biopsies for BI-RADS 4A, 4B, and 4C lesions by 55.1%, 18.9%, and 4.29%, respectively. Conclusion Our DL model for classifying BI-RADS 4 lesions can accurately identify benign and high-risk lesions that do not necessitate biopsy, further enhancing the safety and convenience for patients.

Application of Machine Learning to Breast MR Imaging

Article

Full-text available

Jun 2025
Magn Reson Med Sci

The demand for breast imaging services continues to grow, driven by expanding indications in breast cancer diagnosis and treatment. This increasing demand underscores the potential role of artificial intelligence (AI) to enhance workflow efficiency as well as to further unlock the abundant imaging data to achieve improvements along the breast cancer pathway. Although AI has made significant advancements in mammography and digital breast tomosynthesis, with commercially available computer-aided detection (CAD systems) widely used for breast cancer screening and detection, its adoption in breast MRI has been slower. This lag is primarily attributed to the inherent complexity of breast MRI examinations and also hence the more limited availability of large, well-annotated publicly available breast MRI datasets. Despite these challenges, interest in AI implementation in breast MRI remains strong, fueled by the expanding use and indications for breast MRI. This article explores the implementation of AI in breast MRI across the breast cancer care pathway, highlighting its potential to revolutionize the way we detect and manage breast cancer. By addressing current challenges and examining emerging AI applications, we aim to provide a comprehensive overview of how AI is reshaping breast MRI and improving outcomes for patients.

Meme Karsinomunda Tümörü infiltre eden T Lenfositlerin Yoğunluğunun Prognostik Faktörlerle İlişkisi

Article

Full-text available

Jun 2025

Giriş: Tümörü infiltre eden lenfositler, tümör mikroçevresindeki immün sistem hücreleridir ve kansere karşı oluşan immün yanıtta kritik rol oynar. Meme karsinomunda, tümörü infiltre eden lenfositlerin miktarının prognostik ve prediktif önemi olabileceği ortaya konmuştur. Çalışmamızda, meme kanserine ait tümör dokularındaki inflamatuar hücreler, TILs Working Group standartları göz önünde bulundurularak değerlendirilmiş ve prognostik faktörler ile ilişkisine bakılmıştır. Materyal Metod: Sakarya Üniversitesi Tıp Fakültesi Patoloji Anabilim Dalı laboratuvarında 2011-2015 yılları arasında incelenen, İnvaziv Karsinom, Özel Tip İçermeyen (NST) tanılı, neoadjuvan kemoterapi almamış 100 hastaya ait mastektomi ve meme koruyucu cerrahi materyalleri çalışmaya dahil edilerek, lenf nodu metastazı, tümör çapı evresi, tümörün histolojik derecesi, östrojen; progesteron ve Her2 reseptörü durumu olmak üzere prognostik parametreleri belirlendi. Tümör bloklarından elde edilen kesitlere CD4(+) ve CD8(+) pozitif lenfositleri tespit etmek için immunohistokimyasal çalışma yapıldı. Belirlenen prognostik parametrelerle inflamatuar hücre yoğunluğu arasındaki ilişki değerlendirildi. Bulgular: Vakaların 50’sinde lenf nodu metastazı mevcut iken, 50 hastada lenf nodu metastazı yoktu. Hastalara ait prognoz ile ilişkili değişkenlerin alt gruplarından tümörlerin histolojik derecesine göre hasta dağılımına bakıldığında 24 hasta derece 1, 44 hasta derece 2 ve 32 hasta derece 3 idi. Farklı grade ‘lere göre intratümöral stromal CD8 pozitif T lenfosit infiltrasyonu açısından grade 1 ve grade 3 grupları arasında istatistiksel olarak anlamlı pozitif korelasyon görüldü. Sonuç: Çalışmamıza göre derecesi yüksek tümörlerde CD8(+) T lenfosit infiltrasyonu yoğunluğunun daha fazla olduğu saptanmıştır. Çalışmamız tümörü infiltre eden lenfositlerin yoğunluğundaki artışın prognostik ve prediktif değerinin olabileceği konusunda farkındalık oluşturması açısından önemlidir.

