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• W4307401062 abstract "•It provides recommendations for risk reduction and screening in hereditary breast and ovarian cancer syndrome.•It focuses on risk reduction and screening mainly in unaffected carriers and high-resource settings.•The panel encompasses an international multidisciplinary group of experts.•Recommendations are based on available scientific data and the authors’ collective expert opinion. Hereditary breast and ovarian cancer syndrome (HBOC) is clinically defined by family history criteria, and molecularly defined by identification of germline pathogenic variants (PVs) in clinically validated HBOC genes.1Lee K. Seifert B.A. Shimelis H. et al.Clinical validity assessment of genes frequently tested on hereditary breast and ovarian cancer susceptibility sequencing panels.Genet Med. 2019; 21: 1497-1506Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar These genes are broadly classified as high-risk genes, increasing breast and/or tubo-ovarian cancer risk by at least fourfold, and moderate-risk genes, increasing risk by two- to fourfold (Table 1). There is a large overlap between clinical and molecular HBOC, i.e. individuals with both family history and a PV. The genetic basis of about half of clinical HBOC, however, is currently unknown or unexplained by single-gene variants,2Melchor L. Benitez J. The complex genetic landscape of familial breast cancer.Hum Genet. 2013; 132: 845-863Crossref PubMed Scopus (93) Google Scholar and conversely, approximately half of individuals who harbour PVs in HBOC genes do not have a suggestive family history.3Gabai-Kapara E. Lahad A. Kaufman B. et al.Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2.Proc Natl Acad Sci U S A. 2014; 111: 14205-14210Crossref PubMed Scopus (237) Google ScholarTable 1Lifetime cancer risks in HBOC-associated PVsBreast cancerabreast cancer 11%Tubo-ovarian cancersbovarian cancer 1.3%Pancreatic cancercpancreatic cancer 1.6%Colon cancerdcolon cancer 4%.Other cancersATMYes25%-30%Yes≤5%Yes<5%NoProstate 30%BARD1Yes∼20%NoNoNoNoBRCA1Yes>60%Yes40%-60%Yes<5%NoBRCA2Yes>60%Yes15%-30%Yes<5%NoProstate 33%BRIP1NoYes5%-10%NoNoNoCDH1Yes (LBC)40%NoNoNoDiffuse gastric cancer 35%-45%CHEK2Yes25%-30%NoNoYes15%PALB2Yes40%-60%Yes3%-5%Yes2%-3%NoNoPTENYes40%NoNoYes10%Thyroid 20%; endometrial 20%RAD51CYes20%Yes10%NoNoNoRAD51DYes10%Yes10%NoNoNoSTK11Yes40%NoYes10%-30%Yes30%Gastric 30%; Sertoli-Leydig 10%-20%TP53Yes40%NoPossiblyPossiblySarcoma, brain, leukaemia, adrenocortical carcinomaHBOC, hereditary breast and ovarian cancer syndrome; LBC, lobular breast cancer; PV, pathogenic variant.Lifetime risk in general ‘average-risk’ population:a breast cancer 11%b ovarian cancer 1.3%c pancreatic cancer 1.6%d colon cancer 4%. Open table in a new tab HBOC, hereditary breast and ovarian cancer syndrome; LBC, lobular breast cancer; PV, pathogenic variant. Lifetime risk in general ‘average-risk’ population: Studies of the prevalence of clinical and molecular HBOC are largely based on high-risk genes in individuals of Caucasian/European ancestry, whereas population-level data in unaffected persons are limited. Clinically, HBOC has been estimated to underlie ∼10% of breast cancers. Molecularly, ∼6% of breast cancer patients harbour PVs in HBOC genes: about half (∼3%) in BRCA1, BRCA2 and other high-risk genes (e.g. PALB2), and half (∼3%) in moderate-risk genes (e.g. ATM, CHEK2).4Dorling L. Carvalho S. Allen J. et al.Breast Cancer Association ConsortiumBreast cancer risk genes - association analysis in more than 113,000 women.N Engl J Med. 2021; 384: 428-439Crossref PubMed Scopus (243) Google Scholar,5Hu C. Hart S.N. Gnanaolivu R. et al.A population-based study of genes previously implicated in breast cancer.N Engl J Med. 2021; 384: 440-451Crossref PubMed Scopus (201) Google Scholar The remaining 4% are yet unidentified factors that may be genetic, environmental or a combination of both. In patients with high-grade ovarian cancer, germline PVs are identified in ∼15% of cases.6Norquist B.M. Harrell M.I. Brady M.F. et al.Inherited mutations in women with ovarian carcinoma.JAMA Oncol. 