Pi Is 0923753422018580

SPECIAL ARTICLE
ESOeESMO fifth international consensus guidelines for breast cancer in

young women (BCY5)
S. Paluch-Shimon1*y, F. Cardoso2y, A. H. Partridge3, O. Abulkhair4, H. A. Azim5, G. Bianchi-Micheli6, M. J. Cardoso2,
G. Curigliano7,8, K. A. Gelmon9, O. Gentilini10, N. Harbeck11, B. Kaufman12, S. B. Kim13, Q. Liu14, J. Merschdorf15,
P. Poortmans16, G. Pruneri17, E. Senkus18, B. Sirohi19, T. Spanic20, V. Sulosaari21, F. Peccatori7,22z & O. Pagani23z
1
Hadassah University Hospital & Faculty of Medicine, Hebrew University, Jerusalem, Israel; 2Breast Unit, Champalimaud Clinical Centre/Champalimaud Foundation,
Lisbon, Portugal; 3Dana-Farber Cancer Institute, Boston, USA; 4King Abdulaziz Medical City for National Guard, Riyadh, Saudi Arabia; 5Breast Cancer Center, Hospital
Zambrano Hellion, Tecnologico de Monterrey, San Pedro Garza Garcia, Nuevo Leon, Mexico; 6Breast Unit of Southern Switzerland, Lugano, Switzerland; 7European
Institute of Oncology IRCCS, Milan; 8Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; 9British Columbia Cancer, Vancouver, Canada;
10
San Raffaele Hospital, Milan, Italy; 11Breast Center, Department of OB&GYN and CCCMunich, LMU University Hospital, Munich, Germany; 12Sheba Medical Center,
Ramat Gan, Israel; 13Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; 14Sun Yat-sen Memorial Hospital, Sun Yat-sen University,
Guangzhou, China; 15Young Survival Coalition, New York, USA; 16Iridium Netwerk, Department of Radiation Oncology & University of Antwerp, Faculty of Medicine and
Health Sciences, Wilrijk-Antwerp, Belgium; 17National Cancer Institute, IRCCS Foundation, Milan, Italy; 18Medical University of Gdansk, Gdansk, Poland; 19Max Institute
of Cancer Care, New Delhi and Gurgaon, India; 20Europa Donna Slovenia, Ljubljana, Slovenia; 21European Oncology Nursing Society (EONS) and Turku University of
Applied Sciences, Turku, Finland; 22European Institute of Oncology IRCCS & European School of Oncology, Milan, Italy; 23Interdisciplinary Cancer Service Hospital
Riviera-Chablais Rennaz, Vaud, Geneva University Hospitals, Lugano University, Swiss Group for Clinical Cancer Research (SAKK), Lugano, Switzerland
Available online 4 August 2022
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 the Caribbean and parts of south-central Asia (e.g.

Only 4% of new breast cancer cases in the United States in Afghanistan, Pakistan and Turkmenistan). Reports of
2019 occurred in women <40 years of age, with an esti- increasing incidence of premenopausal breast cancer in
mated cumulative risk of 1 in 65 by the age of 40 years and some high-income industrialized countries (France, Italy,
1 in 209 before 30 years of age.1 In low- and middle-income New Zealand, Norway)2,5 may reflect changes in age de-
countries (LMICs), breast cancer before menopause repre- mographics. In the United States, an increasing incidence of
sents a much greater burden both in incidence (55% of total de novo metastatic disease has recently been reported in
breast cancer cases compared to 25% in high-income young black women.6
countries) and death rates (8.5 and 3.3 deaths/100 000, Compared with their older counterparts, breast cancers
respectively),2-4 the highest mortality being reported in arising in young women are characterized by higher pro-
Africa (with the exception of southern Africa), Melanesia, portion of tumors with aggressive phenotypes7 and less
favorable outcomes irrespective of stage at diagnosis,8,9
particularly in luminal-A like tumors.10 Possible explana-
*Correspondence to: Dr Shani Paluch-Shimon, Sharett Institute of Oncology, tions for the poorer outcome in luminal-like tumors include
Hadassah University Hospital & Faculty of Medicine, Hebrew University, Ein different tumor or host biology, less chemotherapy-induced
Kerem, Jerusalem, 12000, Israel. Tel: þ972-26777755 amenorrhea (CIA), suboptimal endocrine treatment and
E-mail: shanipal@hadassah.org.il (S. Paluch-Shimon).
decreased adherence to adjuvant endocrine therapy (ET).
y
Co-first authors. Young women are under-represented in contemporary
z
Co-last authors.
0923-7534/© 2022 European Society for Medical Oncology. Published by research evaluating risk-stratification models and molecular
Elsevier Ltd. All rights reserved. tools resulting in young patients at risk of being
Volume 33 - Issue 11 - 2022 https://doi.org/10.1016/j.annonc.2022.07.007 1097

Annals of Oncology S. Paluch-Shimon et al.
over-treated based solely on age considerations. Prospec-

Table 1. Levels of evidence and grades of recommendation
tive trials dedicated to young patients are key to answering
many of the outstanding questions to ensure optimal Levels of evidence
management. Two such examples are the POSH cohort I Evidence from at least one large randomized, controlled
study, conducted at 127 hospitals in the UK,11 and the trial of good methodological quality (low potential for bias)
or meta-analyses of well-conducted randomized trials
Helping Ourselves, Helping Others: The Young Women’s without heterogeneity
Breast Cancer Study (HOHO) conducted in the United States II Small randomized trials or large randomized trials with a
and Europe. These studies and others have demonstrated a suspicion of bias (lower methodological quality) or meta-
analyses of such trials or of trials with demonstrated
greater proportion of luminal B and estrogen receptor- heterogeneity
negative (ER) tumors in young patients, increased risk of III Prospective cohort studies
early relapse and a more unfavorable longer-term outcome IV Retrospective cohort studies or case-control studies
V Studies without control group, case reports, experts
for young women with ERþ tumors when compared to opinions
older women.8,11
Grades of recommendation
Consistent with previous guidelines,12-16 the panel
A Strong evidence for efficacy with a substantial clinical
defined ‘young women’ as women under the age of 40 benefit, strongly recommended
years at breast cancer diagnosis and defined ‘advanced B Strong or moderate evidence for efficacy but with a limited
breast cancer in young women’ as diagnosis of inoperable clinical benefit, generally recommended
C Insufficient evidence for efficacy or benefit does not
locally advanced or metastatic disease before the age of 40 outweigh the risk or the disadvantages (adverse events,
years. costs, etc.), optional
Due to the coronavirus disease 2019 (COVID-19) D Moderate evidence against efficacy or for adverse
outcome, generally not recommended
pandemic, the fifth International Consensus Symposium for E Strong evidence against efficacy or for adverse outcome,
Breast Cancer in Young Women (BCY5) took place virtually never recommended
on 10-11 October 2020 with over 1200 participants Adapted from the Infectious Diseases Society of America-United States Public Health
Service Grading System with their permission.
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- women with germline pathogenic variants (PVs). Statements
ety of Breast Cancer Specialists (EUSOMA). All recommen- without grading were considered justified standard clinical
dations are for standard care, outside of clinical trials. All practice by the panel experts.
diagnostic and treatment recommendations should be Supplementary Appendix S1, available at https://doi.org/
considered in the context of national regulatory approval, 10.1016/j.annonc.2022.07.007, presents the definition of
availability and reimbursement. menopause following CIA and detailed supportive and
follow-up care issues, unchanged or slightly modified since
BCY4.
METHODOLOGY BCY5 consensus panel members and their disclosure of
Recommendations from BCY4 formed the basis for the any relationships with the pharmaceutical industry that
current recommendations; new and updated statements could be perceived as a potential conflict of interest are
from BCY4 were circulated amongst the panelists before reported.
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 General considerations when caring for young women
potential conflicts of interest or who did not feel comfort- with breast cancer
able responding (e.g. due to lack of expertise on the topic) Management of young women with breast cancer is multi-
were instructed to abstain for that specific question. Sub- faceted and requires specific and dedicated multidisci-
stantial controversies or disagreements are noted in the plinary care (including but not limited to medical and
discussion of the recommendations. These recommenda- radiation oncologist, gynecologist, pathologist, radiologist,
tions were later circulated to panel members by email for breast and plastic surgeon, nurse specialist, geneticist,
comments, updating based on recent reports and correc- physiotherapist, fertility, sexual therapy and psychosocial
tions as needed. experts), best provided in dedicated breast centers, whose
Previous recommendations not requiring update or only quality control assurance ensures qualified experience and
minor changes were not re-voted and remain part of the care.18 The panel recommended that personalized psycho-
recommendations of BCY5. social support and counseling on genetic predisposition,
Tables 1-6 describe the grading system used as per ESMO fertility, sexual health and socioeconomic consequences be
guidelines methodology (adapted from Dykewicz et al.17; see incorporated into individual treatment planning as well as
http://www.esmo.org/Guidelines/ESMO-Guidelines-Methodo lifelong follow-up care given the improved long-term sur-
logy), general guidelines for the management of young vival with modern therapies and risks of late side-effects.
women with breast cancer including early and advanced Specific guidelines for post-treatment survivorship care19
disease, supportive care and follow-up and management of are available for health care providers.
1098 https://doi.org/10.1016/j.annonc.2022.07.007 Volume 33 - Issue 11 - 2022

