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ESO–ESMO fifth international consensus guidelines for breast cancer in young women (BCY5)

August 2022
Annals of Oncology 33(Suppl)

August 2022
33(Suppl)

DOI:10.1016/j.annonc.2022.07.007

Authors:

Ann Partridge

Dana-Farber Cancer Institute

Show all 23 authorsHide

The 5th International Consensus Symposium for Breast Cancer in Young Women (BCY5) took place virtually in October 2020, organized by the European School of Oncology (ESO) and the European Society of Medical Oncology (ESMO). Consensus recommendations for the management of breast cancer in young women were updated from BCY4 with incorporation of new evidence to inform the guidelines. Areas of research priorities, as well as specificities in different geographic and minority populations were identified. This manuscript summarizes the ESO-ESMO international consensus recommendations, which are also endorsed by the European Society of Breast Specialists (EUSOMA).

Levels of evidence and grades of recommendation Levels of evidence

…

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SPECIAL ARTICLE

ESOeESMO ﬁfth international consensus guidelines for breast cancer in

young women (BCY5)

S. Paluch-Shimon

1*y

, F. Cardoso

, A. H. Partridge

, O. Abulkhair

, H. A. Azim

, G. Bianchi-Micheli

, M. J. Cardoso

G. Curigliano

7,8

, K. A. Gelmon

, O. Gentilini

, N. Harbeck

, B. Kaufman

, S. B. Kim

, Q. Liu

, J. Merschdorf

P. Poortmans

, G. Pruneri

, E. Senkus

, B. Sirohi

, T. Spanic

, V. Sulosaari

, F. Peccatori

7,22z

& O. Pagani

23z

Hadassah University Hospital & Faculty of Medicine, Hebrew University, Jerusalem, Israel;

Breast Unit, Champalimaud Clinical Centre/Champalimaud Foundation,

Lisbon, Portugal;

Dana-Farber Cancer Institute, Boston, USA;

King Abdulaziz Medical City for National Guard, Riyadh, Saudi Arabia;

Breast Cancer Center, Hospital

Zambrano Hellion, Tecnologico de Monterrey, San Pedro Garza Garcia, Nuevo Leon, Mexico;

Breast Unit of Southern Switzerland, Lugano, Switzerland;

European

Institute of Oncology IRCCS, Milan;

Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy;

British Columbia Cancer, Vancouver, Canada;

San Raffaele Hospital, Milan, Italy;

Breast Center, Department of OB&GYN and CCCMunich, LMU University Hospital, Munich, Germany;

Sheba Medical Center,

Ramat Gan, Israel;

Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea;

Sun Yat-sen Memorial Hospital, Sun Yat-sen University,

Guangzhou, China;

Young Survival Coalition, New York, USA;

Iridium Netwerk, Department of Radiation Oncology & University of Antwerp, Faculty of Medicine and

Health Sciences, Wilrijk-Antwerp, Belgium;

National Cancer Institute, IRCCS Foundation, Milan, Italy;

Medical University of Gdansk, Gdansk, Poland;

Max Institute

of Cancer Care, New Delhi and Gurgaon, India;

Europa Donna Slovenia, Ljubljana, Slovenia;

European Oncology Nursing Society (EONS) and Turku University of

Applied Sciences, Turku, Finland;

European Institute of Oncology IRCCS & European School of Oncology, Milan, Italy;

Interdisciplinary Cancer Service Hospital

Riviera-Chablais Rennaz, Vaud, Geneva University Hospitals, Lugano University, Swiss Group for Clinical Cancer Research (SAKK), Lugano, Switzerland

Available online XXX

We dedicate this manuscript in memory of a dear friend and colleague Bella Kaufman.

The ﬁfth International Consensus Symposium for Breast Cancer in Young Women (BCY5) took place virtually in October

2020, organized by the European School of Oncology (ESO) and the European Society of Medical Oncology (ESMO).

Consensus recommendations for the management of breast cancer in young women were updated from BCY4 with

incorporation of new evidence to inform the guidelines. Areas of research priorities as well as speciﬁcities in

different geographic and minority populations were identiﬁed. This manuscript summarizes the ESOeESMO

international consensus recommendations, which are also endorsed by the European Society of Breast Specialists

(EUSOMA).

Key words: young women, breast cancer, fertility

INTRODUCTION

Only 4% of new breast cancer cases in the United States in

2019 occurred in women <40 years of age, with an esti-

mated cumulative risk of 1 in 65 by the age of 40 years and

1 in 209 before 30 years of age.

In low- and middle-income

countries (LMICs), breast cancer before menopause repre-

sents a much greater burden both in incidence (55% of total

breast cancer cases compared to 25% in high-income

countries) and death rates (8.5 and 3.3 deaths/100 000,

respectively),

2-4

the highest mortality being reported in

Africa (with the exception of southern Africa), Melanesia,

the Caribbean and parts of south-central Asia (e.g.

Afghanistan, Pakistan and Turkmenistan). Reports of

increasing incidence of premenopausal breast cancer in

some high-income industrialized countries (France, Italy,

New Zealand, Norway)

2,5

may reﬂect changes in age de-

mographics. In the United States, an increasing incidence of

de novo metastatic disease has recently been reported in

young black women.

Compared with their older counterparts, breast cancers

arising in young women are characterized by higher pro-

portion of tumors with aggressive phenotypes

and less

favorable outcomes irrespective of stage at diagnosis,

8,9

particularly in luminal-A like tumors.

Possible explana-

tions for the poorer outcome in luminal-like tumors include

different tumor or host biology, less chemotherapy-induced

amenorrhea (CIA), suboptimal endocrine treatment and

decreased adherence to adjuvant endocrine therapy (ET).

Young women are under-represented in contemporary

research evaluating risk-stratiﬁcation models and molecular

tools resulting in young patients at risk of being

*Correspondence to: Dr Shani Paluch-Shimon, Sharett Institute of Oncology,

Hadassah University Hospital & Faculty of Medicine, Hebrew University, Ein

Kerem, Jerusalem, 12000, Israel. Tel: þ972-26777755

E-mail: shanipal@hadassah.org.il (S. Paluch-Shimon).

Co-ﬁrst authors.

Co-last authors.

Volume xxx -Issue xxx -2022 https://doi.org/10.1016/j.annonc.2022.07.007 1

over-treated based solely on age considerations. Prospec-

tive trials dedicated to young patients are key to answering

many of the outstanding questions to ensure optimal

management. Two such examples are the POSH cohort

study, conducted at 127 hospitals in the UK,

and the

Helping Ourselves, Helping Others: The Young Women’s

Breast Cancer Study (HOHO) conducted in the United States

and Europe. These studies and others have demonstrated a

greater proportion of luminal B and estrogen receptor-

negative (ER) tumors in young patients, increased risk of

early relapse and a more unfavorable longer-term outcome

for young women with ERþtumors when compared to

older women.

8,11

Consistent with previous guidelines,

12-16

the panel

deﬁned ‘young women’as women under the age of 40

years at breast cancer diagnosis and deﬁned ‘advanced

breast cancer in young women’as diagnosis of inoperable

locally advanced or metastatic disease before the age of 40

years.

Due to the coronavirus disease 2019 (COVID-19)

pandemic, the ﬁfth International Consensus Symposium for

Breast Cancer in Young Women (BCY5) took place virtually

on 10-11 October 2020 with over 1200 participants

including health care professionals and patient advocates.

The BCY5 guidelines are developed by the European School

of Oncology (ESO) and European Society of Medical

Oncology (ESMO) and are endorsed by the European Soci-

ety of Breast Cancer Specialists (EUSOMA). All recommen-

dations are for standard care, outside of clinical trials. All

diagnostic and treatment recommendations should be

considered in the context of national regulatory approval,

availability and reimbursement.

METHODOLOGY

Recommendations from BCY4 formed the basis for the

current recommendations; new and updated statements

from BCY4 were circulated amongst the panelists before

BCY5 and were then presented, discussed, adapted and

voted on during the consensus session. All panel members

were instructed to vote on all questions; members with

potential conﬂicts of interest or who did not feel comfort-

able responding (e.g. due to lack of expertise on the topic)

were instructed to abstain for that speciﬁc question. Sub-

stantial controversies or disagreements are noted in the

discussion of the recommendations. These recommenda-

tions were later circulated to panel members by email for

comments, updating based on recent reports and correc-

tions as needed.

Previous recommendations not requiring update or only

minor changes were not re-voted and remain part of the

recommendations of BCY5.

Tables 1-6 describe the grading system used as per ESMO

guidelines methodology (adapted from Dykewicz et al.

;see

http://www.esmo.org/Guidelines/ESMO-Guidelines-Methodo

logy), general guidelines for the management of young

women with breast cancer including early and advanced

disease, supportive care and follow-up and management of

women with germline pathogenic variants (PVs). Statements

without grading were considered justiﬁed standard clinical

practice by the panel experts.

Supplementary Appendix S1, available at https://doi.org/

10.1016/j.annonc.2022.07.007, presents the deﬁnition of

menopause following CIA and detailed supportive and

follow-up care issues, unchanged or slightly modiﬁed since

BCY4.

BCY5 consensus panel members and their disclosure of

any relationships with the pharmaceutical industry that

could be perceived as a potential conﬂict of interest are

reported.

General considerations when caring for young women

with breast cancer

Management of young women with breast cancer is multi-

faceted and requires speciﬁc and dedicated multidisci-

plinary care (including but not limited to medical and

radiation oncologist, gynecologist, pathologist, radiologist,

breast and plastic surgeon, nurse specialist, geneticist,

physiotherapist, fertility, sexual therapy and psychosocial

experts), best provided in dedicated breast centers, whose

quality control assurance ensures qualiﬁed experience and

care.

The panel recommended that personalized psycho-

social support and counseling on genetic predisposition,

fertility, sexual health and socioeconomic consequences be

incorporated into individual treatment planning as well as

lifelong follow-up care given the improved long-term sur-

vival with modern therapies and risks of late side-effects.

Speciﬁc guidelines for post-treatment survivorship care

are available for health care providers.

Table 1. Levels of evidence and grades of recommendation

Levels of evidence

I Evidence from at least one large randomized, controlled

trial of good methodological quality (low potential for bias)

or meta-analyses of well-conducted randomized trials

without heterogeneity

II Small randomized trials or large randomized 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, experts

opinions

Grades of recommendation

A Strong evidence for efﬁcacy with a substantial clinical

beneﬁt, strongly recommended

B Strong or moderate evidence for efﬁcacy but with a limited

clinical beneﬁt, generally recommended

C Insufﬁcient evidence for efﬁcacy or beneﬁt does not

outweigh the risk or the disadvantages (adverse events,

costs, etc.), optional

D Moderate evidence against efﬁcacy or for adverse

outcome, generally not recommended

E Strong evidence against efﬁcacy or for adverse outcome,

never recommended

Adapted from the Infectious Diseases Society of America-United States Public Health

Service Grading System with their permission.

Annals of Oncology S. Paluch-Shimon et al.

2https://doi.org/10.1016/j.annonc.2022.07.007 Volume xxx -Issue xxx -2022

Table 2. General guidelines

Guidelines LoE/GoR Consensus

Overall, the stage-speciﬁc outcome of young breast cancer patients has improved over the years due to diagnostic and

treatment advances.

Nonetheless, even in countries with universal health care, these improvements are signiﬁcantly lower for women with

low socioeconomic status (SES) compared to those with high SES.

Every young breast cancer patient must have access to optimal cancer treatment and supportive care according to the

highest standards of patient-centered care, irrespective of her social status.

Expert opinion 100%

Many speciﬁc issues in the treatment of young women with breast cancer, both in the early and in the advanced

settings, still lack deﬁnitive proven standards. Therefore, well-designed, independent, prospective randomized trials

should be a global research priority.

Expert opinion

The care of all young patients with breast cancer (either early stage, EBC, or advanced disease, ABC) should be

discussed within a multidisciplinary team before any treatment decision making, and ideally provided in specialized

breast clinics.

Expert opinion

Navigators/navigation tools are of great assistance in optimizing patient care. Navigators should ideally be breast

nurses but lay-health professionals with strong communication skills and sufﬁcient experience may also address

complex care issues and mixed cultural settings.

Expert opinion

In view of the many speciﬁc aspects related to young age, personalized psychosocial support, counseling on genetic

predisposition, fertility, sexual health and socioeconomic impact are highly recommended as part of the individual

treatment planning.

Expert opinion

In young women, innovative and structured communication and supportive tools (e.g. online programs, web-based

interventions) should be developed and scientiﬁcally validated and disseminated in different languages.

This would help young patients to overcome barriers to accessing support, such as child and family care, work

timetables and distance issues.

Expert opinion

In view of the many speciﬁc aspects related to young age, personalized psychosocial support, counseling on genetic

predisposition, fertility, sexual health and socioeconomic impact are highly recommended as part of the individual

treatment planning.

Patient support groups should be developed and promoted.

Open discussion and shared decision making should be promoted in a clear, culturally appropriate manner encouraging

patients to be proactive in their cancer care.

Expert opinion

Young age by itself should not be the reason to prescribe more aggressive therapy than in other age groups. Factors

inﬂuencing choice of treatment should include but not be limited to the biological characteristics of the tumor [ER/PR,

HER2, proliferation markers (e.g. Ki-67), histological grade], tumor stage, genetic status (if available) and patient ’s

comorbidities and preferences.

Expert opinion

Systematic research into age-speciﬁc host-tumor characteristics is needed.

In particular, the identiﬁcation of age-speciﬁc molecular, biological, radiomics-based and/or genomic aberrations with

prognostic and predictive signiﬁcance could open the door for tailored therapeutic interventions.

Expert opinion

National reimbursement policies/algorithms rewarding treatment protocols per number of treatments, dosages,

administration route/use of day hospital or planning complexity (in the case of radiation treatment planning) should be

discouraged.

For exampledradiation therapy should not be reimbursed per fraction nor should physicians receive reimbursement

for administering intravenous chemotherapy.

Expert opinion

Risk factors

Although data about whether obesity is a risk factor for breast cancer in premenopausal women are not conclusive, it

can be said with certainty that obesity is a risk factor for a multitude of serious diseases. For the time being, young

women should be encouraged to maintain BMI 25 kg/m

Expert opinion Y ¼96%

A¼4%

Pharmaco-prevention with tamoxifen has proven to be effective in reducing breast cancer occurrence in high-risk

young women but is underutilized.