2016; 2: 482-490Crossref PubMed Google Scholar Based on objectively determined genealogy and cancer incidence data, ∼12% of unaffected individuals have family history fulfilling the National Comprehensive Cancer Network (NCCN) testing criteria,7Greenberg S. Buys S.S. Edwards S.L. et al.Population prevalence of individuals meeting criteria for hereditary breast and ovarian cancer testing.Cancer Med. 2019; 8: 6789-6798Crossref PubMed Scopus (6) Google Scholar a rough surrogate for clinical HBOC. The prevalence of molecular HBOC in unaffected individuals varies based on family history and ethnicity. Family history is incorporated into tools to predict the probability of harbouring a hereditary PV8Carver T. Hartley S. Lee A. et al.CanRisk tool-a web interface for the prediction of breast and ovarian cancer risk and the likelihood of carrying genetic pathogenic variants.Cancer Epidemiol Biomarkers Prev. 2021; 30: 469-473Crossref PubMed Scopus (36) Google Scholar,9Nelson H.D. Pappas M. Cantor A. et al.Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: updated evidence report and systematic review for the US Preventive Services Task Force.JAMA. 2019; 322: 666-685Crossref PubMed Scopus (69) Google Scholar—some populations harbour founder PVs with high carrier frequencies, e.g. 2.5% (1:40) for the three BRCA1 and BRCA2 founder PVs in Ashkenazi Jews,10Roa B.B. Boyd A.A. Volcik K. et al.Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2.Nat Genet. 1996; 14: 185-187Crossref PubMed Scopus (628) Google Scholar and 0.7%-0.8% (1:125-140) for the BRCA2 founder PV in Iceland.11Stefansdottir V. Thorolfsdottir E. Hognason H.B. et al.Web-based return of BRCA2 research results: one-year genetic counselling experience in Iceland.Eur J Hum Genet. 2020; 28: 1656-1661Crossref PubMed Scopus (5) Google Scholar Studies carried out in non-founder populations, largely of individuals with Caucasian/European ancestry, suggest that the carrier frequency for high-risk genes (i.e. BRCA1, BRCA2, PALB2) is approximately 1:150,12Rowley S.M. Mascarenhas L. Devereux L. et al.Population-based genetic testing of asymptomatic women for breast and ovarian cancer susceptibility.Genet Med. 2019; 21: 913-922Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 13Manickam K. Buchanan A.H. Schwartz M.L.B. et al.Exome sequencing-based screening for BRCA1/2 expected pathogenic variants among adult biobank participants.JAMA Netw Open. 2018; 1e182140Crossref PubMed Scopus (106) Google Scholar, 14Maxwell K.N. Domchek S.M. Nathanson K.L. et al.Population frequency of germline BRCA1/2 mutations.J Clin Oncol. 2016; 34: 4183-4185Crossref PubMed Scopus (85) Google Scholar which is consistent with early epidemiological estimates and is discussed further in Section 1 of the Supplementary Material, available at https://doi.org/10.1016/j.annonc.2022.10.004. •Individuals with significant family history should be offered genetic testing using multigene panels of clinically validated HBOC genes [A].•Clinicians should be aware that family history-based testing misses about half of HBOC syndrome gene carriers, and strategies to identify these high-risk individuals are being developed [A]. Once HBOC syndrome is identified, genetic counselling should address the medical and potential psychological implications for both individuals and their families. Medical implications include impact on treatment of any current cancer and interventions for prevention or early detection of future cancers. Discussion of risks should include the risks for specific types of cancers compared with the population risks.15Daly M.B. Pal T. Berry M.P. et al.Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2021, NCCN Clinical Practice Guidelines in Oncology.J Natl Compr Canc Netw. 2021; 19: 77-102Crossref PubMed Google Scholar As much as possible, risk assessment should be comprehensive and tailored, incorporating not only the specific gene and variant identified, but also other individual risk factors, both non-genetic (e.g. age, reproductive history) and genetic.16Gallagher S. Hughes E. Kurian A.W. et al.Comprehensive breast cancer risk assessment for CHEK2 and ATM pathogenic variant carriers incorporating a polygenic risk score and the Tyrer-Cuzick model.JCO Precis Oncol. 