S. Paluch-Shimon et al. Annals of Oncology
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 Expert opinion 100%
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.
Many specific issues in the treatment of young women with breast cancer, both in the early and in the advanced Expert opinion
settings, still lack definitive proven standards. Therefore, well-designed, independent, prospective randomized trials
should be a global research priority.
The care of all young patients with breast cancer (either early stage, EBC, or advanced disease, ABC) should be Expert opinion
discussed within a multidisciplinary team before any treatment decision making, and ideally provided in specialized
breast clinics.
Navigators/navigation tools are of great assistance in optimizing patient care. Navigators should ideally be breast Expert opinion
nurses but lay-health professionals with strong communication skills and sufficient experience may also address
complex care issues and mixed cultural settings.
In view of the many specific aspects related to young age, personalized psychosocial support, counseling on genetic Expert opinion
predisposition, fertility, sexual health and socioeconomic impact are highly recommended as part of the individual
treatment planning.
In young women, innovative and structured communication and supportive tools (e.g. online programs, web-based Expert opinion
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.
In view of the many specific aspects related to young age, personalized psychosocial support, counseling on genetic Expert opinion
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.
Young age by itself should not be the reason to prescribe more aggressive therapy than in other age groups. Factors Expert opinion
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.
Systematic research into age-specific host-tumor characteristics is needed. Expert opinion
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.
National reimbursement policies/algorithms rewarding treatment protocols per number of treatments, dosages, Expert opinion
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.
Risk factors
Although data about whether obesity is a risk factor for breast cancer in premenopausal women are not conclusive, it Expert opinion Y ¼ 96%
can be said with certainty that obesity is a risk factor for a multitude of serious diseases. For the time being, young A ¼ 4%
women should be encouraged to maintain BMI 25 kg/m2.
Pharmaco-prevention with tamoxifen has proven to be effective in reducing breast cancer occurrence in high-risk IA Y ¼ 96%
young women but is underutilized. A ¼ 4%
Pharmaco-prevention indication, schedule and potential adverse events should be discussed with all young women at
high risk of developing breast cancer.
There is limited evidence to suggest specific lifestyle approaches (e.g. dietary habits, weight management and physical Expert opinion 100%
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.
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 Expert opinion 100%
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.
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.

Table 3. Assessment and treatment guidelines in early breast cancer

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 IA
young women.
Additional consideration may be given to ultrasound and breast MRI in young women particularly in the setting of very Expert opinion
dense breast tissue or consideration of a genetic predisposition or other higher-risk individuals (i.e. radiation therapy
for childhood or young adulthood malignancy).
Diagnosis, imaging and staging in young women should follow standard algorithms consistent with older women. IIC
Additional consideration may be given to ultrasound and breast MRI in young women with very dense breast tissue.
Digital breast tomosynthesis (DBT) is more sensitive than digital mammography in dense breasts, is associated with Expert opinion Y ¼ 80%
marginal increase in radiation dose and should be the preferred diagnostic tool. N ¼ 5%
A ¼ 15%
In patients with dense breasts, abbreviated magnetic resonance imaging (AB-MRI) may represent a valid alternative to Expert opinion Y ¼ 45%
conventional MRI with the advantages of short examination/interpretation times and low costs. N ¼ 15%
A ¼ 40%
For BRCA 1/2 mutation carriers and others at high risk based on family history or predisposing mutations in other IIA
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.
For BRCA 1/2 mutation and other cancer susceptibility genes carriers (e.g. RAD51C, p53, BRIP1) who have not Expert opinion
undergone salpingo-oophorectomy, gynecologic surveillance every 6 months is recommended.
Annual whole body MRI and brain MRI should be offered to women harboring germline p53 pathogenic variants Expert opinion Y ¼ 75%
(LieFraumeni syndrome) for staging and follow-up. A ¼ 25%
Other diagnostic tools (e.g. FDGePETeCT) are still under evaluation in LieFraumeni patients as well as in patients Expert opinion Y ¼ 75%
harboring other germline pathogenic gene variants (e.g. ATM carriers) and should not be part of routine staging and A ¼ 25%
follow-up.
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 Expert opinion Y ¼ 96%
ethnic/racial backgrounds in utilizing and seeking genetic counseling services based on family history of malignancy, A ¼ 4%
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
Every young woman with breast cancer should be offered genetic counseling preferably before starting treatment. Expert opinion
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.
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 Expert opinion 100%
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.
Genes to be tested for depend on personal and family history. Expert opinion 100%
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.
When a hereditary cancer syndrome is suspected and a mutation in BRCA1/2 has not been identified, multi-gene panel Expert opinion
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.
Risk communication and clinical recommendations need to be adapted to the increased complexity and uncertainty of Expert opinion 100%
multi-gene testing.
Health professionals should also be trained to address the related complex psychological scenarios.
The clinical utility (including risk assessment, screening and prevention recommendations) of moderate-risk genes Expert opinion
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.
Multi-gene panel testing (when available) should be proposed when either a hereditary cancer syndrome is suspected Expert opinion
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.
As commercially available multi-gene panels include different genes, the choice of the specific panel should be Expert opinion
performed in quality-controlled laboratories.
For the time being somatic BRCA1/2 testing should not be used as an alternative or in addition to germline pathogenic Expert opinion
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.
Amongst individuals who do not have an identified low-/moderate-/high-risk germline mutation, polygenic risk score Expert opinion Y ¼ 87%
models, evaluating multiple factors for estimating breast cancer risk, are not yet ready for implementation in routine A ¼ 13%
clinical practice.
Continued
Table 3. Continued
Early breast cancer locoregional treatment

Surgical treatment of young patients with EBCdwhile being tailored to the individual patientdshould in general not I
differ from that of older patients.
Breast-conserving surgery should be performed as the first option whenever suitable, as it provides the same overall IA
survival than mastectomy.
Onco-plastic repair techniques should be discussed with all patients treated by BCS in order to maximize cosmetic IC
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) Expert opinion 100%
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.
There is no evidence of an increased false-negative rate or a worse outcome in young patients undergoing SNLB, IB
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 IB
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 Expert opinion
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.
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 Expert opinion
options and adequate psychological support should be offered given the potential long-term sequela and implications.
Indications for adjuvant RT are the same as for older patients. IB
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. Expert opinion Y ¼ 87%
Limited and inconclusive evidence is available in presence of pathogenic gene variants in other predisposing genes A ¼ 13%
(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.
Despite the fact that data on the efficacy and safety of hypofractionation are accumulating in premenopausal women, IB Y ¼ 74%
hypofractionation is not widely adopted as standard radiation therapy for young patients in many countries. A ¼ 26%
Hypofractionated WBI schedules should replace standard fractionated WBI as gold standard for most patients
irrespective of their age.
Ultra-hypofractionated WBI or for the lymph node regions (such as in FAST-Forward) is not yet standard for young Expert opinion Y ¼ 61%
patients. N ¼ 4%
A ¼ 35%
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. IB
Data are stronger for benefits of post-mastectomy RT for young women. IB
Partial breast irradiation (PBI), or accelerated PBI, has not been sufficiently studied in young patients and should not be Expert opinion
performed in this age group.
Post-mastectomy radiation therapy (PMRT) to implant-based breast reconstruction may be associated with a higher Expert opinion Y ¼ 85%
risk of capsular contracture. N ¼ 5%
When PMRT is foreseen the timing and technique of the procedure should be discussed pre-operatively on an A ¼ 10%
individual basis by all the specialists involved.
Adjuvant systemic treatment
Endocrine therapy
All young women should be counseled, before the onset of systemic therapy (either CT or ET), about the risks, Expert opinion
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.
Neoadjuvant ET should not be used in young women outside clinical trials. Expert opinion
All patients with HR-positive disease should receive adjuvant ET. IA
Tamoxifen alone for 5 years is indicated for low-risk patients. IA
Switching to an AI, after 5 years of tamoxifen, should be considered for women who have become definitively IA
postmenopausal. IA
Tamoxifen for 10 years should be considered in high-risk patients, if tolerated. IA
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. IA Y ¼ 90%
The combination of an AI and a GnRH agonist (or oophorectomy) confers a significant absolute benefit in terms of N ¼ 5%
freedom from distant recurrence and should be the preferred option in higher-risk patients. A ¼ 5%
Continued

