Abstract

The guidelines will focus on cancer prevention and screening among individuals known to harbour a pathogenic BRCA1/2 mutation. The presence of a BRCA1 or BRCA2 mutation accounts for the majority of hereditary breast and ovarian cancer syndromes. Genetic susceptibility to breast or ovarian cancer might also be associated with mutations in other genes, some of which are associated with known hereditary cancer syndromes, such as p53, PTEN, CDH1, STK11, MLH1, MSH2, MSH6 and PMS2. The cancer risk association with other genes, such as PALB2, CHEK2, ATM, RAD51C, RAD51D and BRIP1, is still under research or clinical validation. An overview of prevention and screening strategies for these mutations is summarised in Table 1.Table 1Prevention and screening strategies for specific mutationsScreeningPrevention/risk reductionLi Fraumeni Syndrome- p53 mutation1)Clinical breast examination every 6–12 months starting from age 20–25 [V]2)Annual breast MRI at age 20–75. If MRI is not available, mammography may be considered [V]3)Colonoscopy every 5 years from the age of 25 or as clinically indicated4)Annual dermatological and neurological examination5)Consider annual whole-body MRI and 6-monthly complete blood count1)Avoid ionising radiation, e.g. CT2)Consider offering PGD before pregnancies3)Consider risk-reducing mastectomyPTEN/Cowden Syndrome1)Clinical breast examination every 6–12 months starting from age 20–25 [V]2)Annual breast MRI and/or mammogram at age 30–75 [V]3)Annual endometrial ultrasound ± biopsies from age 30–351)Consider risk-reducing mastectomy2)Consider risk-reducing hysterectomy3)Consider offering PGD before pregnanciesATM mutation1)Consider annual breast MRI (no evidence regarding the age of onset)Lynch Syndrome- MLH1, MSH2,MSH6, EPCAM and PMS2 mutations1)Annual colonoscopy from age 20–252)Annual neurological examination for screening of CNS tumours may be considered3)Annual endometrial ultrasound ± biopsies from age 30–35 may be considered1)Consider risk-reducing hysterectomy and RRSO after completion of childbearingRAD51 mutation1)Consider RRSO after the age of 45BRIP1 mutation1)Consider RRSO after the age of 45PALB2 mutation1)Clinical breast examination every 6–12 months starting from age 20–25 [V]2)Annual breast MRI from age 20–293)Annual breast MRI and/or mammogram at age 30–75 [V]1)Consider risk-reducing mastectomyCHEK2 mutation1)Clinical breast examination every 6–12 months starting from age 20–25 [V]2)Annual breast MRI from age 20–293)Annual breast MRI and/or mammogram at age 30–75 [V]STK11 mutation (Peutz–Jeghers Syndrome)1)Clinical breast examination every 6–12 months starting from age 20–25 [V]2)Annual breast MRI from age 20–293)Annual breast MRI and/or mammogram at age 30–75 [V]4)Upper endoscopy and colonoscopy every 2–3 years from late teens5)Screening for pancreatic cancer with EUS or MRI from the age of 306)Annual testicular examination from childhood7)Routine annual gynaecological surveillance8)Counselling to reduce lung cancer risk1)Consider risk-reducing mastectomyCDH1 mutation1)Clinical breast examination every 6–12 months starting from age 20–25 [V]2)Annual breast MRI from age 20–293)Annual breast MRI and/or mammogram at age 30–75 [V]1)Consider risk-reducing mastectomyMRI, magnetic resonance imaging; CT, computed tomography; PGD, pre-implantation genetic diagnosis; CNS, central nervous system; RRSO, risk-reducing salopingo-oophorectomy; EUS, endoscopic ultrasound. Open table in a new tab MRI, magnetic resonance imaging; CT, computed tomography; PGD, pre-implantation genetic diagnosis; CNS, central nervous system; RRSO, risk-reducing salopingo-oophorectomy; EUS, endoscopic ultrasound. For initial risk assessment and the decision when to perform genetic counselling and testing, the reader is referred to the recently updated National Comprehensive Cancer Network (NCCN) guidelines on genetic/familial high-risk assessment [1.NCCN Clinical practice guidelines in oncology: genetic/familial high risk assessment: breast & ovarian Version 2.2016 ed2016. www.nccn.org/professionals/physician_gls/pdg/genetics_screening.pdf (5 August 2016, date last accessed).Google Scholar], and The National Institute for Health and Clinical Excellence (NICE) guidelines [2.Familial breast cancer: classification and care of people at risk of familial breast cancer and management of breast cancer and related risks in people with a family history of breast cancer. Cardiff (UK), 