2021; 5PO.20.00484Google Scholar Available, validated online tools that can aid in this evaluation include CanRisk (https://www.canrisk.org/). Risk reduction and screening recommendations should be evidence-based, where available, and include discussion of personal circumstances and preferences (e.g. family history, family planning and reproductive options).17Hercher L. Discouraging elective genetic testing of minors: a norm under siege in a New Era of genomic medicine.Cold Spring Harb Perspect Med. 2020; 10: a036657Crossref PubMed Scopus (4) Google Scholar Counselling must include clear explanations of familial implications, indicating which relatives, both female and male, need to be informed and offered counselling and testing in addition to counselling on reproductive implications and options [e.g. pregestational testing (PGT)]. Currently, testing is recommended only in adult relatives (except for TP53), although this is an evolving topic.17Hercher L. Discouraging elective genetic testing of minors: a norm under siege in a New Era of genomic medicine.Cold Spring Harb Perspect Med. 2020; 10: a036657Crossref PubMed Scopus (4) Google Scholar,18Frebourg T. Bajalica Lagercrantz S. Oliveira C. et al.Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes.Eur J Hum Genet. 2020; 28: 1379-1386Crossref PubMed Scopus (86) Google Scholar The age of testing of adults can be based on legal adulthood (18 years in most countries) or on the age of potential medical actionability of the PV, which is from approximately age 25. Timing of testing should be tailored to family history, patient preference and if PGT is being considered. Strategies that improve familial testing, including allowing direct communication by the medical team, should be sought. Follow-up is a lifelong endeavour for individuals with HBOC, who manage complex schedules of serial imaging, risk-reducing surgeries (RRSs), risk-reducing medications (RRMeds) and ensuing quality-of-life (QoL) issues. This is best undertaken in specialised, multidisciplinary high-risk clinics including imaging services, gynaecologists, breast and plastic surgeons, genetic counsellors, psychologists and linked oncologists. Such clinics have several advantages: (i) clinical expertise in the high-risk setting, including access to clinical trials; (ii) continuity of care, including updating risk assessment and recommendations based on new evidence; (iii) consistency of care—ensuring that patients do not receive conflicting recommendations; and (iv) a biopsychosocial approach that provides emotional as well as medical support. •Post-test genetic counselling should include discussion of medical and psychological implications for both the individual and the family [A].•Risk management should be individualised and, when available, validated tools should be used to aid decision making [B].•Risk management should be carried out in specialised high-risk clinics that are multidisciplinary and include psychologists where possible [A].•Enhancing awareness and availability of testing in at-risk relatives should be a priority [A]. Recommendations for breast cancer screening and risk reduction in carriers of BRCA1 and BRCA2 PVs are shown in Figures 1 and 2.Figure 2Breast and ovarian cancer screening and risk reduction: BRCA2.Show full captionGrade of recommendation is shown in square brackets. Purple: general categories or stratification; red: surgery; turquoise: combination of treatments or other systemic treatments; white: other aspects of management.BC, breast cancer; BRRM, bilateral risk-reducing mastectomy; CA-125, cancer antigen 125; MRI, magnetic resonance imaging; PV, pathogenic variant; RRBSO, risk-reducing bilateral salpingo-oophorectomy; RRMed, risk-reducing medication; RRS, risk-reducing surgery; TVUS, transvaginal ultrasound; US, ultrasound.