Pharmaco-prevention indication, schedule and potential adverse events should be discussed with all young women at

high risk of developing breast cancer.

IA Y ¼96%

A¼4%

There is limited evidence to suggest speciﬁc lifestyle approaches (e.g. dietary habits, weight management and physical

activity) for ovarian and breast cancer risk reduction among women with a germline BRCA1/2 mutation compared to

the general population.

At this time, before obtaining solid data, recommendations about lifestyle behaviors should follow available guidelines

for the general population.

Expert opinion 100%

Male breast cancer

Male breast cancer should be managed in accordance with international recommendations/guidelines. Expert opinion

Clinical trials should allow for inclusion of male breast cancer patients in both early and advanced settings. Expert opinion

Transgender (TG) and nonbinary (NB) persons

Knowledge about the risks of breast/gynecological cancers in TG and NB persons receiving gender-afﬁrming hormone

therapy is limited.

Even less information exists regarding TG/NB individuals with known genetic predisposition.

Cancer registries should include TG/NB identities, and further education and research should be implemented to ﬁll

the gap in information and counseling in this population.

Expert opinion 100%

In green, NEW/MODIFIED BCY5 guidelines with consensus voting.

ER, estrogen receptor; GoR, grades of recommendation; HER2, human epidermal growth factor receptor 2; LoE, levels of evidence; PR, progesterone receptor.

S. Paluch-Shimon et al. Annals of Oncology

Volume xxx -Issue xxx -2022 https://doi.org/10.1016/j.annonc.2022.07.007 3

Table 3. Assessment and treatment guidelines in early breast cancer

Guidelines LoE/GoR Consensus

Screening, diagnosis and imaging for staging and follow-up

There is no clear role for routine screening by any imaging for early breast cancer detection in healthy, average-risk

young women.

Additional consideration may be given to ultrasound and breast MRI in young women particularly in the setting of very

dense breast tissue or consideration of a genetic predisposition or other higher-risk individuals (i.e. radiation therapy

for childhood or young adulthood malignancy).

Expert opinion

Diagnosis, imaging and staging in young women should follow standard algorithms consistent with older women.

Additional consideration may be given to ultrasound and breast MRI in young women with very dense breast tissue.

IIC

Digital breast tomosynthesis (DBT) is more sensitive than digital mammography in dense breasts, is associated with

marginal increase in radiation dose and should be the preferred diagnostic tool.

Expert opinion Y ¼80%

N¼5%

A¼15%

In patients with dense breasts, abbreviated magnetic resonance imaging (AB-MRI) may represent a valid alternative to

conventional MRI with the advantages of short examination/interpretation times and low costs.

Expert opinion Y ¼45%

N¼15%

A¼40%

For BRCA 1/2 mutation carriers and others at high risk based on family history or predisposing mutations in other

genes (e.g. p53, PALB2, CHEK2, ATM), and for those at increased risk because of a personal history of therapeutic

radiation, annual surveillance with MRI and mammography with or without ultrasound is recommended.

IIA

For BRCA 1/2 mutation and other cancer susceptibility genes carriers (e.g. RAD51C, p53, BRIP1) who have not

undergone salpingo-oophorectomy, gynecologic surveillance every 6 months is recommended.

Expert opinion

Annual whole body MRI and brain MRI should be offered to women harboring germline p53 pathogenic variants

(LieFraumeni syndrome) for staging and follow-up.

Other diagnostic tools (e.g. FDGePETeCT) are still under evaluation in LieFraumeni patients as well as in patients

harboring other germline pathogenic gene variants (e.g. ATM carriers) and should not be part of routine staging and

follow-up.

Expert opinion

Y¼75%

A¼25%

Y¼75%

A¼25%

Risk-adapted early detection and surveillance tools should be researched in young women. Expert opinion

Genetic counseling and testing

Recent literature suggests that health disparities remain amongst young women from minority or disadvantaged

ethnic/racial backgrounds in utilizing and seeking genetic counseling services based on family history of malignancy,

before a breast cancer diagnosis.

Risk-reducing measures are also underutilized in minority BC patients harboring BRCA1/2 pathogenic gene variants.

Strategies to minimize racial/ethnic and social disparities in early access to genetic testing and risk management should

be implemented to optimize preventive interventions

Expert opinion Y ¼96%

A¼4%

Every young woman with breast cancer should be offered genetic counseling preferably before starting treatment.

Practice should follow national/international guidelines on a country-by-country basis. For those women who are not

ready to consider genetic issues at diagnosis, access to genetic counseling should be offered again during follow-up, to

address issues of surveillance and risk reduction of additional primary tumors for the patient, and risk issues for

relatives.

Expert opinion

Genetic testing should be performed only after adequate information is provided by an appropriately trained health

professional who explains the implications of the results, according to national/international regulations.

The patient must be made aware that the presence of a predisposing mutation may have an impact on her

management, follow-up and decision making, as well as family members.

A fast-track process should be available when the identiﬁcation of a pathogenic gene variant could change the

therapeutic approach (e.g. indication for risk-reducing surgery, platinum derivatives, PARP inhibitors, etc.).

Little is known about the clinical/psychosocial factors affecting the communication of genetic test results by young BC

patients with parents and siblings, especially in non-Caucasian women.

Further research and strategies to improve communication among families are needed and should be developed.

Expert opinion 100%

Genes to be tested for depend on personal and family history.

Although BRCA1/2 are the most frequently mutated genes, other additional moderate- to high-penetrance genes may

be considered, if deemed appropriate by the geneticist/genetic counselor or if they will impact therapeutic

interventions.

Development of quality-controlled genetic counseling services is strongly encouraged.

Expert opinion 100%

When a hereditary cancer syndrome is suspected and a mutation in BRCA1/2 has not been identiﬁed, multi-gene panel

testing may be considered. Practice should be guided by high quality national/international guidelines.

As commercially available multi-gene panels include different panels of genes, the choice of the speciﬁc panel and

quality-controlled laboratory is crucial.

Expert opinion

Risk communication and clinical recommendations need to be adapted to the increased complexity and uncertainty of

multi-gene testing.

Health professionals should also be trained to address the related complex psychological scenarios.

Expert opinion 100%

The clinical utility (including risk assessment, screening and prevention recommendations) of moderate-risk genes

identiﬁed on multi-gene panel testing is not yet established and this needs to be clearly communicated to patients in

both the pre- and post-testing counseling consultations.

Expert opinion

Multi-gene panel testing (when available) should be proposed when either a hereditary cancer syndrome is suspected

and a pathogenic gene variant in BRCA1/2 has not been identiﬁed and/or if the personal/family history can be

explained by more than one gene. Practice should be guided by national/international guidelines.

Expert opinion

As commercially available multi-gene panels include different genes, the choice of the speciﬁc panel should be

performed in quality-controlled laboratories.

Expert opinion

For the time being somatic BRCA1/2 testing should not be used as an alternative or in addition to germline pathogenic

gene variant identiﬁcation. The therapeutic implications of somatic BRCA1/2 mutations in breast tumors need to be

further explored within a research setting before they can be used in routine clinical practice.

Expert opinion

Amongst individuals who do not have an identiﬁed low-/moderate-/high-risk germline mutation, polygenic risk score

models, evaluating multiple factors for estimating breast cancer risk, are not yet ready for implementation in routine

clinical practice.

Expert opinion Y ¼87%

A¼13%

Continued

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4https://doi.org/10.1016/j.annonc.2022.07.007 Volume xxx -Issue xxx -2022

Table 3. Continued

Early breast cancer locoregional treatment

Surgical treatment of young patients with EBCdwhile being tailored to the individual patientdshould in general not

differ from that of older patients.

Breast-conserving surgery should be performed as the ﬁrst option whenever suitable, as it provides the same overall

survival than mastectomy.

Onco-plastic repair techniques should be discussed with all patients treated by BCS in order to maximize cosmetic

results and optimize self-image whenever an obvious post-operative asymmetry can be estimated by a dedicated

breast surgical team. Immediate breast reconstruction after mastectomy offers the same survival rates as mastectomy

without reconstruction and should be offered to all patients except those with inﬂammatory breast cancer.

Immediate breast reconstruction after mastectomy is less frequent in patients with low socioeconomic status (SES)

compared to those with high SES, even in countries with universal health care where the inﬂuence of reimbursement

should be negligible.

Immediate breast reconstruction is rarely available in patients from low- and middle-income countries.

Every young BC patient should have access to immediate breast reconstruction and oncoplastic surgery if medically

appropriate.

Expert opinion 100%

There is no evidence of an increased false-negative rate or a worse outcome in young patients undergoing SNLB,

therefore the indications for SNLB are the same as in older patients.

In young women with the diagnosis of either invasive disease or pre-invasive lesions, who are not high-risk mutation

carriers, there is no evidence for improved OS by performing risk-reducing bilateral mastectomy.

For all surgical decisions and particularly for risk-reducing mastectomy, patients must be given proper, thorough and

unbiased information based on the available data, and adequate time to decide. Once an informed decision is made by

the patient it should be respected. Additional psychosocial support should be offered given the potentially high anxiety

and long-term sequela of patients making these difﬁcult decisions.

Expert opinion

Decisions about locoregional treatment after neoadjuvant chemotherapy should be made independent of age. Expert opinion

Mutation status should be part of the individual decision-making algorithm. Sufﬁcient time to discuss the different

options and adequate psychological support should be offered given the potential long-term sequela and implications.

Expert opinion

Indications for adjuvant RT are the same as for older patients.

After breast-conserving surgery, breast radiation + boost are recommended. Young patients should be informed about

the high local recurrence risk if RT is avoided after BCS and about the beneﬁt of RT on reduction of local recurrence and

improvement in OS. This must be balanced with information about the potential long-term toxicities.

Partial breast irradiation (PBI) or accelerated PBI has not been sufﬁciently studied in young patients and should not be

performed in this age group.

Indications for post-operative RT are independent of BRCA status.

Limited and inconclusive evidence is available in presence of pathogenic gene variants in other predisposing genes

(e.g. CHEK2, ATM): in these patients the riskebeneﬁt ratio needs to be individually discussed.

For patients with a germline TP53 mutation, post-operative RT is relatively contraindicated and mastectomy is

preferred.

In these patients, post-mastectomy RT should be discussed only in cases of signiﬁcant risk of locoregional recurrence.

This underscores the importance of early genetic testing at the time of diagnosis to aid optimal treatment planning.

Expert opinion Y ¼87%

A¼13%

Despite the fact that data on the efﬁcacy and safety of hypofractionation are accumulating in premenopausal women,

hypofractionation is not widely adopted as standard radiation therapy for young patients in many countries.

Hypofractionated WBI schedules should replace standard fractionated WBI as gold standard for most patients

irrespective of their age.

IB Y ¼74%

A¼26%

Ultra-hypofractionated WBI or for the lymph node regions (such as in FAST-Forward) is not yet standard for young

patients.

Expert opinion Y ¼61%

N¼4%

A¼35%

Indications and extension of nodal irradiation are the same as in other age groups. IB

Indications for adjuvant RT are the same as for older patients.

Data are stronger for beneﬁts of post-mastectomy RT for young women.

Partial breast irradiation (PBI), or accelerated PBI, has not been sufﬁciently studied in young patients and should not be

performed in this age group.

Expert opinion

Post-mastectomy radiation therapy (PMRT) to implant-based breast reconstruction may be associated with a higher

risk of capsular contracture.

When PMRT is foreseen the timing and technique of the procedure should be discussed pre-operatively on an

individual basis by all the specialists involved.

Expert opinion Y ¼85%

N¼5%

A¼10%

Adjuvant systemic treatment

Endocrine therapy

All young women should be counseled, before the onset of systemic therapy (either CT or ET), about the risks,

associated symptoms and outcomes of treatment-related amenorrhea and premature menopause, referred for special

fertility counseling/consultation and informed of available and approved ameliorative therapies.

Expert opinion

Neoadjuvant ET should not be used in young women outside clinical trials. Expert opinion

All patients with HR-positive disease should receive adjuvant ET.

Tamoxifen alone for 5 years is indicated for low-risk patients.

Switching to an AI, after 5 years of tamoxifen, should be considered for women who have become deﬁnitively

postmenopausal.

Tamoxifen for 10 years should be considered in high-risk patients, if tolerated.

The addition of a GnRH agonist (or ovarian ablation) to tamoxifen or an aromatase inhibitor is indicated in patients at

higher risk of relapse.

AIs without ovarian function suppression are contraindicated in premenopausal women.

The combination of an AI and a GnRH agonist (or oophorectomy) confers a signiﬁcant absolute beneﬁt in terms of

freedom from distant recurrence and should be the preferred option in higher-risk patients.

IA Y ¼90%

N¼5%

A¼5%

Continued

S. Paluch-Shimon et al. Annals of Oncology

Volume xxx -Issue xxx -2022 https://doi.org/10.1016/j.annonc.2022.07.007 5

Table 3. Continued

Adjuvant systemic treatment

Endocrine therapy

Young women with stage I or II breast cancer who cannot take tamoxifen (due to contraindications or severe side-

effects) may receive a GnRH agonist alone, oophorectomy or an aromatase inhibitor + GnRH agonist.

Recommendations for adjuvant GnRH agonist use are based on data from trials with monthly administration. Thus,

current guidelines support monthly use to optimize ovarian function suppression, particularly in very young women

(<35 years of age) and in those receiving an AI.

3-6 monthly use may be considered on a case-by-case basis with very close monitoring of ovarian function, when

monthly use is not feasible or accepted by the patient.

Expert opinion Y¼90%

N¼5%

A¼5%

Estradiol levels should be checked if there are concerns ovarian function is not suppressed, especially if a breakthrough

bleeding occurs and/or the patient is on an AI; if done, the analysis should preferably be performed in the same

laboratory, and when possible in a central reference laboratory. In cases of inadequate suppression alternative

strategies should be discussed (oophorectomy or continuation of tamoxifen alone).

Expert opinion

The method of ovarian suppression (surgical versus medical) requires balancing patient’s wish for potentially

preserving fertility, compliance with frequent injections over a long period of time and cost/availability.

Expert opinion

Radiation to ovaries as a method of ovarian function suppression should be discouraged. Expert opinion Y ¼40%

N¼30%

A¼30%

The addition of a GnRH agonist to tamoxifen can be considered in women at higher risk of relapse resuming ovarian

function within 2 years after chemotherapy completion.