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- IA
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 Expert opinion Y ¼ 90%
monthly use is not feasible or accepted by the patient. N ¼ 5%
A ¼ 5%
Estradiol levels should be checked if there are concerns ovarian function is not suppressed, especially if a breakthrough Expert opinion
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).
The method of ovarian suppression (surgical versus medical) requires balancing patient’s wish for potentially Expert opinion
preserving fertility, compliance with frequent injections over a long period of time and cost/availability.
Radiation to ovaries as a method of ovarian function suppression should be discouraged. Expert opinion Y ¼ 40%
N ¼ 30%
A ¼ 30%
The addition of a GnRH agonist to tamoxifen can be considered in women at higher risk of relapse resuming ovarian IIB
function within 2 years after chemotherapy completion.
Adjuvant CDK4/6 inhibitors
Early data suggest that adjuvant abemaciclib combined with ET may be beneficial in patients with high-risk ER+ disease IB Y ¼ 61%
(3.5% absolute risk reduction in invasive disease-free survival), however follow-up time is short. N ¼ 13%
43% of patients were premenopausal with similar magnitude of benefit observed irrespective of menopausal status. A ¼ 26%
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.
Chemotherapy
Many factors, including patient and tumor characteristics and genomic signatures, should be considered when deciding IB Y ¼ 91%
whether to administer adjuvant chemotherapy in young women with HR+ early BC. Most young women enrolled in A ¼ 9%
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.
Commercially available prognostic genomic assays in HR+ early breast cancer have not been developed to predict Expert opinion
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.
Available data suggest that a discussion of omitting adjuvant chemotherapy in very young women (35 years of age at Expert opinion
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.
The indications for and the choice of adjuvant systemic treatment for invasive breast cancer should be driven, as for IA
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 Expert opinion
status.
The optimal (neo)adjuvant CT regimen specifically for young women in terms of efficacy and long-term toxicity is IA
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. IA
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 IB
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 IA
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 IA
recommended.
In patients with TNBC with indications for pre-operative chemotherapy, the addition of pembrolizumab (with the IA Y ¼ 90%
chemotherapy and for completion of 1 year following surgery) can be considered in selected young patients with high- N ¼ 10%
risk disease, where approved, after careful consideration and discussion with the patient about the possibility of long-
term side-effects.
Continued

Table 3. Continued
Adjuvant PARP inhibitors

Early data suggests that 1 year of adjuvant olaparib following the completion of (neo)adjuvant chemotherapy provides IA Y ¼ 91%
significant benefit in disease-free survival amongst women harboring a germline BRCA1/2 mutation who have high-risk A ¼ 9%
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.
Anti-HER2 therapy
One year treatment with adjuvant trastuzumab, together with chemotherapy, is indicated for women with HER2- IA
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 IIB
paclitaxel and trastuzumab without anthracyclines can be considered
The incorporation of neoadjuvant/adjuvant pertuzumab should be in keeping with current standards, as for older IA
patients, in women with high-risk HER2+ breast cancer.
In case of pathological residual disease (non-pCR) after pre-operative chemotherapy plus anti-HER2 therapy the IA Y ¼ 85%
patient should be offered to complete 1 year of adjuvant anti-HER2 therapy with TDM-1. N ¼ 5%
A ¼ 10%
In HER2+ patients at high risk of relapse (e.g. N+) 1 year adjuvant pertuzumab + trastuzumab can be discussed, as in IC Y ¼ 90%
other age groups. N ¼ 5%
Limited data are available on the efficacy of such treatment in women who received pertuzumab + trastuzumab as part A ¼ 5%
of their pre-operative systemic therapy.
In HER2+/HR+ patients at high risk of relapse (e.g. significant nodal involvement), 1 year of treatment with neratinib IC Y ¼ 80%
after trastuzumab can be discussed, as in other age groups. A ¼ 20%
There is no data about the efficacy of neratinib after 1 year of adjuvant trastuzumab AND pertuzumab or after adjuvant
TDM1.
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 Expert opinion
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.
The management of inflammatory breast cancer in young women should be the same as in the older breast cancer Expert opinion
population.
Data are accumulating about disease-free survival improvement with adjuvant bisphosphonates among IA Y ¼ 57%
premenopausal women under OFS. N ¼ 17%
Zoledronic acid q6 months may be discussed in young women receiving OFS. Optimal duration of treatment is A ¼ 26%
uncertain, and risks and benefits should be considered on a case-by-case basis.
A, abstain; AIs, aromatase inhibitors; BC, breast cancer; BCS, breast-conserving surgery; CT, computed tomography; EBC, early breast cancer; ER, estrogen receptor; FDG, [18F]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.
The National Comprehensive Cancer Network (NCCN) in unchanged for patients with low SES.27 The BCY5 panel
Oncology and the Breast Health Global Initiative developed strongly and unanimously stated that every young breast
resource-stratified and harmonized guidelines/recommen- cancer patient must have access to optimal cancer treatment
dations20,21 and strategies to address the poor outcomes in and supportive care according to the highest standards of
LMICs for young women with breast cancer.22 Prospective patient-centered care, irrespective of her social status.
cohort studies are collecting data on young patients’ con- Panel members re-emphasized that national reimburse-
cerns, in particular about fertility preservation,23,24 selection ment policies/algorithms rewarding treatment protocols
of ovarian function preservation strategies23 and psychoso- per number of treatments, dosages, administration route/
cial and quality-of-life (QoL) issues after diagnosis.25 use of day hospital or planning complexity (in the case of
Young women with a lower socioeconomic status (SES) have radiation treatment) should be discouraged. For example,
worse outcomes compared to those with a higher SES,26 even radiation therapy (RT) should not be reimbursed per frac-
in countries with universal health care27,28 thought to be due tion, nor should physicians receive higher reimbursement
to a higher frequency of comorbidities and limited access to for administering intravenous agents compared to oral
health services. In some studies, differences persist after chemotherapy or ET. To this end, the panel endorses the
adjusting for all these factors. In particular, a large Norwegian 12th European Breast Cancer Conference Manifesto.29
report in premenopausal women (7501 patients aged 30-48 A significant proportion of young patients experience work-
years at diagnosis) showed that 5-year relative survival and insurance-related challenges in the first 2 years after
improved steadily for patients with high SES (by 9% and 36%, diagnosis,30-33 but little is known about the impact of late ef-
for regional and distant disease, respectively), but remained fects of cancer treatment (e.g. fatigue and arm morbidity) on

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

In ABC, age alone is not a reason to prescribe more aggressive therapy and International Consensus Guidelines for Expert opinion
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 IC
extent.
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 IC
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 Expert opinion Y ¼ 87%
worse outcome compared to non-carriers, irrespective of BC subtype. N ¼ 4%
No data on the efficacy of PARPi on CNS involvement are available as none of the phase III PARP trials included patients A ¼ 9%
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)
Many trials in HR+ ABC have not included premenopausal women. IA
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. IA Y ¼ 83%
Platinum and PARP inhibitors have not been compared in the advance setting and preferential use of either or optimal N¼0
sequencing of these treatments is unknown A ¼ 17%
Phase II data suggest a benefit for PARPi in patients with ABC harboring somatic BRCA1/2 mutations or a germline IIB Y ¼ 87%
PALB2 mutation. N¼0
Somatic BRCA1/2 mutations and germline PALB2 mutations are not common; however, tailoring of treatment based on Expert opinion A ¼ 13%
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.
Very little is known about psychosocial challenges and dying concerns in young parents with ABC. Most of the data Expert opinion 100%
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.
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.
long-term work ability.34 Given the length of working years professionals should inform young women about breast
ahead for these women, the BCY5 panel firmly stated that health and other modifiable breast cancer risk factors in
awareness and referral to appropriate resources should be general (e.g. maintaining a BMI 25 kg/m2, as well as
available and further research in this setting is needed. limiting alcohol consumption, smoking and physical
Panel members re-emphasized that many specific issues inactivity).35
in the treatment of young women with breast cancer, in all
settings of the disease, still lack evidence-based standards Diagnostic imaging for screening, staging and follow-up
and that systematic research into age-specific tumor char-
1. Screening: There is no indication for routine screening
acteristics is needed which could open the door for more
by any imaging technique in healthy, average-risk
tailored therapeutic interventions.
young women. Surveillance in high-risk women,
based on family history or pathogenic gene variants in
Risk factors
predisposing genes, and for those at increased risk
Lifestyle-associated risk factors should be discussed with because of a personal history of therapeutic radiation
young women as part of public health initiatives.35 Data are in childhood or young adulthood,37 should follow
inconclusive on whether or not obesity is a risk factor for available guidelines.
breast cancer in premenopausal women and increasing 2. Staging and follow-up: The panel reinforced the recom-
body mass index (BMI) seems inversely correlated with mendation that imaging and staging in young women
breast cancer risk in young women.36 Increases in the waist- including axillary assessment should in principle follow
to-hip ratio, which measures central adiposity, are associ- standard algorithms as for older women.
ated with increased risk of premenopausal breast cancer. As
obesity is associated with increased risk of many serious Breast ultrasound remains the first diagnostic approach for
health issues, the BCY5 panel stated that health care clinical abnormalities in this age group and in pregnant/