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Grade of recommendation is shown in square brackets. Purple: general categories or stratification; red: surgery; turquoise: combination of treatments or other systemic treatments; white: other aspects of management. BC, breast cancer; BRRM, bilateral risk-reducing mastectomy; CA-125, cancer antigen 125; MRI, magnetic resonance imaging; PV, pathogenic variant; RRBSO, risk-reducing bilateral salpingo-oophorectomy; RRMed, risk-reducing medication; RRS, risk-reducing surgery; TVUS, transvaginal ultrasound; US, ultrasound. In the presence of a PV in BRCA1, BRCA2 or PALB2, screening should commence 5 years before the youngest affected family member, or latest at age 30. Clinical breast examination is of no value as a screening tool.19Hettipathirana T. Macdonald C. Xie J. et al.The value of clinical breast examination in a breast cancer surveillance program for women with germline BRCA1 or BRCA2 mutations.Med J Aust. 2021; 215: 460-464Crossref PubMed Scopus (1) Google Scholar Young age is associated with a higher breast density, which interferes with mammographic detection of breast cancer.20Boyd N.F. Guo H. Martin L.J. et al.Mammographic density and the risk and detection of breast cancer.N Engl J Med. 2007; 356: 227-236Crossref PubMed Scopus (1665) Google Scholar Magnetic resonance imaging (MRI) has consistently demonstrated improved early diagnosis of cancer compared with digital mammography and/or ultrasound in women with or without causative PVs.21Mann R.M. Kuhl C.K. Moy L. Contrast-enhanced MRI for breast cancer screening.J Magn Reson Imaging. 2019; 50: 377-390Crossref PubMed Scopus (113) Google Scholar,22Gao Y. Reig B. Heacock L. et al.Magnetic resonance imaging in screening of breast cancer.Radiol Clin North Am. 2021; 59: 85-98Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Breast cancer among women with BRCA1 PVs exhibits fast growth rates more often than sporadic breast cancer. This shortens the ‘lead time’, i.e. the time available to detect the cancer while it is still in a subclinical phase, and explains the need for closer screening intervals, particularly for BRCA1 carriers. In fact, for carriers of a BRCA1 PV, 6-monthly screening is recommended.23Guindalini R.S.C. Zheng Y. Abe H. et al.Intensive surveillance with biannual dynamic contrast-enhanced magnetic resonance imaging downstages breast cancer in BRCA1 mutation carriers.Clin Cancer Res. 2019; 25: 1786-1794Crossref PubMed Scopus (28) Google Scholar For BRCA1 carriers, there appears to be little benefit of additional mammographic screening, irrespective of age; however, in BRCA2 carriers, there may be some added benefit, with no data on PALB2.24Kuhl C. Weigel S. Schrading S. et al.Prospective multicenter cohort study to refine management recommendations for women at elevated familial risk of breast cancer: the EVA trial.J Clin Oncol. 2010; 28: 1450-1457Crossref PubMed Scopus (335) Google Scholar, 25Riedl C.C. Luft N. Bernhart C. et al.Triple-modality screening trial for familial breast cancer underlines the importance of magnetic resonance imaging and questions the role of mammography and ultrasound regardless of patient mutation status, age, and breast density.J Clin Oncol. 2015; 33: 1128-1135Crossref PubMed Scopus (174) Google Scholar, 26Vreemann S. van Zelst J.C.M. Schlooz-Vries M. et al.The added value of mammography in different age-groups of women with and without BRCA mutation screened with breast MRI.Breast Cancer Res. 2018; 20: 84Crossref PubMed Scopus (25) Google Scholar, 27Phi X.A. Saadatmand S. De Bock G.H. et al.Contribution of mammography to MRI screening in BRCA mutation carriers by BRCA status and age: individual patient data meta-analysis.Br J Cancer. 2016; 114: 631-637Crossref PubMed Scopus (0) Google Scholar Whereas 6-monthly MRI would be the optimal strategy for BRCA1 PV carriers,23Guindalini R.S.C. Zheng Y. Abe H. et al.Intensive surveillance with biannual dynamic contrast-enhanced magnetic resonance imaging downstages breast cancer in BRCA1 mutation carriers.Clin Cancer Res. 2019; 25: 1786-1794Crossref PubMed Scopus (28) Google Scholar in most countries, 6-monthly screening MRI is not available; thus, annual MRI may be supplemented (in between the annual MRIs) by ultrasound or mammography depending on age, availability and local guidelines. There are no data on a cessation date of MRI for screening. Current guidelines recommend continuing MRI for as long as the woman is in good health.28Lee C.S. Monticciolo D.L. Moy L. Screening guidelines update for average-risk and high-risk women.AJR Am J Roentgenol. 