IIB

Adjuvant CDK4/6 inhibitors

Early data suggest that adjuvant abemaciclib combined with ET may be beneﬁcial in patients with high-risk ER+ disease

(3.5% absolute risk reduction in invasive disease-free survival), however follow-up time is short.

43% of patients were premenopausal with similar magnitude of beneﬁt observed irrespective of menopausal status.

High-risk features were deﬁned in the clinical trial as 4 LN or 1-3 involved LN with other high-risk features (tumor size

5 cm, grade 3, Ki67 20%).

Abemaciclib could be considered for use in the described high-risk groups, when approved.

IB Y ¼61%

N¼13%

A¼26%

Chemotherapy

Many factors, including patient and tumor characteristics and genomic signatures, should be considered when deciding

whether to administer adjuvant chemotherapy in young women with HR+ early BC. Most young women enrolled in

these studies were not treated with modern, risk-adapted ET. Available data in premenopausal women support the role

for gene expression tests in predicting additional beneﬁt of chemotherapy over ET alone but further data are needed in

order to guide clinical practice and to determine whether the observed beneﬁts are from the cytotoxic therapy or the

chemotherapy-induced OFS.

IB Y ¼91%

A¼9%

Commercially available prognostic genomic assays in HR+ early breast cancer have not been developed to predict

which endocrine therapy is more appropriate according to genomic risk. Therefore, they should not be used at this

time for selecting type or duration of endocrine therapy.

Expert opinion

Available data suggest that a discussion of omitting adjuvant chemotherapy in very young women (35 years of age at

diagnosis) with low-risk ER+ disease is appropriate in highly selected cases with favorable clinical and pathological

features including low gene expression proﬁles where available.

Expert opinion

The indications for and the choice of adjuvant systemic treatment for invasive breast cancer should be driven, as for

women in other age categories, by extent of disease and the biological characteristics of the tumor (including, but not

limited to, ER/PR and HER2 receptors, proliferation and grade) and patient’s comorbidities.

For the time being, the type of systemic treatment of EBC is independent of BRCA or any other constitutional genetic

status.

Expert opinion

The optimal (neo)adjuvant CT regimen speciﬁcally for young women in terms of efﬁcacy and long-term toxicity is

currently unknown. As for all stage I-III breast cancer patients, the preferred regimens are standard anthracycline,

alkylating and taxane-based regimens.

The indication for dose-dense chemotherapy is independent of age.

Young age by itself should not be an indication to prescribe a more intense combination of cytotoxic agents.

Standard duration of chemotherapy (minimum of 4 and maximum of 8 cycles) should be prescribed.

Sequential regimens have at least equal or superior efﬁcacy over combinations and are better tolerated.

The indication for dose-dense chemotherapy is independent of age.

In patients with TNBC or BRCA-associated tumors the incorporation of platinum agents increases pCR rates and may be

considered when neoadjuvant chemotherapy is indicated.

Data on the impact of incremental increases in pCR on long-term outcome are not conclusive.

The use of platinum derivatives has potential additional impact on fertility and increased toxicity that may compromise

standard duration and dosing of systemic treatment, and this needs to be clearly communicated to patients.

For patients with TNBC not achieving a pCR after standard neoadjuvant regimens, the routine addition of adjuvant

chemotherapy with 6-8 cycles of capecitabine may be considered

There are no data on the use of platinum derivatives in the adjuvant setting and therefore these cannot be

recommended.

In patients with TNBC with indications for pre-operative chemotherapy, the addition of pembrolizumab (with the

chemotherapy and for completion of 1 year following surgery) can be considered in selected young patients with high-

risk disease, where approved, after careful consideration and discussion with the patient about the possibility of long-

term side-effects.

IA Y ¼90%

N¼10%

Continued

Annals of Oncology S. Paluch-Shimon et al.

6https://doi.org/10.1016/j.annonc.2022.07.007 Volume xxx -Issue xxx -2022

The National Comprehensive Cancer Network (NCCN) in

Oncology and the Breast Health Global Initiative developed

resource-stratiﬁed and harmonized guidelines/recommen-

dations

20,21

and strategies to address the poor outcomes in

LMICs for young women with breast cancer.

Prospective

cohort studies are collecting data on young patients’con-

cerns, in particular about fertility preservation,

23,24

selection

of ovarian function preservation strategies

and psychoso-

cial and quality-of-life (QoL) issues after diagnosis.

Young women with a lower socioeconomic status (SES) have

worse outcomes compared to those with a higher SES,

even

in countries with universal health care

27,28

thought to be due

to a higher frequency of comorbidities and limited access to

health services. In some studies, differences persist after

adjusting for all these factors. In particular, a large Norwegian

report in premenopausal women (7501 patients aged 30-48

years at diagnosis) showed that 5-year relative survival

improved steadily for patients with high SES (by 9% and 36%,

for regional and distant disease, respectively), but remained

unchanged for patients with low SES.

The BCY5 panel

strongly and unanimously stated that every young breast

cancer patient must have access to optimal cancer treatment

and supportive care according to the highest standards of

patient-centered care, irrespective of her social status.

Panel members re-emphasized that national reimburse-

ment policies/algorithms rewarding treatment protocols

per number of treatments, dosages, administration route/

use of day hospital or planning complexity (in the case of

radiation treatment) should be discouraged. For example,

radiation therapy (RT) should not be reimbursed per frac-

tion, nor should physicians receive higher reimbursement

for administering intravenous agents compared to oral

chemotherapy or ET. To this end, the panel endorses the

12th European Breast Cancer Conference Manifesto.

Asigniﬁcant proportion of young patients experience work-

and insurance-related challenges in the ﬁrst 2 years after

diagnosis,

30-33

but little is known about the impact of late ef-

fects of cancer treatment (e.g. fatigue and arm morbidity) on

Table 3. Continued

Adjuvant PARP inhibitors

Early data suggests that 1 year of adjuvant olaparib following the completion of (neo)adjuvant chemotherapy provides

signiﬁcant beneﬁt in disease-free survival amongst women harboring a germline BRCA1/2 mutation who have high-risk

early breast cancer. High-risk features were deﬁned in the clinical trial as stage 2-3, HER2 negative-TNBC: pT2Nx or

pTxN1-3 or residual disease after NAST; HR+:pTxN2-3 or signiﬁcant residual disease after NAST. It may also reduce the

risk of further primary malignancies. Olaparib, once approved, should be offered to germline BRCA1/2 mutation

carriers that meet the inclusion criteria for the OLYMPIA trial and modiﬁcations which may be approved by the

regulatory bodies.

IA Y ¼91%

A¼9%

Anti-HER2 therapy

One year treatment with adjuvant trastuzumab, together with chemotherapy, is indicated for women with HER2-

positive, node-positive or high-risk node-negative breast cancer (tumor size >0.5 cm), who have a left ventricular

ejection fraction within normal limits and without signiﬁcant cardiovascular risk factors, irrespective of age.

In highly selected patients with small, node-negative, HER2+ breast cancer, the administration of 12 weeks of weekly

paclitaxel and trastuzumab without anthracyclines can be considered

The incorporation of neoadjuvant/adjuvant pertuzumab should be in keeping with current standards, as for older

patients, in women with high-risk HER2+ breast cancer.

IIB

In case of pathological residual disease (non-pCR) after pre-operative chemotherapy plus anti-HER2 therapy the

patient should be offered to complete 1 year of adjuvant anti-HER2 therapy with TDM-1.

IA Y ¼85%

N¼5%

A¼10%

In HER2+ patients at high risk of relapse (e.g. N+) 1 year adjuvant pertuzumab + trastuzumab can be discussed, as in

other age groups.

Limited data are available on the efﬁcacy of such treatment in women who received pertuzumab + trastuzumab as part

of their pre-operative systemic therapy.

IC Y ¼90%

N¼5%

A¼5%

In HER2+/HR+ patients at high risk of relapse (e.g. signiﬁcant nodal involvement), 1 year of treatment with neratinib

after trastuzumab can be discussed, as in other age groups.

There is no data about the efﬁcacy of neratinib after 1 year of adjuvant trastuzumab AND pertuzumab or after adjuvant

TDM1.

IC Y ¼80%

A¼20%

General considerations in the adjuvant setting

In view of the long potential life expectancy, particular attention should be paid to possible long-term toxicities of

adjuvant treatments (e.g. secondary cancers, cardiovascular toxicity, irreversible ovarian failure, weight gain, cognitive

function, bone health).

Clinics dedicated to the assessment and management of early and late treatment side-effects and adherence to

treatment and follow-up guidelines should be developed.

Expert opinion

The management of inﬂammatory breast cancer in young women should be the same as in the older breast cancer

population.

Expert opinion

Data are accumulating about disease-free survival improvement with adjuvant bisphosphonates among

premenopausal women under OFS.

Zoledronic acid q6 months may be discussed in young women receiving OFS. Optimal duration of treatment is

uncertain, and risks and beneﬁts should be considered on a case-by-case basis.

IA Y ¼57%

N¼17%

A¼26%

In green, NEW/MODIFIED BCY5 guidelines with consensus voting.

A, abstain; AIs, aromatase inhibitors; BC, breast cancer; BCS, breast-conserving surgery; CT, computed tomography; EBC, early breast cancer; ER, estrogen receptor; FDG, [

F]2-

ﬂuoro-2-deoxy-D-glucose; GnRH, gonadotropin-releasing hormone; GoR, grades of recommendation; HER2, human epidermal growth factor receptor 2; HR, hormone receptor;

LoE, levels of evidence; MRI, magnetic resonance imaging; N, no; OFS, ovarian function suppression; OS, overall survival; PARP, poly (ADP-ribose) polymerase; pCR, pathological

complete response; PET, positron emission tomography; RT, radiation therapy; SNLB, sentinel lymph node biopsy; TDM-1, trastuzumab-emtansine; TNBC, triple-negative breast

cancer; WBI, whole breast irradiation; Y, yes.

S. Paluch-Shimon et al. Annals of Oncology

Volume xxx -Issue xxx -2022 https://doi.org/10.1016/j.annonc.2022.07.007 7

long-term work ability.

Given the length of working years

ahead for these women, the BCY5 panel ﬁrmly stated that

awareness and referral to appropriate resources should be

available and further research in this setting is needed.

Panel members re-emphasized that many speciﬁc issues

in the treatment of young women with breast cancer, in all

settings of the disease, still lack evidence-based standards

and that systematic research into age-speciﬁc tumor char-

acteristics is needed which could open the door for more

tailored therapeutic interventions.

Risk factors

Lifestyle-associated risk factors should be discussed with

young women as part of public health initiatives.

Data are

inconclusive on whether or not obesity is a risk factor for

breast cancer in premenopausal women and increasing

body mass index (BMI) seems inversely correlated with

breast cancer risk in young women.

Increases in the waist-

to-hip ratio, which measures central adiposity, are associ-

ated with increased risk of premenopausal breast cancer. As

obesity is associated with increased risk of many serious

health issues, the BCY5 panel stated that health care

professionals should inform young women about breast

health and other modiﬁable breast cancer risk factors in

general (e.g. maintaining a BMI 25 kg/m

, as well as

limiting alcohol consumption, smoking and physical

inactivity).

Diagnostic imaging for screening, staging and follow-up

1. Screening: There is no indication for routine screening

by any imaging technique in healthy, average-risk

young women. Surveillance in high-risk women,

based on family history or pathogenic gene variants in

predisposing genes, and for those at increased risk

because of a personal history of therapeutic radiation

in childhood or young adulthood,

should follow

available guidelines.

2. Staging and follow-up: The panel reinforced the recom-

mendation that imaging and staging in young women

including axillary assessment should in principle follow

standard algorithms as for older women.

Breast ultrasound remains the ﬁrst diagnostic approach for

clinical abnormalities in this age group and in pregnant/

Table 4. Assessment and treatment general guidelines in advanced breast cancer

Guidelines LoE/GoR Consensus

In ABC, age alone is not a reason to prescribe more aggressive therapy and International Consensus Guidelines for

management of advanced breast cancer must be applied (ABC guidelines, NCCN guidelines, evidence-based national

guidelines).

Therapeutic recommendations should not differ from those for older women with the same disease characteristics and

extent.

Expert opinion

The BCY5 panel endorses the ESOeESMO ABC5 guidelines for the management of ABC in premenopausal women. IA 100%

Clinical and pathologic characteristics predicting for CNS recurrence often overlap with factors that indicate increased

risk for general metastatic dissemination (i.e. young age, ER- and PR-negativity, HER2 overexpression, high proliferation

and genomic instability). Although young age has been associated with an increased risk of CNS metastases,

surveillance and therapeutic recommendations should not differ from those for older women with the same disease

characteristics and extent.

Preliminary data suggest BC patients harboring BRCA mutations present a higher incidence of CNS involvement and a

worse outcome compared to non-carriers, irrespective of BC subtype.

No data on the efﬁcacy of PARPi on CNS involvement are available as none of the phase III PARP trials included patients

with active CNS metastases.

In subgroup analyses, talazoparib beneﬁt persisted in patients who had stable/treated brain metastases on study entry.

Inclusion of patients with active CNS metastases should be encouraged in all studies investigating new therapies

(unless medically contraindicated)

Expert opinion Y ¼87%

N¼4%

A¼9%

Many trials in HR+ ABC have not included premenopausal women.

Despite this, we recommend that young women with ER+ ABC have adequate ovarian suppression or ablation and then

be treated in the same way as postmenopausal women with endocrine agents targeted therapies.

Future trials exploring new endocrine/endocrine-biological strategies should be designed to allow for enrollment of

both pre- and postmenopausal women and men.

Platinum agents have been demonstrated to be superior to taxanes in BRCA-associated advanced breast cancer. IB

The BCY5 panel endorses all the ABC5 ESMOeESO statements on PARPi for patients with a germline BRCA mutation.

Platinum and PARP inhibitors have not been compared in the advance setting and preferential use of either or optimal

sequencing of these treatments is unknown

IA Y ¼83%

N¼0

A¼17%

Phase II data suggest a beneﬁt for PARPi in patients with ABC harboring somatic BRCA1/2 mutations or a germline

PALB2 mutation.

Somatic BRCA1/2 mutations and germline PALB2 mutations are not common; however, tailoring of treatment based on

these alterations may be considered with caution on a case-by-case basis.

This data underscores the importance of molecular tumor boards and of pooling of data in international registries.

IIB

Expert opinion

Y¼87%

N¼0

A¼13%

Very little is known about psychosocial challenges and dying concerns in young parents with ABC. Most of the data

refer to Caucasian, upper-, middle-class women within nuclear families.