2013.Google Scholar]. Many of the recommendations in the guidelines are based on expert opinion reflecting the need for international collaborations and databases to optimise recommendations and care for screening, prevention and follow-up in this population. Hereditary cancer syndromes arise from a germline mutation, inherited from either parent, resulting in a significantly elevated risk of cancer development relative to that of the general population that does not harbour a mutation in a cancer susceptibility gene. Specifically, a germline mutation in BRCA1 or BRCA2 results in a significantly elevated lifetime risk of developing breast and ovarian cancer, estimated at up to 7 and 25 times (respectively) that of the average risk population [3.Paul A. Paul S. The breast cancer susceptibility genes (BRCA) in breast and ovarian cancers.Front Biosci (Landmark Ed). 2014; 19: 605-618Google Scholar, 4.King M.C. Marks J.H. Mandell J.B. New York Breast Cancer Study Group Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.Science. 2003; 302: 643-646Google Scholar, 5.Walsh T. Casadei S. Lee M.K. et al.Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.Proc Natl Acad Sci USA. 2011; 108: 18032-18087Google Scholar], depending on the population studied. The presence of a mutation in BRCA2 has also been demonstrated in multiple studies to be associated with an increased risk in prostate cancer, melanoma and pancreatic cancer [6.Mersch J. Jackson M.A. Park M. et al.Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian.Cancer. 2015; 121: 2474-2475Google Scholar]. The association between BRCA1 and BRCA2 mutations and elevated risk of gastric cancer, colorectal cancer and uterine cancers remains weak and thus screening and prevention of these cancers among BRCA1/2 mutation carriers is generally not indicated. More than 90% of hereditary cases of breast and ovarian cancer are thought to be a result of a mutation in BRCA1/2 [7.Ford D. Easton D.F. Stratton M. et al.Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.Am J Hum Genet. 1998; 62: 676-689Google Scholar]. The estimated prevalence of BRCA1 and BRCA2 mutations is dependent on the population and can vary between 1 in 300 and 1 in 800, respectively. More than 2000 different mutations have been identified in BRCA1/2 genes, and in some populations, founder mutations are the most prevalent ones—for example up to 2.5% of the general Ashkenazi Jewish population will harbour a mutation in BRCA1 (185delAG [= c.68_69delAG], 5382InsC [=c.5266dupC]) or BRCA2 (6174delT [=c.5946delT]) [8.Roa B.B. Boyd A.A. Volcik K. Richards C.S. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2.Nat Genet. 1996; 14: 185-187Google Scholar]. Founder mutations have also been described in Northern, Western and Eastern Europe. The penetrance is variable and not clearly understood, but a recent population screening study suggested that even among those with no family history of cancer the lifetime risk of developing breast or ovarian cancer by the age of 80 was up to 83% (±7%) in the presence of BRCA1, 76% (±13%) in the presence of a BRCA2 mutation and the risk was higher in the more contemporary birth cohorts [9.Gabai-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 USA. 2014; 111: 14205-14210Google Scholar]. Among men harbouring a BRCA1 or BRCA2 mutation, there is an estimated lifetime risk of breast cancer of 1.2% to ≤8%, respectively [10.Evans D.G. Susnerwala I. Dawson J. et al.Risk of breast cancer in male BRCA2 carriers.J Med Genet. 2010; 47: 710-711Google Scholar, 11.Tai Y.C. Domchek S. Parmigiani G. Chen S. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers.J Natl Cancer Inst. 2007; 99: 1811-1814Google Scholar], and a doubling of prostate cancer risk. Following a diagnosis of the presence of a BRCA1/2 mutation, follow-up counselling outlining options for screening for early detection, risk-reducing measures and issues pertaining to fertility in women who have not completed their family is fundamental [V, B]. The difference between the goals of screening and those of risk-reducing measures (including surgery, chemoprevention and lifestyle measures) should be clarified and the limitations in available evidence for these measures should be clearly stated. Discussion with individuals should address issues of quality of life and the psychosocial impact of risk-reducing interventions [V, B]. Recommendations should emphasise the early onset of disease