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

For survivors harboring a BRCA 1/2 or (other) strongly predisposing mutation, bilateral risk-reducing mastectomy may IIB
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.
For the time being, the radiotherapy treatment of EBC is independent of BRCA or any other constitutional genetic IB
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 Expert opinion
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.
Salpingectomy with delayed oophorectomy remains investigational and should preferably be carried out only within a Expert opinion Y ¼ 85%
clinical trial. N ¼ 10%
A ¼ 5%
Currently, the evidence on the reduction of BC risk and mortality by oophorectomy is conflicting and likely limited to Expert opinion Y ¼ 53%
BRCA1 carriers. N ¼ 17%
A ¼ 30%
A, abstain; BC, breast cancer; EBC, early breast cancer; GoR, grades of recommendation; LoE, levels of evidence; N, no; y, yes.
lactating women.38 Given the data on diagnostic superiority persons with a germline mutation would not be identified.45
of digital breast tomosynthesis (DBT) over digital mammog- A fast-track process, which enables testing before
raphy in young women and in those with dense breasts,39 commencement of therapy, should be available when the
with only marginal increase in radiation dose, a majority of identification of a pathogenic gene variant could change the
the BCY5 panel stated that DBT is the preferred diagnostic therapeutic approach [e.g. indication for risk-reducing sur-
tool. gery, platinum derivatives, poly (ADP-ribose) polymerase
Pre-operative magnetic resonance imaging (MRI) is asso- (PARP) inhibitors (PARPi)]. Although BRCA1/2 genes are the
ciated with increased rates of ipsilateral mastectomy and most frequently mutated genes, testing for other additional
contralateral prophylactic mastectomy in newly diagnosed moderate- to high-penetrance genes using a multi-gene
breast cancer patients, irrespective of age40: its indications panel may be considered, if they will impact therapeutic in-
should strictly follow available recommendations.41 MRI is terventions. In a recent study, genes most commonly asso-
generally superior to other clinical and imaging assessments ciated with breast cancer in woman aged 45 years were
after pre-operative chemotherapy.42 The optimal timing for BRCA, BRCA2, ATM, CHEK2 and PALB246 due to prevalence
carrying out mammography and MRI is the first half of the and impact. The clinical utility (including risk assessment,
menstrual cycle (days 7-14).43 Recent data show that screening and prevention recommendations) of moderate-
abbreviated MRI (AB-MRI), i.e. the acquisition of only two risk genes identified on multi-gene panel testing and poly-
sequences, before and immediately after the administration genic risk score models are not yet established or ready for
of gadolinium, has equivalent performances to standard MRI clinical practice.
protocols in diagnostic clinical settings.44 Although validation Multidisciplinary management of mutation carriers and
with prospective multicenter trials is pending, almost half of high-risk individuals should ideally be provided in dedicated
the BCY5 panelists agreed that AB-MRI may represent a valid high-risk clinics, when available. Clinical trials focusing on
alternative to conventional MRI for persons with dense risk reduction and optimal screening strategies for this
breasts with the advantages of short examination/interpre- group of women are strongly needed. Unaffected carriers
tation times and low costs. should be encouraged to participate in clinical trials evalu-
The panel re-confirmed that in average-risk patients, ating risk-reducing strategies such as the BRCA-P study
imaging surveillance after primary breast cancer treatment evaluating denosumab in women harboring a PV in BRCA1
should follow the same guidelines as in older women. who have not undergone risk-reducing mastectomy
(NCT04711109). With the recent shift to ‘oncologist-led
Genetic counseling and testing mainstream’ testing where the surgeon or oncologist refers
The panel confirmed that genetic counseling should be for testing, and counseling and interpretation are provided
offered to every young woman, irrespective of tumor subtype following test results,47,48 education and training of the
[e.g. triple-negative (TN) disease] or family history of breast involved health care professionals is needed to provide
cancer as studies have reported that if testing is carried out optimal risk communication and clinical recommendations.
based on traditional testing guidelines (largely guided by For women who are not ready to consider genetic testing
personal and family history of malignancy), close to 50% of at the time of diagnosis, access to genetic counseling should

Table 6. Supportive and follow-up care guidelines

Young women with breast cancer face specific physical, psychosocial and sexual issues that should be addressed by a Expert opinion
multidisciplinary group of providers including breast medical, surgical and radiation oncologists, breast care nurses,
social workers, psycho-oncologists, gynecologists and fertility experts, among others.
Young women with breast cancer are at higher risk for psychosocial distress. Patients’ distress and psychosocial needs IIB
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.
The specific psychosocial distress pertaining to body image, sexuality and sexual dysfunction resulting from premature Expert opinion 100%
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.
All young women should be counseled regarding the risk of getting pregnant while on chemotherapy, endocrine or IB
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 Expert opinion
subtype, and alternative strategies should be considered.
All young women (irrespective of stage of disease) should be informed about approved fertility preservation options Expert opinion Y ¼ 96%
and referred for specialist counseling/consultation if interested in fertility preservation before commencement of any A ¼ 4%
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).
Physicians’ knowledge and familiarity with the available international guidelines on fertility preservation, pregnancy Expert opinion Y ¼ 96%
after BC and management of BC during pregnancy should be increased in order to facilitate and improve evidence- A ¼ 4%
based individualized management of young patients with BC.
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 IB Y ¼ 70%
chemotherapy. N ¼ 20%
A ¼ 10%
Biomarkers such as AMH levels may predict ovarian function after chemotherapy though data are limited. Expert opinion Y ¼ 85%
A ¼ 15%
All young women should be counseled about the risks and associated symptoms and outcomes and management of Expert opinion
treatment-related amenorrhea and premature menopause before the onset of systemic therapy (either CT or ET) and
informed of available ameliorative therapies.
Premature menopause and/or treatment-related amenorrhea increase the risk of bone thinning and patients should be IA
counseled, monitored and treated accordingly.
Pregnancy after breast cancer should not be discouraged even in patients with HR-positive disease or those harboring IIA Y ¼ 95%
a germline BRCA mutations. While pregnancy itself does not appear to increase the risk of recurrence the discussion A ¼ 5%
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 Expert opinion Y ¼ 95%
adjuvant ET should complete at least 18-24 months of ET before attempting pregnancy. Treatment should be resumed A ¼ 5%
and completed according to initial planning after delivery and breast-feeding.
There are limited data on breast-feeding after BC. Lactation can be carried out from the unaffected breast and data Expert opinion Y ¼ 96%
suggest that lactation from the previously affected breast may sometimes be feasible, depending on the type of A ¼ 4%
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.
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. Y ¼ 91%
Whenever possible, women with a diagnosis of pregnancy during breast cancer should be managed by a Expert opinion N ¼ 4%
multidisciplinary teams with expertise in this field. A ¼ 5%
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 IIB 100%
biology.
Exposure to ET, bone-modifying agents and anti-HER2 therapies should be avoided during pregnancy. If treatment IIB Y ¼ 91%
cannot be delayed until delivery (e.g. in case of ABC), treatment choices should be carefully discussed with the patient A ¼ 9%
to ensure maternal benefit and reduce fetal risk.
Patients diagnosed in the few years after pregnancy have worse prognosis. Further research is warranted to better Expert opinion Y ¼ 85%
understand their biology and define treatment strategies accordingly. A ¼ 15%
Continued