In general, patients express concerns for their children and their co-parent, and personal concerns which impact their

QoL contribute to the emotional and psychological distress, and increase family dysfunction.

Further research in this setting is needed on patients from diverse backgrounds, non-nuclear families, on the co-

parent, parents and caregivers.

Expert opinion 100%

In green, NEW/MODIFIED BCY5 guidelines with consensus voting.

A, abstain; BC, breast cancer; BCY5, ﬁfth International Consensus Symposium for Breast Cancer in Young Women; CNS, central nervous system; ESMO, European Society of

Medical Oncology; ESO, European School of Oncology; GoR, grades of recommendation; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; LoE, levels of

evidence; N, no; NCCN, National Comprehensive Cancer Network; PARPi, poly (ADP-ribose) polymerase inhibitors; QoL, quality of life; Y, yes.

Annals of Oncology S. Paluch-Shimon et al.

8https://doi.org/10.1016/j.annonc.2022.07.007 Volume xxx -Issue xxx -2022

lactating women.

Given the data on diagnostic superiority

of digital breast tomosynthesis (DBT) over digital mammog-

raphy in young women and in those with dense breasts,

with only marginal increase in radiation dose, a majority of

the BCY5 panel stated that DBT is the preferred diagnostic

tool.

Pre-operative magnetic resonance imaging (MRI) is asso-

ciated with increased rates of ipsilateral mastectomy and

contralateral prophylactic mastectomy in newly diagnosed

breast cancer patients, irrespective of age

: its indications

should strictly follow available recommendations.

MRI is

generally superior to other clinical and imaging assessments

after pre-operative chemotherapy.

The optimal timing for

carrying out mammography and MRI is the ﬁrst half of the

menstrual cycle (days 7-14).

Recent data show that

abbreviated MRI (AB-MRI), i.e. the acquisition of only two

sequences, before and immediately after the administration

of gadolinium, has equivalent performances to standard MRI

protocols in diagnostic clinical settings.

Although validation

with prospective multicenter trials is pending, almost half of

the BCY5 panelists agreed that AB-MRI may represent a valid

alternative to conventional MRI for persons with dense

breasts with the advantages of short examination/interpre-

tation times and low costs.

The panel re-conﬁrmed that in average-risk patients,

imaging surveillance after primary breast cancer treatment

should follow the same guidelines as in older women.

Genetic counseling and testing

The panel conﬁrmed that genetic counseling should be

offered to every young woman, irrespective of tumor subtype

[e.g. triple-negative (TN) disease] or family history of breast

cancer as studies have reported that if testing is carried out

based on traditional testing guidelines (largely guided by

personal and family history of malignancy), close to 50% of

persons with a germline mutation would not be identiﬁed.

A fast-track process, which enables testing before

commencement of therapy, should be available when the

identiﬁcation of a pathogenic gene variant could change the

therapeutic approach [e.g. indication for risk-reducing sur-

gery, platinum derivatives, poly (ADP-ribose) polymerase

(PARP) inhibitors (PARPi)]. Although BRCA1/2 genes are the

most frequently mutated genes, testing for other additional

moderate- to high-penetrance genes using a multi-gene

panel may be considered, if they will impact therapeutic in-

terventions. In a recent study, genes most commonly asso-

ciated with breast cancer in woman aged 45 years were

BRCA, BRCA2, ATM, CHEK2 and PALB2

due to prevalence

and impact. The clinical utility (including risk assessment,

screening and prevention recommendations) of moderate-

risk genes identiﬁed on multi-gene panel testing and poly-

genic risk score models are not yet established or ready for

clinical practice.

Multidisciplinary management of mutation carriers and

high-risk individuals should ideally be provided in dedicated

high-risk clinics, when available. Clinical trials focusing on

risk reduction and optimal screening strategies for this

group of women are strongly needed. Unaffected carriers

should be encouraged to participate in clinical trials evalu-

ating risk-reducing strategies such as the BRCA-P study

evaluating denosumab in women harboring a PV in BRCA1

who have not undergone risk-reducing mastectomy

(NCT04711109). With the recent shift to ‘oncologist-led

mainstream’testing where the surgeon or oncologist refers

for testing, and counseling and interpretation are provided

following test results,

47,48

education and training of the

involved health care professionals is needed to provide

optimal risk communication and clinical recommendations.

For women who are not ready to consider genetic testing

at the time of diagnosis, access to genetic counseling should

Table 5. Additional considerations in women with hereditary-associated breast cancer

Guidelines LoE/GoR Consensus

For survivors harboring a BRCA 1/2 or (other) strongly predisposing mutation, bilateral risk-reducing mastectomy may

be considered, although there is no deﬁnite evidence that it leads to a survival beneﬁt. Therapeutic decisions should

reﬂect a balance between the risk of recurrence of the diagnosed breast cancer and the potential beneﬁt of preventing

an additional primary tumor.

IIB

For the time being, the radiotherapy treatment of EBC is independent of BRCA or any other constitutional genetic

status, with the exception of germline TP53 and ATM mutations, for which a very high risk of secondary cancers has

been described after radiation therapy.

Radiation therapy should be carefully discussed on an individual basis for these patients.

IIC

In the absence of evidence-based recommendations for risk-reducing surgery in patients harboring pathogenic variants

in lowemoderate-penetrance genes, decisions must be taken individually, mainly based on family history.

For breast cancer survivors and asymptomatic carriers harboring a BRCA 1/2 mutation, risk-reducing salpingo-

oophorectomy (RRSO) should be discussed from the age of 35 years provided that the woman has completed family

planning. For BRCA1 mutation carriers RRSO is recommended between age 35 and 40 years and for BRCA2 mutation

carriers around age 40 years, always respecting patient’s preferences and considering the family history.

Indications and timing of risk-reducing salpingo-oophorectomy for other highly penetrant mutations should follow

available international/national guidelines.

Expert opinion

Salpingectomy with delayed oophorectomy remains investigational and should preferably be carried out only within a

clinical trial.

Expert opinion Y ¼85%

N¼10%

A¼5%

Currently, the evidence on the reduction of BC risk and mortality by oophorectomy is conﬂicting and likely limited to

BRCA1 carriers.

Expert opinion Y ¼53%

N¼17%

A¼30%

In green, NEW/MODIFIED BCY5 guidelines with consensus voting.

A, abstain; BC, breast cancer; EBC, early breast cancer; GoR, grades of recommendation; LoE, levels of evidence; N, no; y, yes.

S. Paluch-Shimon et al. Annals of Oncology

Volume xxx -Issue xxx -2022 https://doi.org/10.1016/j.annonc.2022.07.007 9

Table 6. Supportive and follow-up care guidelines

Guidelines LoE/GoR Consensus

Young women with breast cancer face speciﬁc physical, psychosocial and sexual issues that should be addressed by a

multidisciplinary group of providers including breast medical, surgical and radiation oncologists, breast care nurses,

social workers, psycho-oncologists, gynecologists and fertility experts, among others.

Expert opinion

Young women with breast cancer are at higher risk for psychosocial distress. Patients’distress and psychosocial needs

should be regularly assessed.

Psychosocial care should be available and integrated in routine cancer treatments and follow-up.

Partners and family members should be involved early on and couple-based psychosocial interventions should be

promptly proposed if needed.

IIB

The speciﬁc psychosocial distress pertaining to body image, sexuality and sexual dysfunction resulting from premature

menopause, treatment-related amenorrhea, weight gain, hair loss and breast surgery should be routinely addressed by

the health care team in order to ensure provision of appropriate information and support.

This needs to be carried out in a culturally appropriate manner.

Expert opinion 100%

All young women should be counseled regarding the risk of getting pregnant while on chemotherapy, endocrine or

anti-HER2 therapy, despite developing amenorrhea, and of the need for adequate non-hormonal contraception if they

are sexually active and could become pregnant.

Exogenous hormonal contraception is generally contraindicated in young cancer survivors, irrespective of disease

subtype, and alternative strategies should be considered.

Expert opinion

All young women (irrespective of stage of disease) should be informed about approved fertility preservation options

and referred for specialist counseling/consultation if interested in fertility preservation before commencement of any

therapy.

Women should be informed that currently available methods of fertility preservation generally allow for timely start of

chemotherapy schedules.

The BCY5 panel endorses the ABC guidelines statement that the impact of the anticancer therapies on fertility should

be discussed with all women with ABC of childbearing age and their partners, before the start of treatment.

The discussion must also include appropriate information about the prognosis of the disease and the potential

consequences of pregnancy (e.g. stopping ongoing treatment).

Expert opinion Y ¼96%

A¼4%

Physicians’knowledge and familiarity with the available international guidelines on fertility preservation, pregnancy

after BC and management of BC during pregnancy should be increased in order to facilitate and improve evidence-

based individualized management of young patients with BC.

Expert opinion Y ¼96%

A¼4%

The use of GnRH analog concomitant with (neo)adjuvant CT should be offered to reduce the risk of premature ovarian

failure, possibly preserve ovarian function and reduce damage to fertility.

Concomitant GnRHa use during chemotherapy does not replace established fertility preservation methods, which

should still be offered to all young patients.

The effectiveness of GnRHa does not seem to depend on the time of administration in relation to commencement of

chemotherapy.

IB Y ¼70%

N¼20%

A¼10%

Biomarkers such as AMH levels may predict ovarian function after chemotherapy though data are limited. Expert opinion Y ¼85%

A¼15%

All young women should be counseled about the risks and associated symptoms and outcomes and management of

treatment-related amenorrhea and premature menopause before the onset of systemic therapy (either CT or ET) and

informed of available ameliorative therapies.

Expert opinion

Premature menopause and/or treatment-related amenorrhea increase the risk of bone thinning and patients should be

counseled, monitored and treated accordingly.

Pregnancy after breast cancer should not be discouraged even in patients with HR-positive disease or those harboring

a germline BRCA mutations. While pregnancy itself does not appear to increase the risk of recurrence the discussion

about pregnancy should take into account the patient’s prognosis based on initial stage and biology.

Pending results of prospective clinical trials, patients with HR+ disease who are unwilling to wait till the end of

adjuvant ET should complete at least 18-24 months of ET before attempting pregnancy. Treatment should be resumed

and completed according to initial planning after delivery and breast-feeding.

IIA

Expert opinion

Y¼95%

A¼5%

Y¼95%

A¼5%

There are limited data on breast-feeding after BC. Lactation can be carried out from the unaffected breast and data

suggest that lactation from the previously affected breast may sometimes be feasible, depending on the type of

surgery and radiation. Women should be counseled at the time of receipt of radiation therapy that they most likely will

not be able to breast-feed from the irradiated breast.

Young BC survivors who pursue a pregnancy and are interested in breast-feeding should have access to lactation

counseling by trained health professionals.

Expert opinion Y ¼96%

A¼4%

Breast cancer during pregnancy

Treatment of patients with breast cancer during pregnancy should be decided on an individual basis according to

international guidelines within an expert multidisciplinary team, expanded to include obstetricians and perinatologists,

and according to patients’preferences.

Whenever possible, women with a diagnosis of pregnancy during breast cancer should be managed by a

multidisciplinary teams with expertise in this ﬁeld.

Expert opinion

Y¼91%

N¼4%

A¼5%

Pregnancy termination has not been shown to improve patient prognosis and should not be promoted for such reason. IVA 100%

In principle, standard chemotherapy can be offered to most patients, based on the gestational age, tumor stage and

biology.

IIB 100%

Exposure to ET, bone-modifying agents and anti-HER2 therapies should be avoided during pregnancy. If treatment

cannot be delayed until delivery (e.g. in case of ABC), treatment choices should be carefully discussed with the patient

to ensure maternal beneﬁt and reduce fetal risk.

IIB Y ¼91%

A¼9%

Patients diagnosed in the few years after pregnancy have worse prognosis. Further research is warranted to better

understand their biology and deﬁne treatment strategies accordingly.

Expert opinion Y ¼85%

A¼15%

Continued

Annals of Oncology S. Paluch-Shimon et al.

10 https://doi.org/10.1016/j.annonc.2022.07.007 Volume xxx -Issue xxx -2022

be offered on an ongoing basis, and women with previous

limited testing should be considered for a more compre-

hensive contemporary panel in survivorship. Strategies to

minimize recently documented racial/ethnic and social dis-

parities in early access to genetic testing and risk manage-

ment should be implemented to optimize risk-reducing

interventions.

Research is needed to assess the psycho-

social factors affecting the communication of genetic test

results by young breast cancer patients with parents and

siblings, especially in non-Caucasian women.

Screening for other malignancies and risk-reducing surgery

recommendations for women harboring a pathogenic

gene variant

In patients harboring a pathogenic germline variant in TP53

(LieFraumeni syndrome, LFS), the use of ionizing radiation

should be discouraged to avoid increasing the riskof secondary

radio-induced malignancies.

Annual brain and whole body

MRI (WB-MRI) is recommended as contrast-free WB-MRI has

shown to be effective for cancer detection in asymptomatic

carriers and during follow-up in breast cancer patients.

51,52

[

2-ﬂuoro-2-deoxy-D-glucoseepositron emission tomographye

computed tomography (FDGePETeCT) scan has also been

proven to be effective in cancer screening of patients with LFS,

but the availability of safer modalities (e.g. contrast-free WB-

MRI) has limited its incorporation in surveillance protocols.

For those with a BRCA1/2 mutation and other breast cancer-

associated susceptibility genes, timing of risk-reducing salpingo-

oophorectomy (RRSO) and gynecologic surveillance should

follow international guidelines. Ongoing trials will possibly help

clarify the role for salpingectomy with delayed oophorectomy

in women wishing to delay RRSO and early onset of menopause

(ClinicalTrials.gov Identiﬁer: NCT02321228, NCT01907789,

NCT01608074). For now salpingectomy with delayed oopho-

rectomy remains investigational.

Transgender and nonbinary persons

Knowledge about the risks of breast/gynecological cancers in

transgender (TG) and nonbinary (NB) persons receiving

gender-afﬁrming hormone therapy is limited.

Even less in-

formation exists regarding TG/NB individuals with known ge-

netic predisposition. Cancer registries should include TG/NB

identities, and further education and research is needed to ﬁll

the gap in information and counseling in this population.