2020; 214: 316-323Crossref PubMed Scopus (0) Google Scholar Of note, it is not only breast density that drives the lower sensitivity of other breast imaging modalities in PV carriers. Accordingly, it is not recommended to ‘switch’ to mammography screening once density decreases with increasing age. Retrospective studies demonstrate that ‘intensified screening’ results in earlier breast cancer diagnosis and improved outcomes.29Hadar T. Mor P. Amit G. et al.Presymptomatic awareness of germline pathogenic BRCA variants and associated outcomes in women with breast cancer.JAMA Oncol. 2020; 6: 1460-1463Crossref PubMed Scopus (9) Google Scholar ‘Intensified screening’ is defined as screening beyond the level recommended for individuals at average risk. It includes (i) the recommended age of screening onset, (ii) the recommended screening intervals and (iii) the methods involved for screening, as outlined in the summary recommendations below. ‘Intensified screening’ is also cost-effective.30Geuzinge H.A. Obdeijn I.M. Rutgers E.J.T. et al.Cost-effectiveness of breast cancer screening with magnetic resonance imaging for women at familial risk.JAMA Oncol. 2020; 6: 1381-1389Crossref PubMed Scopus (14) Google Scholar Risk-reducing mastectomy (RRM) results in a remaining breast cancer risk lower than that of average risk women with natural breasts. Routine intensified screening is not indicated following RRM; however, a baseline MRI in the first year after RRM to evaluate the amount of residual breast tissue is reasonable and further decisions on whether any imaging screening is mandated should be made on a case-by-case basis. Although there is no available evidence on adopting this approach, it is suggested in order to compensate for the variable surgical styles with which skin-sparing and nipple-sparing RRM is carried out. Of note, there are no validated tools for measuring and quantifying residual breast tissue or for defining the amount of residual tissue that justifies or requires continued surveillance—this is an important area for research. In women with ovarian cancer (including early and advanced stages at diagnosis) in a prolonged remission, intensified breast screening should be considered. Based on data from maintenance poly (ADP-ribose) polymerase (PARP) inhibitor trials in this population, it is reasonable to consider a ‘prolonged remission’ as being free from recurrence for at least 3 years from diagnosis. Institutions that offer screening of HBOC families must establish the same rigorous quality assurance for MRI as done for mammography screening; clinical experience with magnetic resonance (MR)-guided vacuum-assisted biopsy must be available. There are ongoing initiatives in Europe and the United States to collect evidence on the long-term safety of repeated gadolinium exposure; however, to date there are no data to suggest adverse outcomes in the absence of renal insufficiency. •Women with HBOC should be offered intensified screening if they do not opt for RRM [A].•Breast MRI should be considered the essential component of intensified screening programmes [A].•In the presence of a BRCA1, BRCA2 or PALB2 PVs, intensified screening should start at age 30, or 5 years younger than the youngest family member with breast cancer [A].•There is currently no evidence on the appropriate end date of intensified screening; it is suggested to base the decision on individual factors such as breast density, comorbidities and the patient’s priorities [C].•Annual screening intervals are recommended, except for BRCA1 where 6-monthly screening should be considered [A].•If 6-monthly screening is considered, this may be best achieved by annual MRI and, depending on availability, resources and local guidelines, the following imaging may be considered in between annual MRI studies:oin carriers 30-39 years of age, ultrasound with or without mammography [C].oin carriers ≥40 years of age, mammography with or without ultrasound [C].•There is no evidence to support continued routine breast imaging after RRM [D]. A baseline MRI in the first year after RRM to evaluate the amount of residual breast tissue is reasonable, however, and further decisions on imaging screening should be made accordingly on a case-by-case basis [C].