Table 6. Continued
Other issues
Young patients should be strongly encouraged to adopt the following healthy lifestyle changes: Expert opinion
maintain BMI 25
perform regular aerobic exercise
not to smoke
to limit daily alcohol intake
Young BC survivors experience significant job- and insurance-related issues, and potential financial toxicity following Expert opinion Y ¼ 96%
diagnosis. A ¼ 4%
Awareness and referral to appropriate resources should be available for all young patients. Y ¼ 96%
Further research in this setting is needed in order to plan targeted interventions and avoid unnecessary difficulties. Expert opinion A ¼ 4%
Many young BC patients use integrative medicine (complementary and alternative therapies). Health professionals Expert opinion Y ¼ 91%
should proactively promote open communication about integrative medicine with their young BC patients. N ¼ 9%
To ensure patient safety and quality of treatments, when possible, supervised and established integrative medicine Expert opinion Y ¼ 78%
services should be provided within the oncology service at the treating institution. A ¼ 17%
N ¼ 5%
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.
be offered on an ongoing basis, and women with previous gender-affirming hormone therapy is limited.54 Even less in-
limited testing should be considered for a more compre- formation exists regarding TG/NB individuals with known ge-
hensive contemporary panel in survivorship. Strategies to netic predisposition. Cancer registries should include TG/NB
minimize recently documented racial/ethnic and social dis- identities, and further education and research is needed to fill
parities in early access to genetic testing and risk manage- the gap in information and counseling in this population.
ment should be implemented to optimize risk-reducing
interventions.49 Research is needed to assess the psycho- EARLY BREAST CANCER
social factors affecting the communication of genetic test
results by young breast cancer patients with parents and Locoregional treatment
siblings, especially in non-Caucasian women. Surgery. Although young age remains an independent risk
factor for increased locoregional recurrence, irrespective of
Screening for other malignancies and risk-reducing surgery the type of surgery carried out, especially in patients with
recommendations for women harboring a pathogenic human epidermal growth factor receptor 2-positive
gene variant (HER2þ) and TN disease, a decreasing trend in locore-
gional recurrence is reported across continents. The panel
In patients harboring a pathogenic germline variant in TP53
remains concerned about the expanding international trend
(LieFraumeni syndrome, LFS), the use of ionizing radiation
for bilateral mastectomies, particularly in younger women55
should be discouraged to avoid increasing the risk of secondary
despite no improvement in long-term survival.56 Commu-
radio-induced malignancies.50 Annual brain and whole body
nication strategies to optimize decision making for surgical
MRI (WB-MRI) is recommended as contrast-free WB-MRI has
treatment of breast cancer should be implemented to
shown to be effective for cancer detection in asymptomatic
encourage appropriate breast-conserving surgery (BCS).
carriers and during follow-up in breast cancer patients.51,52 [18F]
Decision aid tools focused on the needs of young, average-
2-fluoro-2-deoxy-D-glucoseepositron emission tomographye
risk breast cancer patients are being developed and evalu-
computed tomography (FDGePETeCT) scan has also been
ated and should become a research priority.57
proven to be effective in cancer screening of patients with LFS,
Oncoplastic surgical techniques should be discussed with
but the availability of safer modalities (e.g. contrast-free WB-
all patients scheduled for BCS if post-operative asymmetry
MRI) has limited its incorporation in surveillance protocols.53
is anticipated and should always be carried out by a dedi-
For those with a BRCA1/2 mutation and other breast cancer-
cated breast surgical team. When mastectomy is indicated,
associated susceptibility genes, timing of risk-reducing salpingo-
skin- and nipple-sparing techniques with immediate breast
oophorectomy (RRSO) and gynecologic surveillance should
reconstruction (IBR) can provide oncological control while
follow international guidelines. Ongoing trials will possibly help
also addressing cosmetic needs.58 IBR (irrespective of
clarify the role for salpingectomy with delayed oophorectomy
technique) following mastectomy offers the same survival
in women wishing to delay RRSO and early onset of menopause
outcome rates as mastectomy without reconstruction59 and
(ClinicalTrials.gov Identifier: NCT02321228, NCT01907789,
should be offered to all patients except those with inflam-
NCT01608074). For now salpingectomy with delayed oopho-
matory breast cancer for whom delayed reconstruction is
rectomy remains investigational.
recommended (given the need for extensive radiation and
the recommendation to wait until the highest relapse risk
Transgender and nonbinary persons passes) and those with locally advanced disease at pre-
Knowledge about the risks of breast/gynecological cancers in sentation with poor response to primary systemic therapy.
transgender (TG) and nonbinary (NB) persons receiving The increasing use of pre-operative therapy for stage 2-3

disease particularly in the more aggressive subtypes has term adverse effects as in the FAST-Forward Trial (five frac-
reduced past concerns that wound healing complications tions in 1 week with 15% of premenopausal patients
from IBR will delay any necessary systemic therapy. Higher enrolled).68 The BCY5 panel therefore recommended against
SES is associated with higher IBR rates among both young ultra-hypofractionated WBI or for irradiation of the lymph
and older women, including in countries with universal node regions (such as in FAST-Forward) for young patients.
health care.60,61 IBR is rarely available for patients from As partial breast irradiation (PBI), or accelerated PBI, has
LMICs.62 The BCY5 panel unanimously stated that every not been sufficiently studied in young patients,63 the panel
young breast cancer patient should have access to IBR and recommended against its use outside of clinical trials.
oncoplastic surgery if medically appropriate. Indications of post-operative RT are independent of BRCA
The panel confirmed that the indications for sentinel lymph status. Prophylactic radiation to the unaffected contralat-
node biopsy and surgical management of patients with eral breast in BRCA carriers who decline contralateral
sentinel lymph node involvement should be the same as in mastectomy should not be carried out outside of clinical
older patients and that, despite the fact that optimal locore- trials.69 Although a recent study demonstrated fewer ipsi-
gional treatment after pre-operative chemotherapy remains lateral breast recurrences amongst BRCA1/2 carriers who
controversial, decisions should be made irrespective of age. had undergone PMRT compared to those without PMRT,70
Germline mutation status should be part of the individual further data are needed. There is limited evidence about
decision-making algorithm when young women are making the safety of radiation for those harboring a moderate-
breast surgery choices. In the absence of evidence-based penetrance pathogenic gene variant (e.g. CHEK2, ATM)71
recommendations for risk-reducing surgery in patients and the riskebenefit ratio needs to be individually dis-
with PVs in lowemoderate-penetrance genes, decisions cussed, but there is no clear contraindication to RT. PMRT
must be tailored to the individual, guided by family history may be discussed in cases of significant risk of locoregional
and patient preference. recurrence in patients with a germline TP53 mutation, for
whom radiotherapy is otherwise contraindicated to the high
Radiation therapy. Indications for post-operative RT are the risk of secondary malignancies. These recommendations
same as for older patients63; however, data are more robust underscore the importance of early genetic testing at the
for benefits of post-mastectomy radiation therapy (PMRT) time of diagnosis to aid optimal treatment planning.
amongst young women. PMRT after implant-based breast
reconstruction is associated with higher risk of reconstruc- Adjuvant systemic treatment
tive failure (>15%) and capsular contracture (>30%). Rates
of capsular contracture are lower with PMRT with tissue Adjuvant systemic treatment decisions for invasive breast
cancer should be based on the extent of disease and bio-
expanders, but reconstructive failure is more common.64
logical characteristics of the tumor (including, but not
These complications may translate into poor aesthetic
limited to, tumor size, nodal status, hormone receptor and
outcomes, decreased satisfaction and lower QoL. Given the
HER2 overexpression/amplification, Ki67, proliferation and
lack of definitive evidence for optimal reconstructive algo-
grade), patient’s comorbidities and preferences similar to as
rithms and techniques (implant-based or autologous tissue
in older women.
reconstructions), shared decision making with the patient
and optimal integration of plastic surgery and radiation
oncology are crucial.65 When PMRT is foreseen, the panel Gene expression signatures
recommended that timing and technique of the recon- Although gene expression signatures, such as Oncotype Dx,
structive procedure should be discussed pre-operatively on MammaPrint, Prosigna, Endopredict and Breast Cancer In-
an individual basis by all the specialists involved. PMRT is dex, provide additional information on an individual’s
not a stand-alone reason to postpone reconstruction. recurrence risk and some signatures have demonstrated
Indications and extent of nodal irradiation are the same as clinical utility for adjuvant chemotherapy decision mak-
in other age groups.63 Modern techniques to minimize long- ing,72-74 women younger than 40 are grossly under-
term side-effects are necessitated. The use of respiratory represented in both retrospective and prospective studies.
control is the most common approach to reduce the dose to Additionally, most of the premenopausal patients in these
heart and lungs, offering a more favorable irradiation ge- studies did not receive contemporary risk-adapted ET.
ometry by inflating the lungs and increasing the distance In TAILORx, patients with a low-risk recurrence score (RS),
between the heart and the chest wall.66 A boost to the site defined as RS 0-10 (30% of whom were premenopausal but
of the radical local excision in case of BCS remains standard only 4% aged <40 years), had a 5-year distant recurrence-
pending the results of modern randomized trials (e.g. the free survival of 99%72 with ET alone. For those with an
Young Boost Phase III trialdNCT00212121). intermediate-risk RS (RS 11-25), the 9-year distant
The BCY5 panel affirmed that moderately hypofractio- recurrence-free survival was 94.5% for the ET-only group
nated whole breast irradiation (WBI) schedules should and 95% for those who received chemotherapy and ET.73
replace standard fractionated WBI as gold standard for most Exploratory, unplanned subgroup analyses of women aged
patients. Ultra-hypofractionated schedules were either not 50 years suggested a benefit from chemotherapy amongst
tested in premenopausal women, such as in the FAST trial those with an intermediate RS within the range of 16-2573
(once-weekly five fractions),67 or not mature yet for long- and further analyses suggested that clinical risk level