EARLY BREAST CANCER

Locoregional treatment

Surgery. Although young age remains an independent risk

factor for increased locoregional recurrence, irrespective of

the type of surgery carried out, especially in patients with

human epidermal growth factor receptor 2-positive

(HER2þ) and TN disease, a decreasing trend in locore-

gional recurrence is reported across continents. The panel

remains concerned about the expanding international trend

for bilateral mastectomies, particularly in younger women

despite no improvement in long-term survival.

Commu-

nication strategies to optimize decision making for surgical

treatment of breast cancer should be implemented to

encourage appropriate breast-conserving surgery (BCS).

Decision aid tools focused on the needs of young, average-

risk breast cancer patients are being developed and evalu-

ated and should become a research priority.

Oncoplastic surgical techniques should be discussed with

all patients scheduled for BCS if post-operative asymmetry

is anticipated and should always be carried out by a dedi-

cated breast surgical team. When mastectomy is indicated,

skin- and nipple-sparing techniques with immediate breast

reconstruction (IBR) can provide oncological control while

also addressing cosmetic needs.

IBR (irrespective of

technique) following mastectomy offers the same survival

outcome rates as mastectomy without reconstruction

and

should be offered to all patients except those with inﬂam-

matory breast cancer for whom delayed reconstruction is

recommended (given the need for extensive radiation and

the recommendation to wait until the highest relapse risk

passes) and those with locally advanced disease at pre-

sentation with poor response to primary systemic therapy.

The increasing use of pre-operative therapy for stage 2-3

Table 6. Continued

Other issues

Young patients should be strongly encouraged to adopt the following healthy lifestyle changes:

maintain BMI 25

perform regular aerobic exercise

not to smoke

to limit daily alcohol intake

Expert opinion

Young BC survivors experience signiﬁcant job- and insurance-related issues, and potential ﬁnancial toxicity following

diagnosis.

Awareness and referral to appropriate resources should be available for all young patients.

Further research in this setting is needed in order to plan targeted interventions and avoid unnecessary difﬁculties.

Expert opinion

Y¼96%

A¼4%

Y¼96%

A¼4%

Many young BC patients use integrative medicine (complementary and alternative therapies). Health professionals

should proactively promote open communication about integrative medicine with their young BC patients.

To ensure patient safety and quality of treatments, when possible, supervised and established integrative medicine

services should be provided within the oncology service at the treating institution.

Expert opinion

Y¼91%

N¼9%

Y¼78%

A¼17%

N¼5%

In green, NEW/MODIFIED BCY5 guidelines with consensus voting.

A, abstain; ABC, advanced breast cancer; AMH, anti-Müllerian hormone; BC, breast cancer; BCY5, ﬁfth International Consensus Symposium for Breast Cancer in Young Women;

BMI, body mass index; CT, computed tomography; ET, endocrine therapy; GnRHa, gonadotropin-releasing hormone agonist; GoR, grades of recommendation; HER2, human

epidermal growth factor receptor 2; HR, hormone receptor; LoE, levels of evidence; N, no; Y, yes.

S. Paluch-Shimon et al. Annals of Oncology

Volume xxx -Issue xxx -2022 https://doi.org/10.1016/j.annonc.2022.07.007 11

disease particularly in the more aggressive subtypes has

reduced past concerns that wound healing complications

from IBR will delay any necessary systemic therapy. Higher

SES is associated with higher IBR rates among both young

and older women, including in countries with universal

health care.

60,61

IBR is rarely available for patients from

LMICs.

The BCY5 panel unanimously stated that every

young breast cancer patient should have access to IBR and

oncoplastic surgery if medically appropriate.

The panel conﬁrmed that the indications for sentinel lymph

node biopsy and surgical management of patients with

sentinel lymph node involvement should be the same as in

older patients and that, despite the fact that optimal locore-

gional treatment after pre-operative chemotherapy remains

controversial, decisions should be made irrespective of age.

Germline mutation status should be part of the individual

decision-making algorithm when young women are making

breast surgery choices. In the absence of evidence-based

recommendations for risk-reducing surgery in patients

with PVs in lowemoderate-penetrance genes, decisions

must be tailored to the individual, guided by family history

and patient preference.

Radiation therapy. Indications for post-operative RT are the

same as for older patients

; however, data are more robust

for beneﬁts of post-mastectomy radiation therapy (PMRT)

amongst young women. PMRT after implant-based breast

reconstruction is associated with higher risk of reconstruc-

tive failure (>15%) and capsular contracture (>30%). Rates

of capsular contracture are lower with PMRT with tissue

expanders, but reconstructive failure is more common.

These complications may translate into poor aesthetic

outcomes, decreased satisfaction and lower QoL. Given the

lack of deﬁnitive evidence for optimal reconstructive algo-

rithms and techniques (implant-based or autologous tissue

reconstructions), shared decision making with the patient

and optimal integration of plastic surgery and radiation

oncology are crucial.

When PMRT is foreseen, the panel

recommended that timing and technique of the recon-

structive procedure should be discussed pre-operatively on

an individual basis by all the specialists involved. PMRT is

not a stand-alone reason to postpone reconstruction.

Indications and extent of nodal irradiation are the same as

in other age groups.

Modern techniques to minimize long-

term side-effects are necessitated. The use of respiratory

control is the most common approach to reduce the dose to

heart and lungs, offering a more favorable irradiation ge-

ometry by inﬂating the lungs and increasing the distance

between the heart and the chest wall.

A boost to the site

of the radical local excision in case of BCS remains standard

pending the results of modern randomized trials (e.g. the

Young Boost Phase III trialdNCT00212121).

The BCY5 panel afﬁrmed that moderately hypofractio-

nated whole breast irradiation (WBI) schedules should

replace standard fractionated WBI as gold standard for most

patients. Ultra-hypofractionated schedules were either not

tested in premenopausal women, such as in the FAST trial

(once-weekly ﬁve fractions),

or not mature yet for long-

term adverse effects as in the FAST-Forward Trial (ﬁve frac-

tions in 1 week with 15% of premenopausal patients

enrolled).

The BCY5 panel therefore recommended against

ultra-hypofractionated WBI or for irradiation of the lymph

node regions (such as in FAST-Forward) for young patients.

As partial breast irradiation (PBI), or accelerated PBI, has

not been sufﬁciently studied in young patients,

the panel

recommended against its use outside of clinical trials.

Indications of post-operative RT are independent of BRCA

status. Prophylactic radiation to the unaffected contralat-

eral breast in BRCA carriers who decline contralateral

mastectomy should not be carried out outside of clinical

trials.

Although a recent study demonstrated fewer ipsi-

lateral breast recurrences amongst BRCA1/2 carriers who

had undergone PMRT compared to those without PMRT,

further data are needed. There is limited evidence about

the safety of radiation for those harboring a moderate-

penetrance pathogenic gene variant (e.g. CHEK2, ATM)

and the riskebeneﬁt ratio needs to be individually dis-

cussed, but there is no clear contraindication to RT. PMRT

may be discussed in cases of signiﬁcant risk of locoregional

recurrence in patients with a germline TP53 mutation, for

whom radiotherapy is otherwise contraindicated to the high

risk of secondary malignancies. These recommendations

underscore the importance of early genetic testing at the

time of diagnosis to aid optimal treatment planning.

Adjuvant systemic treatment

Adjuvant systemic treatment decisions for invasive breast

cancer should be based on the extent of disease and bio-

logical characteristics of the tumor (including, but not

limited to, tumor size, nodal status, hormone receptor and

HER2 overexpression/ampliﬁcation, Ki67, proliferation and

grade), patient’s comorbidities and preferences similar to as

in older women.

Gene expression signatures

Although gene expression signatures, such as Oncotype Dx,

MammaPrint, Prosigna, Endopredict and Breast Cancer In-

dex, provide additional information on an individual’s

recurrence risk and some signatures have demonstrated

clinical utility for adjuvant chemotherapy decision mak-

ing,

72-74

women younger than 40 are grossly under-

represented in both retrospective and prospective studies.

Additionally, most of the premenopausal patients in these

studies did not receive contemporary risk-adapted ET.

In TAILORx, patients with a low-risk recurrence score (RS),

deﬁned as RS 0-10 (30% of whom were premenopausal but

only 4% aged <40 years), had a 5-year distant recurrence-

free survival of 99%

with ET alone. For those with an

intermediate-risk RS (RS 11-25), the 9-year distant

recurrence-free survival was 94.5% for the ET-only group

and 95% for those who received chemotherapy and ET.

Exploratory, unplanned subgroup analyses of women aged

50 years suggested a beneﬁt from chemotherapy amongst

those with an intermediate RS within the range of 16-25

and further analyses suggested that clinical risk level

Annals of Oncology S. Paluch-Shimon et al.

12 https://doi.org/10.1016/j.annonc.2022.07.007 Volume xxx -Issue xxx -2022

combined with RS identiﬁed women aged 50 years to be

more likely to beneﬁt from the addition of chemotherapy to

ET alone.

Only 13% of premenopausal women received

ovarian function suppression (OFS).

The RxPONDER trial randomized patients with lowein-

termediate-risk RS (0-25) with 1-3 lymph nodes to either ET

alone or chemotherapy plus ET: 33% of participants were

premenopausal, 2.9% were <40 years of age and 21.5%

were aged 40-49 years. While no beneﬁt was demonstrated

in the postmenopausal population with the addition of

chemotherapy, in the premenopausal women an absolute

beneﬁt of 5.2% favoring chemotherapy was demonstrated

both for low and intermediate RS, with an invasive disease-

free survival (iDFS) of 94.2% versus 89% [hazard ratio (HR)

0.54, 95% conﬁdence interval (CI) 0.38-0.76].

In the ET-

only arm, 16% received OFS compared to only 3% in the

chemotherapy arm.

In the WGS ADAPT ERþ/HER2study, all patients with

0-3 involved lymph nodes and a low RS of 0-11 received ET

alone [mostly tamoxifen in pre- and aromatase inhibitor

(AI) in postmenopausal patients]. Those with intermediate

RS (12-25) were given 3 weeks of ET before surgery. Pa-

tients with a Ki67 10% in the surgical specimen were

considered endocrine responders and received ET alone (of

whom 23.3% were aged 50 years), while those with a

Ki67 >10% were classiﬁed as endocrine non-responsive

and received chemotherapy in addition to ET (of whom

64.7% were aged 50 years). Amongst endocrine re-

sponders with an RS of 12-25 and limited nodal burden (up

to two nodes), despite no data in women <40 years of age,

there was no difference in outcome between the low and

intermediate RS groups, with a 5-year distant DFS (DDFS) of

96.8% and 97.4%, respectively, in patients aged 50 years.

Outcome was also similar to that of patients aged >50

years with 0-3 nodes and RS 0-25 who received ET alone.

Derived from the ADAPT data, the ENREP algorithm

(https://enrep.info) can help to estimate endocrine

responsiveness based on clinical and immunohistochemical

factors.

The MINDACT trial assessed all patients for recurrence

risk by both clinicalepathological factors (clinical risk) and

MammaPrint (genomic risk) and assigned those with clinical

low/genomic low to ET alone. Patients with high clinical/

high genomic risk were assigned to CT followed by ET. Pa-

tients with discordant risk proﬁles underwent randomiza-

tion to determine use of chemotherapy.

Only 6.2% of the

study population was aged <40 years.

An exploratory

analysis demonstrated a 5% beneﬁt in distant metastases-

free survival favoring the addition of chemotherapy in

women 50 years of age who were clinically high risk,

genomic low risk

but it is unclear if these results indicate

true beneﬁt from chemotherapy or a chemoendocrine ef-

fect given among the 50-year-old patients who did not

receive chemotherapy, 55% received tamoxifen alone for 5

years, and only 20% received OFS.

Favorable outcomes were seen in the SOFT and TEXT

studies and the Austrian Breast and Colorectal Cancer

Study Group (ABCSG) 12 trial, among premenopausal

patients with low-risk disease who did not receive

chemotherapy.

80,81

In SOFTeTEXTdamongst women aged

<35 years with HER2disease only 57 women (out of

442) did not receive chemotherapyd94% were node

negative, 84% had T1 and 23% grade 1 tumors. In this

group, 14% had an early invasive breast cancer event

(including three distant recurrences and one death) at 6-

year and 5.6-year follow-up in TEXT and SOFT, respec-

tively.

Thus, omitting adjuvant chemotherapy in young

and very young women (35 years old at diagnosis) may

be appropriate in selected cases with favorable clinical,

genomic and pathological features.

Pharmaco-prevention

Five years of tamoxifen 20 mg daily reduces breast cancer

risk by 35%-40% and is recommended as pharmaco-

prevention for women with an elevated breast cancer

risk.

Despite the riskebeneﬁt ratio being in favor of

tamoxifen in all women <50 years of age, irrespective of

the degree of risk, the uptake of tamoxifen for breast cancer

prevention is low (10%-12%).

Higher-risk premenopausal

women appear more likely to accept tamoxifen,

with the

main reasons for non-initiation being concerns about side-

effects, tamoxifen being perceived as a ‘cancer drug’, min-

imal beneﬁt and fertility concerns.

84,85

Low-dose tamoxifen

(5 mg/day for 3 years) may be an alternative to full-dose

tamoxifen in women with breast intraepithelial neoplasia

given its efﬁcacy and limited toxicity.

86,87

The BCY5 panel

recommends discussing pharmaco-prevention with young

women at high risk of developing breast cancer.

Pre-operative endocrine therapy

There are no new data regarding pre-operative ET in young

women since BCY4. The BCY5 panel agreed with the pub-

lished American Society of Clinical Oncology (ASCO) guide-

lines

that pre-operative ET should not be routinely

recommended for young women outside of clinical trials.

Nevertheless, a short pre-operative ET (2-4 weeks) with

subsequent Ki67 determination in the surgical specimen for

assessing endocrine responsiveness may help adjuvant

treatment decision making as demonstrated by the ADAPT

trial also for young women.

Trials evaluating the efﬁcacy

of cyclin-dependent kinase (CDK) 4/6 inhibitors plus ET in

the pre-operative setting are ongoing.

Adjuvant endocrine therapy

Based on the updated results of the SOFT and TEXT

studies

and in line with existing guidelines,

16,90,91

BCY5

conﬁrmed that tamoxifen alone remains the standard of

care in premenopausal women at low risk of relapse, as

deﬁned by clinical and immunohistochemical parameters,

who did not receive adjuvant chemotherapy. More than

97% of these women are free of distant recurrence and

alive at 8 years, with no additional beneﬁt by escalating ET

to OFS plus tamoxifen or exemestane.