characteristics among BRCA1/2 mutation carriers and the limitations in techniques for early detection of ovarian cancer. Individuals above the age of 25 years from a family known to harbour a BRCA1/2 mutation who have not yet been tested should be encouraged to undergo testing and, if positive, to consider risk-reducing measures [V, B]. Until mutation status has been assessed and in women declining genetic testing or risk reduction measures, screening recommendations as for known mutation carriers should be followed. If available, carriers should be encouraged to participate in dedicated high-risk follow-up clinics that specifically focus on follow-up and screening of individuals with a known hereditary cancer syndrome [V, B]. Numerous observational studies have suggested that breastfeeding may reduce the risk of breast cancer among BRCA1/2 carriers. Therefore, if possible, breastfeeding should be encouraged [IV, B]. Regular exercise, maintaining healthy body weight and limiting alcohol consumption should also be encouraged, and hormone replacement therapy (HRT) should be avoided [V, B]. Clinical breast examination every 6–12 months is recommended from the age of 25 or 10 years before the youngest breast cancer diagnosis in the family, whichever is earlier [V, B]. All carriers should be encouraged to be ‘breast-aware’ and to seek immediate medical attention if they perceive any changes in their breast or lumps in the axilla [V, B]. Breast magnetic resonance imaging (MRI) is well established as the most sensitive screening tool for the high-risk population [12.Warner E. Plewes D.B. Hill K.A. et al.Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination.JAMA. 2004; 292: 1317-1325Google Scholar, 13.Kriege M. Brekelmans C.T. Boetes C. et al.Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition.N Engl J Med. 2004; 351: 427-437Google Scholar, 14.Kuhl C.K. Schrading S. Leutner C.C. et al.Mammography, breast ultrasound, and magnetic resonance imaging for surveillance of women at high familial risk for breast cancer.J Clin Oncol. 2005; 23: 8469-8476Google Scholar, 15.Chiarelli A.M. Prummel M.V. Muradali D. et al.Effectiveness of screening with annual magnetic resonance imaging and mammography: results of the initial screen from the Ontario high risk breast screening program.J Clin Oncol. 2014; 32: 2224-2230Google Scholar]. Annual screening MRI should be commenced from the age of 25 with the addition of annual mammography from the age of 30 [II, A]. Retrospective data suggest an association between increased breast cancer risk and exposure to diagnostic radiation before the age of 30 [16.Pijpe A. Andrieu N. Easton D.F. et al.Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK).BMJ. 2012; 345: e5660Google Scholar]. Thus, if MRI screening is not available, annual mammography should be utilised from the age of 30 [III, B]. The decision to implement breast mammography under the age of 40 should take into consideration any increased breast density at younger ages and the availability of annual screening MRI. In women under 30 years of age, breast ultrasonography can be considered if MRI is unavailable [IV, B]. There are no robust data supporting alternating 6-monthly radiology surveillance with MRI and mammography in the high-risk population; results from a study evaluating this issue are awaited. Ultrasound may be considered as an adjunct to mammography at all ages and as an alternative when MRI is not available (at all ages). Limited data are available about the use of selective oestrogen receptor modulators (tamoxifen, raloxifene) and aromatase inhibitors as primary prevention among BRCA1/2 mutations carriers. Use of tamoxifen may be considered; however, the level of evidence is weak [IV, C]. Several observational studies have suggested that among BRCA1/2-associated breast cancer patients, tamoxifen use reduces the risk of contralateral breast cancer [17.Phillips 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: 3091-3099Google Scholar, 18.Narod S.A. Brunet J.S. Ghadirian P. et al.Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Group.Lancet. 