•Women in follow-up after breast-conserving treatment or unilateral mastectomy for non-metastatic hereditary breast cancer should continue with intensified screening [A].•In women with ovarian cancer (including early and advanced stages at diagnosis) with no evidence of recurrence in a prolonged remission, intensified breast screening should be considered [C].•There should be rigorous quality assurance of intensified screening programmes, including benchmarking of programme sensitivity, false-positive rate and recall rates and availability of MR-guided biopsy [A]. All studies of lifestyle factors and hereditary breast cancer risk are observational, with potential for bias and residual confounding. Many risk factors confer consistent relative risks (RRs) across the risk spectrum, resulting in greater absolute increases for those with higher underlying genetic risk. Studies of BRCA1/2 PV carriers are limited by relatively small sample sizes and selection bias, but findings are mostly consistent with those for the general population. Physical inactivity and being overweight postmenopausally are associated with increased breast cancer risk in those at increased familial risk.31Kehm R.D. Genkinger J.M. MacInnis R.J. et al.Recreational physical activity is associated with reduced breast cancer risk in adult women at high risk for breast cancer: A cohort study of women selected for familial and genetic risk.Cancer Res. 2020; 80: 116-125Crossref PubMed Scopus (23) Google Scholar,32Hopper J.L. Dite G.S. MacInnis R.J. et al.Age-specific breast cancer risk by body mass index and familial risk: prospective family study cohort (ProF-SC).Breast Cancer Res. 2018; 20: 132Crossref PubMed Scopus (31) Google Scholar Breastfeeding is associated with reduced breast cancer risk for BRCA1 PV carriers, but less so for BRCA2,33Terry M.B. Liao Y. Kast K. et al.The influence of number and timing of pregnancies on breast cancer risk for women with BRCA1 or BRCA2 mutations.JNCI Cancer Spectr. 2018; 2: pky078Crossref PubMed Google Scholar,34Friebel T.M. Domchek S.M. Rebbeck T.R. Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis.J Natl Cancer Inst. 2014; 106: dju091Crossref PubMed Scopus (139) Google Scholar which is consistent with studies in the general population demonstrating a stronger inverse association for estrogen receptor-negative disease. Conversely, the inverse associations with breast cancer risk seen in the general population for earlier age at first birth and higher parity are less clear for BRCA1/2 PV carriers.33Terry M.B. Liao Y. Kast K. et al.The influence of number and timing of pregnancies on breast cancer risk for women with BRCA1 or BRCA2 mutations.JNCI Cancer Spectr. 2018; 2: pky078Crossref PubMed Google Scholar,34Friebel T.M. Domchek S.M. Rebbeck T.R. Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis.J Natl Cancer Inst. 2014; 106: dju091Crossref PubMed Scopus (139) Google Scholar Current use of hormonal contraceptives and combined hormone replacement therapy (HRT) is associated with increased breast cancer risk in the general population;35Collaborative Group on Hormonal Factors in Breast C. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence.Lancet. 2019; 394: 1159-1168Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar,36Morch L.S. Dehlendorff C. Baandrup L. et al.Use of antidepressants and risk of epithelial ovarian cancer.Int J Cancer. 2017; 141: 2197-2203Crossref PubMed Scopus (22) Google Scholar but whether this holds true for BRCA1/2 PV carriers is less clear.34Friebel T.M. Domchek S.M. Rebbeck T.R. Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis.J Natl Cancer Inst. 2014; 106: dju091Crossref PubMed Scopus (139) Google Scholar,37Schrijver L.H. Olsson H. Phillips K.A. et al.Oral contraceptive use and breast cancer risk: Retrospective and prospective analyses from a BRCA1 and BRCA2 mutation carrier cohort study.JNCI Cancer Spectr. 2018; 2: pky023Crossref PubMed Scopus (12) Google Scholar,38Gordhandas S. Norquist B.M. Pennington K.P. et al.Hormone replacement therapy after risk reducing salpingo-oophorectomy in patients with BRCA1 or BRCA2 mutations; a systematic review of risks and benefits.Gynecol Oncol. 