In women at higher risk of relapse, adding OFS to ET is

associated with a signiﬁcant improvement in outcomes

S. Paluch-Shimon et al. Annals of Oncology

Volume xxx -Issue xxx -2022 https://doi.org/10.1016/j.annonc.2022.07.007 13

including distant recurrence compared to tamoxifen

alone.

In high-risk patients, the combination of OFS and

an AI should be the preferred option and OFS and tamox-

ifen for those with toxicity to the AI. An overall survival (OS)

beneﬁt was evident in the SOFT study amongst patients

who received adjuvant chemotherapy followed by OFS plus

oral ET; however, this was not yet demonstrated in the TEXT

study. Given that the risk of disease recurrence continues

for >20 years,

long-term follow-up will be key to ascertain

if the positive effects on DFS will translate into improve-

ments in OS and also to deﬁne potential longer-term safety

issues (e.g. second primaries), particularly relevant in young

patients.

An online tool (https://rconnect.dfci.harvard.edu/Compo

siteRiskSTEPP/) has been developed for clinicians to use in

daily practice to estimate individual risk-based beneﬁtof

escalating ET for women with HER2disease. This is a

composite measure of the distant recurrence risk according

to traditional prognostic features (i.e. patient age, tumor

size, grade, lymph node status, ER, progesterone receptor

and Ki67 expression) derived from the SOFTeTEXT popu-

lation.

Although the relative efﬁcacy of escalating ET is

independent of age, women aged <35 years have the

largest magnitude of absolute improvement in outcomes

with OFS.

80,82

OFS timing (concurrent versus sequential) in

women receiving adjuvant chemotherapy does not impact

breast cancer outcomes. Notably, in women <40 years old

who are less likely to develop CIA,

94,95

gonadotropin-

releasing hormone agonist (GnRHa) concomitant with

chemotherapy has the added beneﬁt of ovarian function

protection.

GnRHa in combination with tamoxifen or an AI should be

prescribed for 5 years based on the SOFT/TEXT data. A

shorter duration was associated with excellent mid- and

long-term outcomes in women with lower or intermediate

risk who did not necessarily receive chemotherapy (ABCSG-

12 in which only 5% received chemotherapy and the AST-

TRA trials).

81,97

Adding OFS to tamoxifen signiﬁcantly im-

proves the 5-year DFS, compared to tamoxifen alone,

including in women with late (within 2 years) resumption of

ovarian function after chemotherapy,

suggesting that

ovarian function should be monitored long term. Switching

from 2-3 years of tamoxifen to Ais plus goserelin for a total

treatment duration of 5 years versus continuing tamoxifen

alone was associated with more adverse events but no

improvement in disease outcomes in a small phase II trial

with short follow-up.

Extending tamoxifen beyond 5 years should be considered

in high-risk patients

99,100

as the riskof recurrence continues for

>20 years.

The impact ofextended OFS and tamoxifen or an

AI beyond 5 years is unknown.

OFS always needs to be given in young women with

otherwise intact ovarian function who receive an AI. AIs

alone are contraindicated in premenopausal women:

caution must be taken when considering an AI in premen-

opausal women who became amenorrheic during the

course of treatment due to the potential for recovery of

ovarian function.

101,102

The criteria for deﬁning menopausal

status following CIA are deﬁned in the BCY2 paper

and

reported in Supplementary Appendix S1, available at

https://doi.org/10.1016/j.annonc.2022.07.007.

BCY5 conﬁrmed that hormone levels should be checked

under GnRH therapy if there are concerns that ovarian

function is not suppressed, especially if breakthrough

bleeding occurs and/or the patient is on an AI. A gas

chromatography/mass spectroscopy method, if available, is

preferred to monitor therapy.

103,104

The updated results of

the SOFT-EST sub-study, at over 4 years of treatment, were

consistent with the ﬁrst-year results showing that OFS does

not achieve optimal estrogen suppression in up to 17% of

patients.

105

Based on the limited available data

106-108

and concerns

about suboptimal OFS with depot formulations, monthly

formulations of GnRHa are preferred,

especially in women

<35 years of age and in those receiving an AI. However,

when monthly use is not feasible or accepted by the pa-

tient, 3-6 monthly administration may be considered on a

case-by-case basis with close monitoring of ovarian

function.

107

The method of ovarian suppression (surgical versus

medical) requires balancing patient’s wish for potentially

preserving fertility and compliance with frequent injections

over a long period of time and cost/availability. The BCY5

panel was divided when discussing radiation to ovaries as a

method of OFS: a narrow majority voted that it should be

discouraged if alternatives exist. New RT techniques better

delineate the position of the ovaries, thus improving

effectiveness and minimizing the adverse events.

109

Younger age is associated with lower adherence and

persistence to adjuvant ET,

82,110

which has been associated

with reduced OS.

111

Determinants of treatment persis-

tence

112

may vary according to race and ethnicity

113,114

potentially modiﬁable factors should be identiﬁed with

targeted interventions.

115,116

Three recently reported neo/adjuvant trials investigating

the impact of adding the CDK4/6 inhibitors abemaciclib

117

and palbociclib

118,119

to ET have provided mixed results.

Almost 50% of enrolled patients were premenopausal in

each trial. In the PALLAS adjuvant trial, 3-year iDFS did not

differ between the two arms (88.2% with palbociclib and

88.5% with ET). Similarly, in PENELOPE-B, at a median

follow-up of 42.8 months, palbociclib did not improve the 3-

year iDFS in women with residual invasive disease after pre-

operative chemotherapy (81.2% with palbociclib, 77.7%

with placebo). However, the monarchE study which added

abemaciclib to standard ET demonstrated an absolute 3.5%

improvement in the 2-year iDFS (92.2% versus 88.7%), and

5.4% at 3 years.

117,120

There are several possible reasons for

different ﬁndings including the patient populations, rates of

discontinuation and the speciﬁc CDK4/6 inhibitor. Longer

follow-up and the results of ongoing trials (NATALEE triald

NCT03701334; ADAPTcycle trialdNCT4055493; ADAPTlate

trialdNCT4565054) may provide more data but the BCY5

panel stated that abemaciclib could be considered in high-

risk patients similar to those enrolled in the monarchE

study (4 involved nodes, or 1-3 involved nodes with other

Annals of Oncology S. Paluch-Shimon et al.

14 https://doi.org/10.1016/j.annonc.2022.07.007 Volume xxx -Issue xxx -2022

high-risk features, i.e. tumor size 5 cm, grade 3, Ki67

20%).

GnRH agonists and ovarian function preservation

In line with the most recent guidelines focused on fertility

after cancer,

121,122

BCY5 conﬁrmed that the use of GnRHa

concomitant with (neo)-adjuvant chemotherapy should

be offered to all patients to reduce the risk of premature

ovarian insufﬁciency and possibly preserve ovarian func-

tion. It is important to note that there are no clinical data

whether use of a GnRHa for the purpose of ovarian

function suppression is necessary or recommended dur-

ing use of post-neoadjuvant capecitabine, olaparib and

immunotherapy (noteworthy, in the CREATE-X study

evaluating post-neoadjuvant capecitabine, over half of

the patients were premenopausal; however, no data are

available about GnRHa use). The recently reported results

from the OPTION trial

123

suggest that patients experience

a short-term decrease in QoL from the addition of

goserelin to chemotherapy to preserve ovarian function,

a price that women may decide to pay if adequately

informed.

Because fertility outcome data after temporary OFS

during chemotherapy are still insufﬁcient,

the BCY5 panel

conﬁrmed that GnRHa use during chemotherapy does not

replace established fertility preservation methods, which

should be offered to all young patients interested in sub-

sequent pregnancies. The efﬁcacy of GnRHa in preserving

the ovarian reserve seems unrelated to the timing of

administration before chemotherapy,

124,125

but scheduling

after oocyte cryopreservation should be coordinated be-

tween the fertility and oncology teams to avoid a potential

ovarian hyperstimulation syndrome.

126

Anti-Müllerian hor-

mone may predict ovarian function recovery after GnRHa

during chemotherapy.

124,127-129

Neo/adjuvant chemotherapy

Proportional risk reductions with taxane- and/or

anthracycline-based adjuvant regimens are not signiﬁcantly

affected by age

130

: since no studies have speciﬁcally

investigated different chemotherapy regimens/scheduling

in young women previous statements remain valid. At the

time of BCY5, the majority of the panel did not support

routine use of non-anthracycline-based regimens. While

anthracyclines have long been the backbone of neo/adju-

vant chemotherapy, they carry long-term risks of cardiac

failure and leukemia/myelodysplastic syndromes. In light of

these risks, numerous studies have evaluated non-

anthracycline-based regimens and there is now a growing

body of evidence supporting non-anthracycline-based regi-

mens for endocrine-responsive tumors with a low tumor

burden that require chemotherapy and in HER2 over-

expressing tumors.

131,132

The recent shift in practice and

the emergent data will be formally discussed and voted

upon in a consensus statement at BCY6.

The question of whether to incorporate platinum agents

in the pre-operative setting for TN- or BRCA-associated

tumors remains unresolved.

16,133

A recent study comparing

Acx4 to 4 cycles of cisplatin in the neoadjuvant setting for

BRCA-associated triple-negative breast cancer (TNBC)

demonstrated that Doxorubicin and cyclophosphamide was

superior to the 4 cisplatin cycles for achieving pathological

complete response (pCR).

134

The BRIGHTNESS neoadjuvant

study reported that pCR and event-free survival (EFS) were

inferior for paclitaxel monotherapy compared to either

carboplatin/paclitaxel or carboplatin/paclitaxel/veliparib, all

followed by 4 cycles of cyclophosphamide and doxorubicin

in TNBC.

135

While platinum agents may be considered in

selected patients, risk of additional gonado-toxicity should

be considered. There are still no data on the use of platinum

agents in the adjuvant setting. For patients with TN disease

without a pCR after standard pre-operative regimens,

addition of 6-8 cycles of capecitabine may be considered, as

in other age groups.

136

Recent data demonstrated that

substituting a platinum for capecitabine in this setting did

not improve outcomes.

137

The phase III KEYNOTE 522 study evaluated the incor-

poration of immunotherapy in the pre-operative setting.

Pembrolizumab with chemotherapy was compared to pla-

cebo with chemotherapy followed by a year of pem-

brolizumab or placebo, respectively. In the most recent

update, a beneﬁt is seen for pCR (64.8% versus 51.2%, P¼

0.00055) and for EFS [91.3% versus 85.3%, HR 0.63 (95% CI

0.43-0.93)] favoring the pembrolizumab arm.

138

An impor-

tant consideration is immune-related endocrinopathies,

some of which are irreversible, and the impact on female

fertility and ovarian function recovery is for the time being

unknown. The IMPASSION-031 randomized patients to pre-

operative chemotherapy with or without atezolizumab fol-

lowed by a year of atezolizumab or placebo. pCR was

superior for the atezolizumab arm, 58% versus 41%

(P¼0.0044),

139

but outcome data are awaited. Gepar-

Nuevo, a phase II study with 174 patients, evaluated

incorporation of durvalumab in the pre-operative setting

alone, and demonstrated superior pCR, iDFS, DDFS and OS

favoring the durvalumab-containing arm.

140

The incorpo-

ration of pembrolizumab in this setting may be considered

in young women.

Adjuvant anti-HER2 therapy

The beneﬁt of adjuvant trastuzumab appears independent

of age

141

and anti-HER2 therapies should be the same as for

other age groups. No additional data from randomized

studies were published after BCY4; therefore, all recom-

mendations remain unchanged.

Adjuvant bisphosphonates

As new data on DFS improvement with adjuvant

bisphosphonates among premenopausal women emerged

after BCY4,

142

the panel stated that zoledronic acid q6

months may be discussed in young women receiving OFS

but given the limited data on long-term outcomes,

143

risks

and beneﬁts should be balanced on a case-by-case basis.

Optimal treatment duration and dosing interval are

S. Paluch-Shimon et al. Annals of Oncology

Volume xxx -Issue xxx -2022 https://doi.org/10.1016/j.annonc.2022.07.007 15

uncertain and alternative schedules are under investiga-

tion.

144

As a result of the long half-life of bisphosphonates,

caution is needed in women interested in future concep-

tion, given the increased rates of neonatal complications

and spontaneous abortions in a recent case-control study

on pregnant women.

145

There are no data for beneﬁt from

adjuvant denosumab in young women.

Side-effects of adjuvant therapy

In view of the long life expectancy of young women, the

panel reinforced the need to monitor potential long-term

toxicities (i.e. cardiovascular, bone morbidity, cognitive

impairment, secondary malignancies).

INFLAMMATORY BREAST CANCER

Inﬂammatory breast cancer should be managed the same as

for the older breast cancer population.

Advanced breast cancer

The BCY5 panel endorses the ESOeESMO ABC5 guidelines

for the management of advanced breast cancer (ABC)

146

and reiterated that young age alone should not be a

reason to prescribe more aggressive therapy including

combination chemotherapy over sequential use of

monotherapy. BCY5 panelists endorse the ABC5 statements

that (i) young women with ERþABC should have adequate

OFS/ovarian function ablation and be treated as post-

menopausal women, with endocrine agents, with or

without targeted therapies and (ii) that future trials

exploring new endocrine-based strategies should allow

enrolment of pre- and postmenopausal women, and men,

recognizing nonetheless that this ﬁeld has evolved in recent

years.

Young women with ABC have unique medical and psy-

chosocial concerns that need to be considered and

addressed.

147

While pregnancy in the setting of ABC is not

considered safe or desirable from a medical perspective,

concerns for fertility and family planning need to be

cautiously discussed and explored even in the setting of

advanced disease. In patients with long-term responses and

prolonged progression-free survival (e.g. in HER2þdisease),

the safety of interrupting anti-HER2 therapies for patients

who may be interested in a pregnancy is unknown.

Locoregional relapse

Young age is a risk factor for local relapse. Therefore, careful

attention to margin status is warranted in young women.

148

Following locoregional relapse, BCY5 conﬁrmed that

chemotherapy should be considered in women with ER

tumors, as demonstrated in the CALOR study.

149

For ERþ

disease, ET should be given and for HER2þdisease,

trastuzumab-based therapy is recommended albeit based

only on expert opinion level of evidence.

Unique populations

BRCA mutation carriers. There remains no deﬁnitive

conclusion on the optimal chemotherapy regimen for BRCA-

associated breast cancer in the neo/adjuvant setting and

the panel recommended that standard prognostic features

should be used to decide treatment in early disease.