2000; 356: 1876-1881Google Scholar]. One study suggested a benefit for contralateral risk reduction even among patients with oestrogen receptor negative tumours who received tamoxifen; however, the study numbers were limited, and the majority of patients had received chemotherapy [17.Phillips 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: 3091-3099Google Scholar]. There is no evidence to suggest that, with respect to hormonal therapy, patients with BRCA1/2-associated breast cancer should be treated any differently to those with non-BRCA-associated breast cancer; as such, adjuvant hormonal therapy should be administered as clinically indicated, irrespective of BRCA status. Bilateral risk-reducing mastectomy (RRM) is the most effective method for reducing breast cancer risk among BRCA1/2 mutation carriers [III, B]. RRM reduces the risk of breast cancer by ∼90% depending on the study reported and depending on the type of surgery carried out [19.Hartmann L.C. Schaid D.J. Woods J.E. et al.Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer.N Engl J Med. 1999; 340: 77-84Google Scholar, 20.Hartmann L.C. Sellers T.A. Schaid D.J. et al.Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers.J Natl Cancer Inst. 2001; 93: 1633-1637Google Scholar, 21.Heemskerk-Gerritsen B.A. Brekelmans C.T. Menke-Pluymers M.B. et al.Prophylactic mastectomy in BRCA1/2 mutation carriers and women at risk of hereditary breast cancer: long-term experiences at the Rotterdam Family Cancer Clinic.Ann Surg Oncol. 2007; 14: 3335-3344Google Scholar, 22.Meijers-Heijboer H. van Geel B. van Putten W.L. et al.Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation.N Engl J Med. 2001; 345: 159-164Google Scholar, 23.Rebbeck T.R. Friebel T. Lynch H.T. et al.Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group.J Clin Oncol. 2004; 22: 1055-1062Google Scholar, 24.Domchek S.M. Friebel T.M. Singer C.F. et al.Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.JAMA. 2010; 304: 967-973Google Scholar, 25.Evans D.G. Baildam A.D. Anderson E. et al.Risk reducing mastectomy: outcomes in 10 European centres.J Med Genet. 2009; 46: 254-258Google Scholar, 26.Skytte A.B. Crüger D. Gerster M. et al.Breast cancer after bilateral risk-reducing mastectomy.Clin Genet. 2011; 79: 431-437Google Scholar]. The studies have been either retrospective or prospective in nature, many with over 10 years of long-term follow-up, and all but one study demonstrated a benefit in risk reduction [27.Mulligan A.M. Couch F.J. Barrowdale D. et al.Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.Breast Cancer Res. 2011; 13: R110Google Scholar]. However, no randomised controlled studies on this issue have been carried out. No survival benefits have been demonstrated in women who have undergone RRM. A variety of techniques exist: ranging from total mastectomy, through to skin-sparing mastectomy (SSM) and nipple-sparing mastectomy (NSM), which aim to improve cosmetic results. Immediate breast reconstruction should be offered [V, C] [28.Morrow M. Mehrara B. Prophylactic mastectomy and the timing of breast reconstruction.Br J Surg. 2009; 96: 1-2Google Scholar]. SSM and NSM have similar safety outcomes as total mastectomy, after breast cancer diagnosis [29.Niemeyer M. Paepke S. Schmid R. et al.Extended indications for nipple-sparing mastectomy.Breast J. 2011; 17: 296-299Google Scholar, 30.Chung A.P. Sacchini V. Nipple-sparing mastectomy: where are we now?.Surg Oncol. 2008; 17: 261-266Google Scholar]. Limited data exist about these techniques as a risk-reducing measure. However, available data on safety are encouraging and cosmetic outcome is improved. Thus, SSM and NSM are accepted alternatives to total mastectomy [III, C]. It can be assumed that following NSM there is a slightly higher residual risk, as the technique leaves behind the breast envelope and nipple areola complex. Benefits, limitations, risks of surgical complications and psychosocial impact should be discussed with the individual patient/carrier. The possibility of an occult breast cancer being diagnosed at the time of surgery is <5%, and thus, routine sentinel lymph node biopsy is not indicated. Studies assessing psychosocial aspects of RRM have, for the most part, demonstrated a favourable impact among women undergoing the procedure both in short- and long-term follow-up. These studies identified an association between reconstruction complications and communication issues with the treating physician as causes for dissatisfaction and also found that women that chose risk-reducing surgery (RRS) were more likely to perceive their risk of breast cancer more highly than women who did not opt for surgery. These issues should be taken into consideration when counselling women about RRM. Contralateral risk-reducing mastectomy (CRRM) among patients with a previous breast cancer diagnosis can be considered [III, B]. Several retrospective and prospective studies with long-term follow-up have all demonstrated a significant reduction in contralateral breast cancer events, and two studies demonstrated a significant reduction in the risk of breast cancer-related death [31.Kiely B.E. Jenkins M.A. McKinley J.M. et al.Contralateral risk-reducing mastectomy in BRCA1 and BRCA2 mutation carriers and other high-risk women in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab).Breast Cancer Res Treat. 