combined with RS identified women aged 50 years to be patients with low-risk disease who did not receive
more likely to benefit from the addition of chemotherapy to chemotherapy.80,81 In SOFTeTEXTdamongst women aged
ET alone.75 Only 13% of premenopausal women received <35 years with HER2 disease only 57 women (out of
ovarian function suppression (OFS). 442) did not receive chemotherapyd94% were node
The RxPONDER trial randomized patients with lowein- negative, 84% had T1 and 23% grade 1 tumors. In this
termediate-risk RS (0-25) with 1-3 lymph nodes to either ET group, 14% had an early invasive breast cancer event
alone or chemotherapy plus ET: 33% of participants were (including three distant recurrences and one death) at 6-
premenopausal, 2.9% were <40 years of age and 21.5% year and 5.6-year follow-up in TEXT and SOFT, respec-
were aged 40-49 years. While no benefit was demonstrated tively.82 Thus, omitting adjuvant chemotherapy in young
in the postmenopausal population with the addition of and very young women (35 years old at diagnosis) may
chemotherapy, in the premenopausal women an absolute be appropriate in selected cases with favorable clinical,
benefit of 5.2% favoring chemotherapy was demonstrated genomic and pathological features.
both for low and intermediate RS, with an invasive disease-
free survival (iDFS) of 94.2% versus 89% [hazard ratio (HR) Pharmaco-prevention
0.54, 95% confidence interval (CI) 0.38-0.76].76 In the ET- Five years of tamoxifen 20 mg daily reduces breast cancer
only arm, 16% received OFS compared to only 3% in the risk by 35%-40% and is recommended as pharmaco-
chemotherapy arm. prevention for women with an elevated breast cancer
In the WGS ADAPT ERþ/HER2 study, all patients with risk.83 Despite the riskebenefit ratio being in favor of
0-3 involved lymph nodes and a low RS of 0-11 received ET tamoxifen in all women <50 years of age, irrespective of
alone [mostly tamoxifen in pre- and aromatase inhibitor the degree of risk, the uptake of tamoxifen for breast cancer
(AI) in postmenopausal patients]. Those with intermediate prevention is low (10%-12%).84 Higher-risk premenopausal
RS (12-25) were given 3 weeks of ET before surgery. Pa- women appear more likely to accept tamoxifen,84 with the
tients with a Ki67 10% in the surgical specimen were main reasons for non-initiation being concerns about side-
considered endocrine responders and received ET alone (of effects, tamoxifen being perceived as a ‘cancer drug’, min-
whom 23.3% were aged 50 years), while those with a imal benefit and fertility concerns.84,85 Low-dose tamoxifen
Ki67 >10% were classified as endocrine non-responsive (5 mg/day for 3 years) may be an alternative to full-dose
and received chemotherapy in addition to ET (of whom tamoxifen in women with breast intraepithelial neoplasia
64.7% were aged 50 years). Amongst endocrine re- given its efficacy and limited toxicity.86,87 The BCY5 panel
sponders with an RS of 12-25 and limited nodal burden (up recommends discussing pharmaco-prevention with young
to two nodes), despite no data in women <40 years of age, women at high risk of developing breast cancer.
there was no difference in outcome between the low and
intermediate RS groups, with a 5-year distant DFS (DDFS) of Pre-operative endocrine therapy
96.8% and 97.4%, respectively, in patients aged 50 years.
Outcome was also similar to that of patients aged >50 There are no new data regarding pre-operative ET in young
years with 0-3 nodes and RS 0-25 who received ET alone.77 women since BCY4. The BCY5 panel agreed with the pub-
Derived from the ADAPT data, the ENREP algorithm lished American Society of Clinical Oncology (ASCO) guide-
(https://enrep.info) can help to estimate endocrine lines88 that pre-operative ET should not be routinely
responsiveness based on clinical and immunohistochemical recommended for young women outside of clinical trials.
factors. Nevertheless, a short pre-operative ET (2-4 weeks) with
The MINDACT trial assessed all patients for recurrence subsequent Ki67 determination in the surgical specimen for
risk by both clinicalepathological factors (clinical risk) and assessing endocrine responsiveness may help adjuvant
MammaPrint (genomic risk) and assigned those with clinical treatment decision making as demonstrated by the ADAPT
low/genomic low to ET alone. Patients with high clinical/ trial also for young women.89 Trials evaluating the efficacy
high genomic risk were assigned to CT followed by ET. Pa- of cyclin-dependent kinase (CDK) 4/6 inhibitors plus ET in
tients with discordant risk profiles underwent randomiza- the pre-operative setting are ongoing.
tion to determine use of chemotherapy.74 Only 6.2% of the
study population was aged <40 years.74 An exploratory Adjuvant endocrine therapy
analysis demonstrated a 5% benefit in distant metastases- Based on the updated results of the SOFT and TEXT
free survival favoring the addition of chemotherapy in studies80 and in line with existing guidelines,16,90,91 BCY5
women 50 years of age who were clinically high risk, confirmed that tamoxifen alone remains the standard of
genomic low risk78 but it is unclear if these results indicate care in premenopausal women at low risk of relapse, as
true benefit from chemotherapy or a chemoendocrine ef- defined by clinical and immunohistochemical parameters,
fect given among the 50-year-old patients who did not who did not receive adjuvant chemotherapy. More than
receive chemotherapy, 55% received tamoxifen alone for 5 97% of these women are free of distant recurrence and
years, and only 20% received OFS.79 alive at 8 years, with no additional benefit by escalating ET
Favorable outcomes were seen in the SOFT and TEXT to OFS plus tamoxifen or exemestane.
studies and the Austrian Breast and Colorectal Cancer In women at higher risk of relapse, adding OFS to ET is
Study Group (ABCSG) 12 trial, among premenopausal associated with a significant improvement in outcomes

including distant recurrence compared to tamoxifen status following CIA are defined in the BCY2 paper14 and
alone.80 In high-risk patients, the combination of OFS and reported in Supplementary Appendix S1, available at
an AI should be the preferred option and OFS and tamox- https://doi.org/10.1016/j.annonc.2022.07.007.
ifen for those with toxicity to the AI. An overall survival (OS) BCY5 confirmed that hormone levels should be checked
benefit was evident in the SOFT study amongst patients under GnRH therapy if there are concerns that ovarian
who received adjuvant chemotherapy followed by OFS plus function is not suppressed, especially if breakthrough
oral ET; however, this was not yet demonstrated in the TEXT bleeding occurs and/or the patient is on an AI. A gas
study. Given that the risk of disease recurrence continues chromatography/mass spectroscopy method, if available, is
for >20 years,92 long-term follow-up will be key to ascertain preferred to monitor therapy.103,104 The updated results of
if the positive effects on DFS will translate into improve- the SOFT-EST sub-study, at over 4 years of treatment, were
ments in OS and also to define potential longer-term safety consistent with the first-year results showing that OFS does
issues (e.g. second primaries), particularly relevant in young not achieve optimal estrogen suppression in up to 17% of
patients. patients.105
An online tool (https://rconnect.dfci.harvard.edu/Compo Based on the limited available data106-108 and concerns
siteRiskSTEPP/) has been developed for clinicians to use in about suboptimal OFS with depot formulations, monthly
daily practice to estimate individual risk-based benefit of formulations of GnRHa are preferred,90 especially in women
escalating ET for women with HER2 disease. This is a <35 years of age and in those receiving an AI. However,
composite measure of the distant recurrence risk according when monthly use is not feasible or accepted by the pa-
to traditional prognostic features (i.e. patient age, tumor tient, 3-6 monthly administration may be considered on a
size, grade, lymph node status, ER, progesterone receptor case-by-case basis with close monitoring of ovarian
and Ki67 expression) derived from the SOFTeTEXT popu- function.107
lation.93 Although the relative efficacy of escalating ET is The method of ovarian suppression (surgical versus
independent of age, women aged <35 years have the medical) requires balancing patient’s wish for potentially
largest magnitude of absolute improvement in outcomes preserving fertility and compliance with frequent injections
with OFS.80,82 OFS timing (concurrent versus sequential) in over a long period of time and cost/availability. The BCY5
women receiving adjuvant chemotherapy does not impact panel was divided when discussing radiation to ovaries as a
breast cancer outcomes. Notably, in women <40 years old method of OFS: a narrow majority voted that it should be
who are less likely to develop CIA,94,95 gonadotropin- discouraged if alternatives exist. New RT techniques better
releasing hormone agonist (GnRHa) concomitant with delineate the position of the ovaries, thus improving
chemotherapy has the added benefit of ovarian function effectiveness and minimizing the adverse events.109
protection.96 Younger age is associated with lower adherence and
GnRHa in combination with tamoxifen or an AI should be persistence to adjuvant ET,82,110 which has been associated
prescribed for 5 years based on the SOFT/TEXT data. A with reduced OS.111 Determinants of treatment persis-
shorter duration was associated with excellent mid- and tence112 may vary according to race and ethnicity113,114:
long-term outcomes in women with lower or intermediate potentially modifiable factors should be identified with
risk who did not necessarily receive chemotherapy (ABCSG- targeted interventions.115,116
12 in which only 5% received chemotherapy and the AST- Three recently reported neo/adjuvant trials investigating
TRA trials).81,97 Adding OFS to tamoxifen significantly im- the impact of adding the CDK4/6 inhibitors abemaciclib117
proves the 5-year DFS, compared to tamoxifen alone, and palbociclib118,119 to ET have provided mixed results.
including in women with late (within 2 years) resumption of Almost 50% of enrolled patients were premenopausal in
ovarian function after chemotherapy,97 suggesting that each trial. In the PALLAS adjuvant trial, 3-year iDFS did not
ovarian function should be monitored long term. Switching differ between the two arms (88.2% with palbociclib and
from 2-3 years of tamoxifen to Ais plus goserelin for a total 88.5% with ET). Similarly, in PENELOPE-B, at a median
treatment duration of 5 years versus continuing tamoxifen follow-up of 42.8 months, palbociclib did not improve the 3-
alone was associated with more adverse events but no year iDFS in women with residual invasive disease after pre-
improvement in disease outcomes in a small phase II trial operative chemotherapy (81.2% with palbociclib, 77.7%
with short follow-up.98 with placebo). However, the monarchE study which added
Extending tamoxifen beyond 5 years should be considered abemaciclib to standard ET demonstrated an absolute 3.5%
in high-risk patients99,100 as the risk of recurrence continues for improvement in the 2-year iDFS (92.2% versus 88.7%), and
>20 years.92 The impact of extended OFS and tamoxifen or an 5.4% at 3 years.117,120 There are several possible reasons for
AI beyond 5 years is unknown. different findings including the patient populations, rates of
OFS always needs to be given in young women with discontinuation and the specific CDK4/6 inhibitor. Longer
otherwise intact ovarian function who receive an AI. AIs follow-up and the results of ongoing trials (NATALEE triald
alone are contraindicated in premenopausal women: NCT03701334; ADAPTcycle trialdNCT4055493; ADAPTlate
caution must be taken when considering an AI in premen- trialdNCT4565054) may provide more data but the BCY5
opausal women who became amenorrheic during the panel stated that abemaciclib could be considered in high-
course of treatment due to the potential for recovery of risk patients similar to those enrolled in the monarchE
ovarian function.101,102 The criteria for defining menopausal study (4 involved nodes, or 1-3 involved nodes with other