The role of PARPi in the early breast cancer setting has

been established by the OlympiA study which randomized

patients with BRCA1/2-associated breast cancer to a year of

adjuvant olaparib or placebo. The study included patients

with high-risk features deﬁned as stages 2 and 3, TNBC with

residual disease after pre-operative chemotherapy or node

positive or pT2 irrespective of nodal status or ERþdisease

with four or more involved lymph nodes or signiﬁcant re-

sidual disease after pre-operative chemotherapy.The median

age in this study was 42 (range 36-50) years, most patients

being premenopausal. At a median follow-up of 2.5 years, the

3-year iDFS was improved by 8.8% in the olaparib group.

150

Noteworthy is the observation of fewer new primary malig-

nancies in the olaparib treatment arm, which may be

particularly important for younger patients. The BCY5 panel

stated that olaparib should be offered to germline BRCA1/2

mutation carriers who meet the OLYMPIA inclusion criteria or

the regulatory approval criteria.

The BCY5 panel endorses all the ABC5 statements on

systemic treatment for patients with a germline BRCA mu-

tation, germline PALB2 mutation and somatic BRCA1/2

mutations, recognizing the importance of molecular tumor

boards and of data pooling in international registries.

Preliminary data suggest that breast cancer patients

harboring BRCA mutations present a higher incidence of

central nervous system (CNS) involvement. Although sub-

group analyses in both OlympiAD and EMBRACA showed a

beneﬁt in persons with stable/treated brain metastases,

none of the phase III PARPi trials included patients with

active CNS metastases.

151

BCY5 panelists encourage the

inclusion of patients with active CNS metastases in studies

investigating new therapies.

MALE BREAST CANCER

Male breast cancer accounts for w1% of all breast cancers;

the lifetime risk is w1 : 1 000, and represents a small mi-

nority in males <40 years.

152,153

Breast cancer in young

men is rare; however, it would likely amplify the psycho-

logical distress already experienced by men with a breast

cancer diagnosis. Treatment should follow international

guidelines,

154

men should be included in clinical trials,

particularly in trials exploring ET as the expected differential

efﬁcacy in males versus females is greatest in this setting,

germline testing carried out to aid in treatment and pre-

vention measures and distinctive histopathologic and

genomic features investigated.

155,156

Supportive and follow-up care

Many breast cancer patients use integrative medicine

(complementary and alternative therapiesdCAM)

157

but

very few data are available in young women. In a recent

Annals of Oncology S. Paluch-Shimon et al.

16 https://doi.org/10.1016/j.annonc.2022.07.007 Volume xxx -Issue xxx -2022

German study, 62.5% of 827 young breast cancer patients

had used CAM. Its use was signiﬁcantly higher in women

with higher educational level and employment status, and

in those feeling they had not received sufﬁcient informa-

tion.

158

The BCY5 panel stated that health professionals

should proactively promote open communication about

integrative medicine with their young breast cancer pa-

tients. As effectiveness and safety of many therapies remain

under-explored, the BCY5 panel also approved that, if

possible, supervised and established integrative medicine

services should be provided within the oncology service.

BCY5 conﬁrmed that follow-up care and supportive

treatment/prevention of speciﬁc symptoms and side-effects

in young women should follow the same guidelines as in

older women. New shared-care models involving cancer

specialists, general practitioners and breast nurses are being

evaluated to improve cost-effectiveness.

The panel also reiterated that standardized patient-

reported outcome measurements may enable timely

collection of treatment side-effects, enabling the develop-

ment of targeted interventions.

Dedicated survivorship clinics that assess and manage

early and late treatment toxicities and treatment adherence

are valuable in this population.

Psychosocial issues. Young breast cancer patients are at

greater risk of psychosocial morbidity, not only during the

active treatment period but also long term

159

and when

facing ABC.

160

Psychosocial care should be available and

integrated in routine cancer treatments and follow-up. The

BCY5 panel recommended that the speciﬁc psychosocial

distress pertaining to body image, sexuality and sexual

dysfunction resulting from premature menopause,

treatment-related amenorrhea, weight gain, hair loss and

breast surgery should be routinely addressed by the health

care team in a culturally appropriate manner to ensure

provision of appropriate information and support.

Partners and family members should be involved early on

and couple-based and/or familial psychosocial interventions

should be promptly proposed during the different phases of

the disease. Offspring having a mother diagnosed with breast

cancer may experience high levels of psychological distress.

161

Partners of young breast cancer survivors (3-8 years post-

treatment) report poorer overall, physical, social, psychologi-

cal and spiritual QoL compared to partners of healthy

women.

162-164

Social issues that need to be addressed include

return to work, family planning and ﬁnancial loss. The scarce

data about end-of-life concerns of young patients with ABC

derive from Caucasian, upper-/middle-class women within

nuclear families and include worries about children and co-

parents which affect their QoL and family functioning.

165

The

BCY5 panelists recognized that further research in this setting

is needed on patients from diverse backgrounds, non-nuclear

families, on the co-parent, parents and caregivers.

Despite not being the topic of BCY5, we recognize the

impact of COVID-19 pandemic on patients’psychological

health

166

due to disruption of oncology service organization

and perceived increased loneliness.

Considerations and recommendations by the BCY5 panel

for fertility preservation, contraception and premature

menopause, sexual functioning, pregnancy after breast

cancer, bone health, cognitive impairment, lifestyle changes

and breast cancer during pregnancy are updated in

Supplementary Appendix S1, available at https://doi.org/

10.1016/j.annonc.2022.07.007.

Patient advocacy statements

BCY5 included the second patient advocacy workshop, and

for the third time, included a patient advocacy-dedicated

session for young women with breast cancer and the

consensus session included two young breast cancer survi-

vors as panelists. Since BCY3, a closed Facebook group for

young breast cancer survivors has been active and now has

over 53 active global members. The importance of the

worldwide breast cancer community to work together was

apparent throughout the meeting.

At BCY5, a presentation was made announcing Project

528, the ﬁrst-ever global needs assessment of young adults

diagnosed with breast cancer. This will be a global survey

that is created in true partnership with Young Survival

Coalition and Europa Donna Slovenia to learn the global

needs of young adults. Project 528 has four clear goals: (i)

identify the unmet needs of young adults diagnosed with

breast cancer and their caregivers; (ii) understand the

geographic difference in patient experiences; (iii) discover

existing services available to young adults diagnosed with

breast cancer globally; and (iv) understand the QoL burden

of young adults diagnosed with breast cancer.

Everyone interested in participating in this important

survey are encouraged to sign up and learn more at https://

project528.youngsurvival.org.

CONCLUSIONS

Since BCY4, progress has been made. More clinical trials in

the metastatic setting are incorporating young women with

breast cancer by allowing for OFS as an acceptable surrogate

for physiological menopause. The impact of germline muta-

tions in BRCA1/2 has now substantial therapeutic implica-

tions in both early breast cancer and ABC. One of the many

challenges in the treatment of premenopausal ERþearly

breast cancer is how to incorporate and interpret gene

expression signatures into treatment algorithms to deter-

mine which patients need chemotherapy in addition to

optimal ET. Urgent research is needed to address adherence

to available treatments, health disparities and needs of mi-

norities, and a global effort is required to help bridge the gaps

in LMICs. A multidisciplinary approach remains the backbone

of care to ensure optimal outcomes for young women with

breast cancer given their many concerns and care needs.

FUNDING

No external funding has been received for the preparation

of these guidelines. Production costs have been covered by

ESMO from central funds.

S. Paluch-Shimon et al. Annals of Oncology

Volume xxx -Issue xxx -2022 https://doi.org/10.1016/j.annonc.2022.07.007 17

DISCLOSURE

SPS: Advisory Board consultancy, speaker’s bureau: Astra-

Zeneca, Pﬁzer, Novartis, Lilly, Roche, MSD, Exact Sciences.

Research Funding: Pﬁzer. HAA: Recipient of grants/research

supports: Amgen. Recipient of honoraria or consultation

fees: Novartis, Roche. Employment: Pierre Fabre. FC:

Recipient of honoraria or consultation fees: Amgen, Astel-

las/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai,

GE Oncology, Genentech, GlaxoSmithKline, Macrogenics,

Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma,

Novartis, Pﬁzer, Pierre-Fabre, prIME Oncology, Roche,

Samsung Bioepis. GC: Recipient of grants/research sup-

ports: Merck, Astra Zeneca. Recipient of honoraria or

consultation fees: Daichii Sankyo. Participation in a spon-

sored speakers’bureau: Novartis, Pﬁzer, Lilly. KAG: Recipient

of grants/research supports: Pﬁzer, Astra Zeneca. Recipient

of honoraria or consultation fees: Pﬁzer, Lilly, Astrazeneca,

Novartis, Mylan, Benentech, Merck, Roche, Nanostring. NH:

Honoraria for lectures and/or consulting from Amgen, Astra

Zeneca, Daiichi-Sankyo, Exact Sciences, Lilly, MSD, Novartis,

Pierre Fabre, Pﬁzer, Roche, Sandoz, Seagen (all outside the

submitted work). SBK: Research funding from Novartis,

Sanoﬁ-Aventis and DongKook Pharm Co; consultant in

advisory boardsdNovartis, AstraZeneca, Lilly, Dae Hwa

Pharmaceutical Co. Ltd, ISU Abxis, Daiichi-Sankyo and Bei-

gene; and stocksdGenopeaks, NeogeneTC (all outside the

submitted work). FP: Recipient of honoraria or consultation

fees: Roche Diagnostics, Ipsen, Merck (all outside the sub-

mitted work). ES: Recipient of grants/research supports:

Amgen, AstraZeneca, Boehringer, Eli Lilly, Merck, Novartis,

Pﬁzer, Roche, Samsung. Recipient of honoraria or consul-

tation fees: Amgen, AstraZeneca, Clinigen, Egis, Eli Lilly,

Genomic Health, Novartis, Pﬁzer, Pierre Fabre, Roche, San-

doz, TLC Biopharmaceuticals. Travel support: Amgen,

AstraZeneca, Egis, Novartis, Pﬁzer, Roche. All other authors

have declared no conﬂicts of interest.

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Effectiveness of gonadotropin-releasing hormone agonists for ovarian function suppression in premenopausal patients with hormone receptor-positive breast cancer: a retrospective single-center real-world study

Article

Full-text available

May 2024
BREAST CANCER RES TR

Purpose This study evaluated the effectiveness of ovarian function suppression (OFS) of various gonadotropin-releasing hormone agonists (GnRHa) combined with aromatase inhibitors (AI) in premenopausal patients with hormone receptor-positive (HR-positive) breast cancer. Potential risk factors associated with insufficient OFS were analyzed. Patients and methods Premenopausal HR-positive breast cancer patients who had received AI with GnRHa were studied retrospectively. Patients were divided into different groups according to monthly or trimonthly GnRHa schedules they received, and the effectiveness of OFS was compared between groups. Insufficient OFS was defined as at least one instance of estradiol ≥ 30 pg/ml. Patient data was gathered from medical records for this comparison. Results Of the 264 patients enrolled in this study, 117 were administered 3.6 mg of goserelin monthly (goserelin 1 M group), 63 received 3.75 mg of leuprorelin monthly (leuprorelin 1 M group) and 84 were given 11.25 mg of leuprorelin every three months (leuprorelin 3 M group). Overall, 7.20% experienced insufficient OFS. The incidence rates in the three GnRHa depot groups were 7.69%, 6.35%, and 7.14%, respectively, without a significant statistical difference (P = 0.900). Notably, younger patients exhibited a higher likelihood of insufficient OFS [OR = 0.900, 95%CI (0.824–0.982), P = 0.018]. Conclusion Insufficient OFS remains a concern during GnRHa and AI treatment. The effectiveness of the three GnRHa depots commonly used in China seems comparable. Younger patients face a heightened risk of insufficient OFS.

Development and validation of a pathological model predicting the efficacy of neoadjuvant therapy for breast cancer based on RCB scoring

Article

May 2024

Introduction Breast cancer has become the most prevalent malignant tumor among women globally, posing a serious threat to women's life and health. Neoadjuvant therapy (NAT) has emerged as one of the standard treatment approaches for breast cancer patients. However, due to varying responses to NAT among different patients, significant differences in treatment effectiveness occur, impacting the timely alteration of treatment strategies for patients. Material and methods Based on clinical and pathological characteristics along with the RCB scoring, we utilized a support vector machine (SVM) algorithm to construct a Breast Cancer Pathological Characteristics(PBCS) prediction model. We thoroughly validated the PBCS and compared it to a Pathomics Signatures (PS) prediction model. Results we developed a pathological prediction label, named PS. Subsequently, through univariate and multivariate analysis, we discovered a significant correlation between HER2 and the patients' RCB scores. Integrating HER2 into PS, we constructed a breast cancer pathological prediction model, named PBCS.PBCS exhibits good performance in predicting the effectiveness of postoperative therapy（RCB 0~Ⅰ） in both the training sets(AUC0.86[95%CI0.7988-0.9173])and validation sets（AUC0.83[95%CI0.7219-0.9382 ]). In the validation set, PBCS significantly outperforms the PS（AUC0.65[95%CI0.5121-0.7886 ]）.Calibration curves and clinical decision curves also strongly support PBCS's ability to effectively predict the efficacy of therapy（RCB 0~Ⅰ）. Conclusions Conclusions PBCS can assist clinical and pathological physicians in accurately predicting patients' post-treatment RCB grading before initiating NAT. This offers a new approach to forecast breast cancer patients' responsiveness to NAT, aiding in devising personalized treatment strategies for patients.