2019; 153: 192-200Abstract Full Text Full Text PDF PubMed Google Scholar Although alcohol is associated with increased risk for breast cancer in the general population,39Chen W.Y. Rosner B. Hankinson S.E. et al.Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk.JAMA. 2011; 306: 1884-1890Crossref PubMed Scopus (327) Google Scholar studies have not demonstrated a clear association for BRCA1/2 PV carriers.34Friebel T.M. Domchek S.M. Rebbeck T.R. Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis.J Natl Cancer Inst. 2014; 106: dju091Crossref PubMed Scopus (139) Google Scholar,40Li H. Terry M.B. Antoniou A.C. et al.Alcohol consumption, cigarette smoking, and risk of breast cancer for BRCA1 and BRCA2 mutation carriers: Results from The BRCA1 and BRCA2 cohort consortium.Cancer Epidemiol Biomarkers Prev. 2020; 29: 368-378Crossref PubMed Scopus (12) Google Scholar •Physical exercise most days at moderate or strenuous intensity should be encouraged if appropriate (more is better); avoid being overweight or obese and encourage breastfeeding [B].•Minimise alcohol intake [C].•Decisions about hormonal contraception should weigh the possible increase in breast cancer risk against contraceptive efficacy, convenience and reduction in risk of ovarian cancer [C]. RRMed is an option for women who postpone, or do not undergo, elective bilateral RRM (BRRM). In randomised placebo-controlled trials for women with an elevated lifetime risk (LTR) of breast cancer (genetic status was only available in a very small subset of these women), the selective estrogen receptor modulators, tamoxifen and raloxifene, and the aromatase inhibitors, anastrozole and exemestane, reduced breast cancer incidence by ∼30%-60%, especially estrogen receptor-positive disease. The absolute risk of serious side-effects was low, particularly for premenopausal women.41USPST Force Owens D.K. Davidson K.W. et al.Medication use to reduce risk of breast cancer: US Preventive Services Task Force Recommendation Statement.JAMA. 2019; 322: 857-867Crossref PubMed Scopus (0) Google Scholar Five years of daily tamoxifen (20 mg) or anastrozole (1 mg) reduces risk for at least 20 and 10 years, respectively. Lower dose, shorter-duration tamoxifen is an option if the 20 mg dose is not tolerated. Tamoxifen is the only option for premenopausal women. Side-effect profiles should be considered when choosing between agents for postmenopausal women, including risks of thrombosis, endometrial cancer and osteoporosis. Data pertaining specifically to women with PVs in germline predisposition genes are extremely limited. The underpowered LIBER trial showed no reduction in first breast cancers in carriers of BRCA1/2 PVs randomised to letrozole versus placebo.42Pujol P. Roca L. Lortholary A. et al.Five year letrozole versus placebo in BRCA1/2 germline mutations carriers: Final results of LIBER, a double-blind randomized phase III breast cancer prevention trial.J Clin Oncol. 2020; 38 (1534-1534)Crossref Google Scholar A subgroup analysis of the effect of tamoxifen for individuals with BRCA1 and BRCA2 in the NSABP-P1 trial was too small and thus uninterpretable.43King M.C. Wieand S. Hale K. et al.Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial.JAMA. 2001; 286: 2251-2256Crossref PubMed Google Scholar Observational studies of tamoxifen and aromatase inhibitors for risk reduction of contralateral breast cancer have suggested benefits for carriers of both BRCA1 and BRCA2 PVs.44Phillips K.A. Milne R.L. Rookus M.A. et al.Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.J Clin Oncol. 2013; 31: 3091-3099Crossref PubMed Scopus (144) Google Scholar There are no data pertaining to PVs in other breast cancer predisposition genes. •RRMeds can be considered for primary risk reduction of breast cancer and risk re" @default.
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• W4307401062 title "Risk reduction and screening of cancer in hereditary breast-ovarian cancer syndromes: ESMO Clinical Practice Guideline" @default.
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