high-risk features, i.e. tumor size 5 cm, grade 3, Ki67 tumors remains unresolved.16,133 A recent study comparing
20%). Acx4 to 4 cycles of cisplatin in the neoadjuvant setting for
BRCA-associated triple-negative breast cancer (TNBC)
GnRH agonists and ovarian function preservation demonstrated that Doxorubicin and cyclophosphamide was
superior to the 4 cisplatin cycles for achieving pathological
In line with the most recent guidelines focused on fertility
complete response (pCR).134 The BRIGHTNESS neoadjuvant
after cancer,121,122 BCY5 confirmed that the use of GnRHa
study reported that pCR and event-free survival (EFS) were
concomitant with (neo)-adjuvant chemotherapy should
inferior for paclitaxel monotherapy compared to either
be offered to all patients to reduce the risk of premature
carboplatin/paclitaxel or carboplatin/paclitaxel/veliparib, all
ovarian insufficiency and possibly preserve ovarian func-
followed by 4 cycles of cyclophosphamide and doxorubicin
tion. It is important to note that there are no clinical data
in TNBC.135 While platinum agents may be considered in
whether use of a GnRHa for the purpose of ovarian
selected patients, risk of additional gonado-toxicity should
function suppression is necessary or recommended dur-
be considered. There are still no data on the use of platinum
ing use of post-neoadjuvant capecitabine, olaparib and
agents in the adjuvant setting. For patients with TN disease
immunotherapy (noteworthy, in the CREATE-X study
without a pCR after standard pre-operative regimens,
evaluating post-neoadjuvant capecitabine, over half of
addition of 6-8 cycles of capecitabine may be considered, as
the patients were premenopausal; however, no data are
in other age groups.136 Recent data demonstrated that
available about GnRHa use). The recently reported results
substituting a platinum for capecitabine in this setting did
from the OPTION trial123 suggest that patients experience
not improve outcomes.137
a short-term decrease in QoL from the addition of
The phase III KEYNOTE 522 study evaluated the incor-
goserelin to chemotherapy to preserve ovarian function,
poration of immunotherapy in the pre-operative setting.
a price that women may decide to pay if adequately
Pembrolizumab with chemotherapy was compared to pla-
informed.
cebo with chemotherapy followed by a year of pem-
Because fertility outcome data after temporary OFS
brolizumab or placebo, respectively. In the most recent
during chemotherapy are still insufficient,96 the BCY5 panel
update, a benefit is seen for pCR (64.8% versus 51.2%, P ¼
confirmed that GnRHa use during chemotherapy does not
0.00055) and for EFS [91.3% versus 85.3%, HR 0.63 (95% CI
replace established fertility preservation methods, which
0.43-0.93)] favoring the pembrolizumab arm.138 An impor-
should be offered to all young patients interested in sub-
tant consideration is immune-related endocrinopathies,
sequent pregnancies. The efficacy of GnRHa in preserving
some of which are irreversible, and the impact on female
the ovarian reserve seems unrelated to the timing of
fertility and ovarian function recovery is for the time being
administration before chemotherapy,124,125 but scheduling
unknown. The IMPASSION-031 randomized patients to pre-
after oocyte cryopreservation should be coordinated be-
operative chemotherapy with or without atezolizumab fol-
tween the fertility and oncology teams to avoid a potential
lowed by a year of atezolizumab or placebo. pCR was
ovarian hyperstimulation syndrome.126 Anti-Müllerian hor-
superior for the atezolizumab arm, 58% versus 41%
mone may predict ovarian function recovery after GnRHa
(P ¼ 0.0044),139 but outcome data are awaited. Gepar-
during chemotherapy.124,127-129
Nuevo, a phase II study with 174 patients, evaluated
incorporation of durvalumab in the pre-operative setting
Neo/adjuvant chemotherapy alone, and demonstrated superior pCR, iDFS, DDFS and OS
Proportional risk reductions with taxane- and/or favoring the durvalumab-containing arm.140 The incorpo-
anthracycline-based adjuvant regimens are not significantly ration of pembrolizumab in this setting may be considered
affected by age130: since no studies have specifically in young women.
investigated different chemotherapy regimens/scheduling
in young women previous statements remain valid. At the Adjuvant anti-HER2 therapy
time of BCY5, the majority of the panel did not support
The benefit of adjuvant trastuzumab appears independent
routine use of non-anthracycline-based regimens. While
of age141 and anti-HER2 therapies should be the same as for
anthracyclines have long been the backbone of neo/adju-
other age groups. No additional data from randomized
vant chemotherapy, they carry long-term risks of cardiac
studies were published after BCY4; therefore, all recom-
failure and leukemia/myelodysplastic syndromes. In light of
mendations remain unchanged.
these risks, numerous studies have evaluated non-
anthracycline-based regimens and there is now a growing
body of evidence supporting non-anthracycline-based regi- Adjuvant bisphosphonates
mens for endocrine-responsive tumors with a low tumor As new data on DFS improvement with adjuvant
burden that require chemotherapy and in HER2 over- bisphosphonates among premenopausal women emerged
expressing tumors.131,132 The recent shift in practice and after BCY4,142 the panel stated that zoledronic acid q6
the emergent data will be formally discussed and voted months may be discussed in young women receiving OFS
upon in a consensus statement at BCY6. but given the limited data on long-term outcomes,143 risks
The question of whether to incorporate platinum agents and benefits should be balanced on a case-by-case basis.
in the pre-operative setting for TN- or BRCA-associated Optimal treatment duration and dosing interval are