Ready the treasure at our feet, MRI feature analysis in young women with breast cancer

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Jun 2024
EUR RADIOL

Catherine J. Moran

Contemporary Review of the Management and Treatment of Young Breast Cancer Patients

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Jun 2024
CLIN BREAST CANCER

Different dosage forms of GnRHa with endocrine therapy in premenopausal hormone Receptor-Positive breast cancer

Article

Jun 2024
J NATL CANCER I

Background Despite the wide use of a 3-month gonadotropin-releasing hormone (GnRH) agonist for ovarian function suppression in premenopausal breast cancer patients, it remains unclear whether it is as effective and safe as a 1-month GnRH agonist regimen when combined with selective estrogen receptor modulators or aromatase inhibitors, especially in younger patients. Methods This retrospective cohort study included 1109 premenopausal hormone receptor–positive breast cancer patients treated with GnRH agonist plus selective estrogen receptor modulator or aromatase inhibitor. The estradiol (E2) inhibition rate within 1-24 months after treatment with 1-month or 3-month GnRH agonist in cohorts and different subgroups was analyzed. Results Following 1:1 propensity score matching, 950 patients with a mean age of 39 years and a median follow-up of 46 months were included. Both the 1-month and 3-month groups achieved more than 90% E2 inhibition within 24 months (94.53% vs 92.84%, with a 95% confidence interval for the difference ranging from −4.78% to 1.41%), confirming the noninferiority of 3-month GnRH agonist. Both 1-month and 3-month GnRH agonist rapidly and consistently reduced E2 levels. Of the patients, 60 (6.3%) experienced incomplete ovarian function suppression, with similar rates in the 1-month and 3-month groups (5.5% vs 7.2%). Incomplete ovarian function suppression mainly occurred within the first 12 months, with age younger than 40 years and no prior chemotherapy being the risk factors. Similar disease-free survival and overall survival were found in the 1-month and 3-month groups and in patients with complete and incomplete ovarian function suppression (P > .05). Conclusions The ovarian function suppression with 3-month GnRH agonist was not inferior to that with 1-month GnRH agonist, regardless of age or combination with a selective estrogen receptor modulator or an aromatase inhibitor.

Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy

Article

May 2024
J CLIN ONCOL

PURPOSE We investigated time to pregnancy, efficacy and safety of fertility preservation, and assisted reproductive technologies (ARTs) in women with early hormone receptor–positive breast cancer (BC) desiring future pregnancy. PATIENTS AND METHODS POSITIVE is an international, single-arm, prospective trial, in which 518 women temporarily interrupted adjuvant endocrine therapy to attempt pregnancy. We evaluated menstruation recovery and factors associated with time to pregnancy and investigated if ART use was associated with achieving pregnancy. The cumulative incidence of BC-free interval (BCFI) events was estimated according to the use of ovarian stimulation at diagnosis. The median follow-up was 41 months. RESULTS Two hundred seventy-three patients (53%) reported amenorrhea at enrollment, of whom 94% resumed menses within 12 months. Among 497 patients evaluable for pregnancy, 368 (74%) reported at least one pregnancy. Young age was the main factor associated with shorter time to pregnancy with cumulative incidences of pregnancy by 1 year of 63.5%, 54.3%, and 37.7% for patients age <35, 35-39, and 40-42 years, respectively. One hundred and seventy-nine patients (36%) had embryo/oocyte cryopreservation at diagnosis, of whom 68 reported embryo transfer after enrollment. Cryopreserved embryo transfer was the only ART associated with higher chance of pregnancy (odds ratio, 2.41 [95% CI, 1.75 to 4.95]). The cumulative incidence of BCFI events at 3 years was similar for women who underwent ovarian stimulation for cryopreservation at diagnosis, 9.7% (95% CI, 6.0 to 15.4), compared with those who did not, 8.7% (95% CI, 6.0 to 12.5). CONCLUSION In POSITIVE, fertility preservation using ovarian stimulation was not associated with short-term detrimental impact on cancer prognosis. Pregnancy rates were highest among those who underwent embryo/oocyte cryopreservation followed by embryo transfer.

6th and 7th International Consensus Guidelines for the management of advanced breast cancer (ABC Guidelines 6 and 7)

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May 2024
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May 2024
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Multicenter Study on the Frequency of Low Bone Mineral Density in Young Women With Breast Cancer and Associated Factors

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Revisiting ovarian function suppression with GnRH agonists for premenopausal women with breast cancer: Who should use and the impact on survival outcomes

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May 2024
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Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study

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Full-text available

Oct 2021
ANN ONCOL

Background Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. Patients and methods This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. Results At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. Conclusion Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials

Article

Full-text available

Aug 2021
LANCET ONCOL

Background Trastuzumab targets the extracellular domain of the HER2 protein. Adding trastuzumab to chemotherapy for patients with early-stage, HER2-positive breast cancer reduces the risk of recurrence and death, but is associated with cardiac toxicity. We investigated the long-term benefits and risks of adjuvant trastuzumab on breast cancer recurrence and cause-specific mortality. Methods We did a collaborative meta-analysis of individual patient data from randomised trials assessing chemotherapy plus trastuzumab versus the same chemotherapy alone. Randomised trials that enrolled women with node-negative or node-positive, operable breast cancer were included. We collected individual patient-level data on baseline characteristics, dates and sites of first distant breast cancer recurrence and any previous local recurrence or second primary cancer, and the date and underlying cause of death. Primary outcomes were breast cancer recurrence, breast cancer mortality, death without recurrence, and all-cause mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, oestrogen receptor (ER) status, and trial yielded first-event rate ratios (RRs). Findings Seven randomised trials met the inclusion criteria, and included 13 864 patients enrolled between February, 2000, and December, 2005. Mean scheduled treatment duration was 14·4 months and median follow-up was 10·7 years (IQR 9·5 to 11·9). The risks of breast cancer recurrence (RR 0·66, 95% CI 0·62 to 0·71; p<0·0001) and death from breast cancer (0·67, 0·61 to 0·73; p<0·0001) were lower with trastuzumab plus chemotherapy than with chemotherapy alone. Absolute 10-year recurrence risk was reduced by 9·0% (95% CI 7·4 to 10·7; p<0·0001) and 10-year breast cancer mortality was reduced by 6·4% (4·9 to 7·8; p<0·0001), with a 6·5% reduction (5·0 to 8·0; p<0·0001) in all-cause mortality, and no increase in death without recurrence (0·4%, –0·3 to 1·1; p=0·35). The proportional reduction in recurrence was largest in years 0–1 after randomisation (0·53, 99% CI 0·46 to 0·61), with benefits persisting through years 2–4 (0·73, 0·62 to 0·85) and 5–9 (0·80, 0·64 to 1·01), and little follow-up beyond year 10. Proportional recurrence reductions were similar irrespective of recorded patient and tumour characteristics, including ER status. The more high risk the tumour, the larger the absolute reductions in 5-year recurrence (eg, 5·7% [95% CI 3·1 to 8·3], 6·8% [4·7 to 9·0], and 10·7% [7·7 to 13·6] in N0, N1–3, and N4+ disease). Interpretation Adding trastuzumab to chemotherapy for early-stage, HER2-positive breast cancer reduces recurrence of, and mortality from, breast cancer by a third, with worthwhile proportional reductions irrespective of recorded patient and tumour characteristics. Funding Cancer Research UK, UK Medical Research Council.

Adjuvant olaparib for patients with BRCA1- Or BRCA2-mutated breast cancer

Article

Full-text available

Jun 2021

Background Poly(adenosine diphosphate–ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation–associated early breast cancer. Methods We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)–negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease–free survival. Results A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease–free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease–free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P=0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest. Conclusions Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.)

Endocrine Therapy Response and 21-Gene Expression Assay for Therapy Guidance in HR+/HER2– Early Breast Cancer

Article

Apr 2022

PURPOSE To our knowledge, WSG-ADAPT-HR+/HER2– ( NCT01779206 ; n = 5,625 registered) is the first trial combining the 21-gene expression assay (recurrence score [RS]) and response to 3-week preoperative endocrine therapy (ET) to guide systemic therapy in early breast cancer. MATERIALS AND METHODS Baseline and postendocrine Ki67 (Ki67 post ) were evaluated centrally. In the endocrine trial, all patients received exclusively ET: patients with pathologic regional lymph node status (pN) 0-1 (ie, 0-3 involved lymph nodes) entered control arm if RS ≤ 11 and experimental arm if RS12-25 with ET response (Ki67 post ≤ 10%). All other patients (including N0-1 RS12-25 without ET response) received dose-dense chemotherapy (CT) followed by ET in the CT trial. Primary end point of the endocrine trial was noninferiority of 5-year invasive disease-free survival (5y-iDFS) in experimental ( v control) arm; secondary end points included distant DFS, overall survival, and translational research. RESULTS Intention-to-treat population comprised 2,290 patients (n = 1,422 experimental v n = 868 control): 26.3% versus 34.6% premenopausal and 27.4% versus 24.0% pN1. One-sided 95% lower confidence limit of the 5y-iDFS difference was –3.3%, establishing prespecified noninferiority ( P = .05). 5y-iDFS was 92.6% (95% CI, 90.8 to 94.0) in experimental versus 93.9% (95% CI, 91.8 to 95.4) in control arm; 5-year distant DFS was 95.6% versus 96.3%, and 5-year overall survival 97.3% versus 98.0%, respectively. Differences were similar in age and nodal subgroups. In N0-1 RS12-25, outcome of ET responders (ET alone) was comparable with that of ET nonresponders (CT) for age > 50 years and superior for age ≤ 50 years. ET response was more likely with aromatase inhibitors (mostly postmenopausal) than with tamoxifen (mostly premenopausal): 78.1% versus 41.1% ( P < .001). ET response was 78.8% in RS0-11, 62.2% in RS12-25, and 32.7% in RS > 25 (n = 4,203, P < .001). CONCLUSION WSG-ADAPT-HR+/HER2– demonstrates that guiding systemic treatment by both RS and ET response is feasible in clinical routine and spares CT in pre- and postmenopausal patients with ≤ 3 involved lymph nodes.

21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer

Article

Dec 2021

Background The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary lymph-node–negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear. Methods In a prospective trial, we randomly assigned women with hormone-receptor–positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease–free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse–free survival. Results A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease–free survival differed according to menopausal status (P=0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease–free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P=0.89). Among premenopausal women, invasive disease–free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P=0.002), with a similar increase in distant relapse–free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P=0.009). The relative chemotherapy benefit did not increase as the recurrence score increased. Conclusions Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease–free survival and distant relapse–free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.)

119O Event-free survival (EFS), overall survival (OS), and safety of adding veliparib (V) plus carboplatin (Cb) or carboplatin alone to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) after ≥4 years of follow-up: BrighTNess, a randomized phase III trial

Article

Sep 2021
ANN ONCOL

Young, Empowered and Strong: A Web-Based Education and Supportive Care Intervention for Young Women With Breast Cancer Across the Care Continuum

Article

Aug 2021

PURPOSE Patient-centered digital interventions may help empower young women to self-manage symptoms and psychosocial concerns and support informational needs often unaddressed in clinic. METHODS Young, Empowered and Strong (YES) is an interactive web-based intervention designed to engage young women with personalized education and symptom self-management resources on the basis of responses to patient-reported outcome–based questionnaires. We piloted YES among young women (< 45 years) with newly diagnosed early breast cancer (EBC) or metastatic breast cancer (MBC) and breast cancer survivors (BCSs). Assessments were deployed weekly (EBC and MBC) or every 4 weeks (BCSs) over 12 weeks. At study completion, use, feasibility, and acceptability of YES were evaluated via a survey and semistructured interview. RESULTS Thirty women were enrolled between April and June 2019: 10 EBC, 10 BCSs, and 10 MBC. The mean age at diagnosis and enrollment was 36 (range 25-44) and 39 (range 31-44) years, respectively. Most participants were actively treated (96%, 27 of 28) with endocrine therapy (54%, 15 of 28) or chemotherapy (43%, 12 of 28). Overall, 61% (180 of 296) of assessments were completed (EBC: 70%, BCSs: 63%, and MBC: 52%). Of 37 patient-reported outcome and need domains, the most frequently triggered were sexual health (EBC: 90%, BCSs: 90%, and MBC: 90%), anxiety (EBC: 80%, BCSs: 90%, and MBC: 90%), stress and mindfulness (EBC: 80%, BCSs: 90%, and MBC: 90%), and fatigue (EBC: 90%, BCSs: 80%, and MBC: 90%). On postpilot survey, participants reported that YES helped them to learn (50%, 7 of 14), monitor (43%, 6 of 14), and manage (57%, 8 of 14) their symptoms. CONCLUSION YES is a feasible and acceptable digital intervention to support young women across the breast cancer care continuum. The nearly universal triggering of sexual and mental health needs suggests suboptimal management in the clinical setting and the potential for self-management through a digital platform.

VP7-2021: KEYNOTE-522: Phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early-stage TNBC

Article

Jul 2021
ANN ONCOL

Prognostic relevance of Ki67 expression in primary male breast cancer: Determination of cut-off points by different evaluation methods and statistical examinations

Conference Paper

Jun 2021

Randomized Phase III Postoperative Trial of Platinum-Based Chemotherapy Versus Capecitabine in Patients With Residual Triple-Negative Breast Cancer Following Neoadjuvant Chemotherapy: ECOG-ACRIN EA1131

Article

Jun 2021

PURPOSE Patients with triple-negative breast cancer (TNBC) and residual invasive disease (RD) after completion of neoadjuvant chemotherapy (NAC) have a high-risk for recurrence, which is reduced by adjuvant capecitabine. Preclinical models support the use of platinum agents in the TNBC basal subtype. The EA1131 trial hypothesized that invasive disease-free survival (iDFS) would not be inferior but improved in patients with basal subtype TNBC treated with adjuvant platinum compared with capecitabine. PATIENTS AND METHODS Patients with clinical stage II or III TNBC with ≥ 1 cm RD in the breast post-NAC were randomly assigned to receive platinum (carboplatin or cisplatin) once every 3 weeks for four cycles or capecitabine 14 out of 21 days every 3 weeks for six cycles. TNBC subtype (basal v nonbasal) was determined by PAM50 in the residual disease. A noninferiority design with superiority alternative was chosen, assuming a 4-year iDFS of 67% with capecitabine. RESULTS Four hundred ten of planned 775 participants were randomly assigned to platinum or capecitabine between 2015 and 2021. After median follow-up of 20 months and 120 iDFS events (61% of full information) in the 308 (78%) patients with basal subtype TNBC, the 3-year iDFS for platinum was 42% (95% CI, 30 to 53) versus 49% (95% CI, 39 to 59) for capecitabine. Grade 3 and 4 toxicities were more common with platinum agents. The Data and Safety Monitoring Committee recommended stopping the trial as it was unlikely that further follow-up would show noninferiority or superiority of platinum. CONCLUSION Platinum agents do not improve outcomes in patients with basal subtype TNBC RD post-NAC and are associated with more severe toxicity when compared with capecitabine. Participants had a lower than expected 3-year iDFS regardless of study treatment, highlighting the need for better therapies in this high-risk population.

ESO–ESMO fifth international consensus guidelines for breast cancer in young women (BCY5)

Abstract and Figures

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