Patient preferences for treatment pathways in early-stage breast cancer: application of a discrete choice experiment

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Jun 2025
Future Oncol

Prognostic significance of receptor conversion following neoadjuvant therapy in breast cancer: a systematic review & meta-analysis

Article

Jun 2025
BREAST

Tumor-Infiltrating Lymphocytes and Prognosis: A Pooled Individual Patient Analysis of Early-Stage Triple-Negative Breast Cancers

Article

Full-text available

Jan 2019

Purpose: The aim of the current study was to conduct a pooled analysis of studies that have investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in early-stage triple negative breast cancer (TNBC). Methods: Participating studies had evaluated the percentage infiltration of stromally located TILs (sTILs) that were quantified in the same manner in patient diagnostic samples of early-stage TNBC treated with anthracycline-based chemotherapy with or without taxanes. Cox proportional hazards regression models stratified by trial were used for invasive disease-free survival (iDFS; primary end point), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors. Results: We collected individual data from 2,148 patients from nine studies. Average age was 50 years (range, 22 to 85 years), and 33% of patients were node negative. The average value of sTILs was 23% (standard deviation, 20%), and 77% of patients had 1% or more sTILs. sTILs were significantly lower with older age ( P = .001), larger tumor size ( P = .01), more nodal involvement ( P = .02), and lower histologic grade ( P = .001). A total of 736 iDFS and 548 D-DFS events and 533 deaths were observed. In the multivariable model, sTILs added significant independent prognostic information for all end points (likelihood ratio χ2, 48.9 iDFS; P < .001; χ2, 55.8 D-DFS; P < .001; χ2, 48.5 OS; P < .001). Each 10% increment in sTILs corresponded to an iDFS hazard ratio of 0.87 (95% CI, 0.83 to 0.91) for iDFS, 0.83 (95% CI, 0.79 to 0.88) for D-DFS, and 0.84 (95% CI, 0.79 to 0.89) for OS. In node-negative patients with sTILs ≥ 30%, 3-year iDFS was 92% (95% CI, 89% to 98%), D-DFS was 97% (95% CI, 95% to 99%), and OS was 99% (95% CI, 97% to 100%). Conclusion: This pooled data analysis confirms the strong prognostic role of sTILs in early-stage TNBC and excellent survival of patients with high sTILs after adjuvant chemotherapy and supports the integration of sTILs in a clinicopathologic prognostic model for patients with TNBC. This model can be found at www.tilsinbreastcancer.org .

PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results.

Article

Full-text available

May 2018

The 2019 WHO classification of tumours of the breast

Article

Feb 2020

The newly published World Health Organization (WHO) Classification of Tumours of the breast features significant changes compared to earlier editions. In this review, we outline the major changes in this important reference source for those diagnosing tumours, or engaged in cancer research, and describe the significant changes. For breast cancer, the overview acknowledges the treatment‐relevant subtypes of invasive carcinoma (based on ER and HER2 status) and new data is added to support the differences in pathogenesis, treatment response and prognosis of these clinically relevant groupings. The WHO Classification of Tumours is increasingly evidence‐based, with a clear update cycle, improved quality of illustrations, as well as content, led by an editorial board comprising pathologists, but increasingly incorporating input from other disciplines. The advent of the new website allows the use of whole slide images, and hyperlinks to evidence or external bodies that produce guidance on staging or reporting.

EUSOMA position regarding breast implant associated anaplastic large cell lymphoma (BIA-ALCL) and the use of textured implants

Article

Apr 2019
BREAST

During the last two decades the number of breast implants used in aesthetic, oncologic and risk reducing surgery has increased substantially mainly due to the improvement and confirmed safety of these devices. Since identification of the first case of anaplastic large cell lymphoma associated with a breast implant (BIA-ALCL) 20 years ago, there has been an increase in the number of reports of this very rare disease, demonstrating a clear association with breast implants. Whilst the majority of cases are localised and cured by implant removal and full capsulectomy, a small percentage require chemotherapy and the mortality rate is very low. The evidence linking BIA-ALCL to implant surface texturing, as the majority of cases were diagnosed in patients with textured implants, has raised concerns about the long term safety of these devices resulting in patient and regulatory authority concerns globally. We hereby present the current published knowledge about the link between BIA-ALCL and implant surface texture and a review of current regulatory and professional body advice across Europe, which may enable a better understanding of this rare disease, how to manage and ultimately prevent it. We conclude by giving EUSOMA recommendation, towards the unnecessary change in attitudes towards implant based surgery, according to the most recent available published evidence as long as patients are properly informed about the risk of BIA-ALCL.

Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer

Article

Dec 2018

Background Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)–targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody–drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy. Methods We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease–free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause). Results At the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease–free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone. Conclusions Among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. (Funded by F. Hoffmann–La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472.)

Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial

Article

Dec 2017
LANCET ONCOL

Background: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. Methods: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1–3c (modified to stage 2–3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1–3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. Findings: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1–5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57–0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3–91·8) in the neratinib group and 87·7% (85·7–89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3–4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo. Interpretation: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses—ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast—without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.

Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries: Global Cancer Statistics 2018

Article

Sep 2018
CA-CANCER J CLIN

This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high‐quality cancer registry data, the basis for planning and implementing evidence‐based cancer control programs, are not available in most low‐ and middle‐income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1‐31. © 2018 American Cancer Society

9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: Results of the phase III multicentric Italian study Short-HER.

Article

May 2017

501 Background: 1-year trastuzumab with chemotherapy is the standard adjuvant treatment for HER2+ breast cancer patients (pts). The efficacy of less extended trastuzumab exposure is still under investigation. The Short-HER study is an independent, non-profit study aimed to test the non-inferiority of 9 weeks vs 1 year of adjuvant trastuzumab. Methods: This is a phase III, multicenter, Italian trial where pts with HER2+ breast cancer were randomly assigned to: Arm A (Long) AC or ECx4 followed by 4 courses of 3-weekly docetaxel in combination with trastuzumab, followed by 14 additional courses of 3-weekly trastuzumab; or Arm B (Short) 3 courses of 3-weekly docetaxel plus weekly trastuzumab for 9 doses followed by FEC x3. When indicated, radiation therapy was administered after the completion of chemotherapy. Hormonal therapy started at the completion of chemotherapy for pts with hormone receptor positive tumors. This is a non-inferiority trial with disease-free survival (DFS) as primary end-point.Overall survival (OS) is evaluated as second primary analysis outcome. The sample size of 1250 pts has been estimated based on a hazard ratio <1.29 for the short arm to be non-inferior. The definitive analysis will take place after 198 DFS events. Secondary aims include 2-yrs failure rate, cardiac toxicity, correlative biomarkers analyses. Hazard ratio for DFS and OS (90% CI) will be estimated according to the Cox model. Data will also be analyzed by the Bayesian approach. Results: from Dec-2007 to Oct-2013, 1254 pts from 82 centers have been randomized. Pts characteristics are the following: median age 55 yrs (25-78), stage I 37.3%, IIA 40%, IIB 20.6%, III 2.1%. 30% of the pts had 1-3 positive nodes, 16% >=4. Sixty-eight% of the pts had ER+ tumors. Characteristics were balanced between the two arms. At the time of this writing, 95% of the planned DFS events have been reported. 105 Grade ≥2 cardiac events have been reported, 78 in arm A (long) and 27 in arm B (short). Grade 3-4 cardiac events were 20 in arm A and 11 in arm B. Conclusions: Shorter trastuzumab administration almost halves the rate of severe cardiac toxicity. Final DFS data will be available at the time of the meeting. Clinical trial information: NCT00629278.

Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer

Article

Jun 2018
NEW ENGL J MED

Background In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials. Methods Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy. Results In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression (P=0.009 for tamoxifen alone vs. tamoxifen plus ovarian suppression). The 8-year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression (P=0.01 for tamoxifen alone vs. tamoxifen plus ovarian suppression); among the women who remained premenopausal after chemotherapy, the rates were 85.1%, 89.4%, and 87.2%, respectively. Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group, 31.0% of the tamoxifen–ovarian suppression group, and 32.3% of the exemestane–ovarian suppression group. Conclusions Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease-free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence. The frequency of adverse events was higher in the two groups that received ovarian suppression than in the tamoxifen-alone group. (Funded by Pfizer and others; SOFT and TEXT ClinicalTrials.gov numbers, NCT00066690 and NCT00066703, respectively.)

Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer

Article

Jun 2018
NEW ENGL J MED

Background The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. Methods We performed a prospective trial involving 10,273 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease–free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). Results Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease–free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local–regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease–free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25. Conclusions Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger. (Funded by the National Cancer Institute and others; TAILORx ClinicalTrials.gov number, NCT00310180.)

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