uncertain and alternative schedules are under investiga- Unique populations

tion.144 As a result of the long half-life of bisphosphonates, BRCA mutation carriers. There remains no definitive
caution is needed in women interested in future concep- conclusion on the optimal chemotherapy regimen for BRCA-
tion, given the increased rates of neonatal complications associated breast cancer in the neo/adjuvant setting and
and spontaneous abortions in a recent case-control study the panel recommended that standard prognostic features
on pregnant women.145 There are no data for benefit from should be used to decide treatment in early disease.
adjuvant denosumab in young women. 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
Side-effects of adjuvant therapy adjuvant olaparib or placebo. The study included patients
In view of the long life expectancy of young women, the with high-risk features defined as stages 2 and 3, TNBC with
panel reinforced the need to monitor potential long-term residual disease after pre-operative chemotherapy or node
toxicities (i.e. cardiovascular, bone morbidity, cognitive positive or pT2 irrespective of nodal status or ERþ disease
impairment, secondary malignancies). 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
INFLAMMATORY BREAST CANCER being premenopausal. At a median follow-up of 2.5 years, the
Inflammatory breast cancer should be managed the same as 3-year iDFS was improved by 8.8% in the olaparib group.150
for the older breast cancer population. 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
Advanced breast cancer stated that olaparib should be offered to germline BRCA1/2
The BCY5 panel endorses the ESOeESMO ABC5 guidelines mutation carriers who meet the OLYMPIA inclusion criteria or
for the management of advanced breast cancer (ABC)146 the regulatory approval criteria.
and reiterated that young age alone should not be a The BCY5 panel endorses all the ABC5 statements on
reason to prescribe more aggressive therapy including systemic treatment for patients with a germline BRCA mu-
combination chemotherapy over sequential use of tation, germline PALB2 mutation and somatic BRCA1/2
monotherapy. BCY5 panelists endorse the ABC5 statements mutations, recognizing the importance of molecular tumor
that (i) young women with ERþ ABC should have adequate boards and of data pooling in international registries.
OFS/ovarian function ablation and be treated as post- Preliminary data suggest that breast cancer patients
menopausal women, with endocrine agents, with or harboring BRCA mutations present a higher incidence of
without targeted therapies and (ii) that future trials central nervous system (CNS) involvement. Although sub-
exploring new endocrine-based strategies should allow group analyses in both OlympiAD and EMBRACA showed a
enrolment of pre- and postmenopausal women, and men, benefit in persons with stable/treated brain metastases,
recognizing nonetheless that this field has evolved in recent none of the phase III PARPi trials included patients with
years. active CNS metastases.151 BCY5 panelists encourage the
Young women with ABC have unique medical and psy- inclusion of patients with active CNS metastases in studies
chosocial concerns that need to be considered and investigating new therapies.
addressed.147 While pregnancy in the setting of ABC is not
MALE BREAST CANCER
considered safe or desirable from a medical perspective,
concerns for fertility and family planning need to be Male breast cancer accounts for w1% of all breast cancers;
cautiously discussed and explored even in the setting of the lifetime risk is w1 : 1 000, and represents a small mi-
advanced disease. In patients with long-term responses and nority in males <40 years.152,153 Breast cancer in young
prolonged progression-free survival (e.g. in HER2þ disease), men is rare; however, it would likely amplify the psycho-
the safety of interrupting anti-HER2 therapies for patients logical distress already experienced by men with a breast
who may be interested in a pregnancy is unknown. cancer diagnosis. Treatment should follow international
guidelines,154 men should be included in clinical trials,
particularly in trials exploring ET as the expected differential
Locoregional relapse efficacy in males versus females is greatest in this setting,
Young age is a risk factor for local relapse. Therefore, careful germline testing carried out to aid in treatment and pre-
vention measures and distinctive histopathologic and
attention to margin status is warranted in young women.148
genomic features investigated.155,156
Following locoregional relapse, BCY5 confirmed that
chemotherapy should be considered in women with ER
tumors, as demonstrated in the CALOR study.149 For ERþ Supportive and follow-up care
disease, ET should be given and for HER2þ disease, Many breast cancer patients use integrative medicine
trastuzumab-based therapy is recommended albeit based (complementary and alternative therapiesdCAM)157 but
only on expert opinion level of evidence. very few data are available in young women. In a recent

German study, 62.5% of 827 young breast cancer patients Considerations and recommendations by the BCY5 panel
had used CAM. Its use was significantly higher in women for fertility preservation, contraception and premature
with higher educational level and employment status, and menopause, sexual functioning, pregnancy after breast
in those feeling they had not received sufficient informa- cancer, bone health, cognitive impairment, lifestyle changes
tion.158 The BCY5 panel stated that health professionals and breast cancer during pregnancy are updated in
should proactively promote open communication about Supplementary Appendix S1, available at https://doi.org/
integrative medicine with their young breast cancer pa- 10.1016/j.annonc.2022.07.007.
tients. As effectiveness and safety of many therapies remain
under-explored, the BCY5 panel also approved that, if
Patient advocacy statements
possible, supervised and established integrative medicine
services should be provided within the oncology service. BCY5 included the second patient advocacy workshop, and
BCY5 confirmed that follow-up care and supportive for the third time, included a patient advocacy-dedicated
treatment/prevention of specific symptoms and side-effects session for young women with breast cancer and the
in young women should follow the same guidelines as in consensus session included two young breast cancer survi-
older women. New shared-care models involving cancer vors as panelists. Since BCY3, a closed Facebook group for
specialists, general practitioners and breast nurses are being young breast cancer survivors has been active and now has
evaluated to improve cost-effectiveness. over 53 active global members. The importance of the
The panel also reiterated that standardized patient- worldwide breast cancer community to work together was
reported outcome measurements may enable timely apparent throughout the meeting.
collection of treatment side-effects, enabling the develop- At BCY5, a presentation was made announcing Project
ment of targeted interventions. 528, the first-ever global needs assessment of young adults
Dedicated survivorship clinics that assess and manage diagnosed with breast cancer. This will be a global survey
early and late treatment toxicities and treatment adherence that is created in true partnership with Young Survival
are valuable in this population. Coalition and Europa Donna Slovenia to learn the global
needs of young adults. Project 528 has four clear goals: (i)
Psychosocial issues. Young breast cancer patients are at identify the unmet needs of young adults diagnosed with
greater risk of psychosocial morbidity, not only during the breast cancer and their caregivers; (ii) understand the
active treatment period but also long term159 and when geographic difference in patient experiences; (iii) discover
facing ABC.160 Psychosocial care should be available and existing services available to young adults diagnosed with
integrated in routine cancer treatments and follow-up. The breast cancer globally; and (iv) understand the QoL burden
BCY5 panel recommended that the specific psychosocial of young adults diagnosed with breast cancer.
distress pertaining to body image, sexuality and sexual Everyone interested in participating in this important
dysfunction resulting from premature menopause, survey are encouraged to sign up and learn more at https://
treatment-related amenorrhea, weight gain, hair loss and project528.youngsurvival.org.
breast surgery should be routinely addressed by the health
care team in a culturally appropriate manner to ensure CONCLUSIONS
provision of appropriate information and support. Since BCY4, progress has been made. More clinical trials in
Partners and family members should be involved early on the metastatic setting are incorporating young women with
and couple-based and/or familial psychosocial interventions breast cancer by allowing for OFS as an acceptable surrogate
should be promptly proposed during the different phases of for physiological menopause. The impact of germline muta-
the disease. Offspring having a mother diagnosed with breast tions in BRCA1/2 has now substantial therapeutic implica-
cancer may experience high levels of psychological distress.161 tions in both early breast cancer and ABC. One of the many
Partners of young breast cancer survivors (3-8 years post- challenges in the treatment of premenopausal ERþ early
treatment) report poorer overall, physical, social, psychologi- breast cancer is how to incorporate and interpret gene
cal and spiritual QoL compared to partners of healthy expression signatures into treatment algorithms to deter-
women.162-164 Social issues that need to be addressed include mine which patients need chemotherapy in addition to
return to work, family planning and financial loss. The scarce optimal ET. Urgent research is needed to address adherence
data about end-of-life concerns of young patients with ABC to available treatments, health disparities and needs of mi-
derive from Caucasian, upper-/middle-class women within norities, and a global effort is required to help bridge the gaps
nuclear families and include worries about children and coin LMICs. A multidisciplinary approach remains the backbone
parents which affect their QoL and family functioning.165 The of care to ensure optimal outcomes for young women with
BCY5 panelists recognized that further research in this setting breast cancer given their many concerns and care needs.
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 FUNDING
impact of COVID-19 pandemic on patients’ psychological No external funding has been received for the preparation
health166 due to disruption of oncology service organization of these guidelines. Production costs have been covered by
and perceived increased loneliness. ESMO from central funds.

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SPECIAL ARTICLE

ESOeESMO ﬁfth international consensus guidelines for breast cancer in

Available online 4 August 2022

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

Volume 33 - Issue 11 - 2022 https://doi.org/10.1016/j.annonc.2022.07.007 1097

over-treated based solely on age considerations. Prospec-

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Table 2. General guidelines

Guidelines LoE/GoR Consensus

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Table 3. Assessment and treatment guidelines in early breast cancer

Guidelines LoE/GoR Consensus

Early breast cancer locoregional treatment

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Adjuvant systemic treatment

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Adjuvant PARP inhibitors

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

Guidelines LoE/GoR Consensus

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

Guidelines LoE/GoR Consensus

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Table 6. Supportive and follow-up care guidelines

Guidelines LoE/GoR Consensus

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uncertain and alternative schedules are under investiga- Unique populations

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DISCLOSURE 9. Fu J, Zhong C, Wu L, et al. Young patients with hormone receptor-

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