2010; 120: 715-723Google Scholar, 32.Metcalfe K. Gershman S. Ghadirian P. et al.Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis.BMJ. 2014; 348: g226Google Scholar, 33.Heemskerk-Gerritsen B.A. Rookus M.A. Aalfs C.M. et al.Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis.Int J Cancer. 2015; 136: 668-677Google Scholar]. It is important to note that, in these studies, the majority of patients were under 50 years of age at the time of surgery and the majority had early (stage I–II) breast cancer at initial diagnosis. Risk-reducing salpingo-oophorectomy (RRSO) has repeatedly been reported in several retrospective and prospective studies to reduce the risk of breast cancer among BRCA1/2 mutation carriers when carried out in premenopausal women [24.Domchek S.M. Friebel T.M. Singer C.F. et al.Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.JAMA. 2010; 304: 967-973Google Scholar, 34.Rebbeck T.R. Levin A.M. Eisen A. et al.Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers.J Natl Cancer Inst. 1999; 91: 1475-1479Google Scholar, 35.Rebbeck T.R. Kauff N.D. Domchek S.M. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers.J Natl Cancer Inst. 2009; 101: 80-87Google Scholar]. However, a recent prospective cohort study, controlling for potential biases, suggested that no benefit in breast cancer risk reduction existed following RRSO [36.Heemskerk-Gerritsen B.A. Seynaeve C. van Asperen C.J. et al.Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction.J Natl Cancer Inst. 2015; 107: djv033Google Scholar]. Use of the oral contraceptive pill (OCP) has consistently been demonstrated to have a significant risk-reducing effect on the development of ovarian cancer by 40%–60% [37.Friebel 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: dju091Google Scholar]. The use of the OCP may be considered as a risk-reducing measure for ovarian cancer [II, C], particularly among those seeking a form of contraception during their reproductive years. It should however be noted that there are conflicting data whether OCP increases breast cancer risk among BRCA1/2 carriers [37.Friebel 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: dju091Google Scholar]. The long-term clinical significance of OCP use as a risk reduction measure for ovarian cancer is unclear, given that mutation carriers are encouraged to undergo RRSO by age 40 and that, before age 40, ovarian cancer is relatively uncommon even among mutation carriers. There are no data proving that screening for ovarian cancer reduces mortality. A recent study in the UK, in the average-risk population, demonstrated promising results with serial Ca125 screening [38.Menon U. Ryan A. Kalsi J. et al.Risk algorithm using serial biomarker measurements doubles the number of screen-detected cancers compared with a single-threshold rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening.J Clin Oncol. 2015; 33: 2062-2071Google Scholar]. A sister trial for high-risk women is ongoing (https://www.ucl.ac.uk/instituteforwomenshealth/womens-cancer/gcrc/ukfocss) as is the GOG 19–9 trial [39.Greene M.H. Piedmonte M. Alberts D. et al.A prospective study of risk-reducing salpingo-oophorectomy and longitudinal CA-125 screening among women at increased genetic risk of ovarian cancer: design and baseline characteristics: a Gynecologic Oncology Group study.Cancer Epidemiol Biomarkers Prev. 2008; 17: 594-604Google Scholar]. Before RRSO, 6-monthly, trans-vaginal ultrasound and measures of serum Ca125 may be considered from the age of 30; however, the limited value of these tools as an effective screening measure should be communicated to individuals [V, C]. The most effective measure for reducing the risk of ovarian cancer is RRSO [I, A] (specifically RRS should incorporate removal of both the ovaries and the fallopian tubes), which has consistently been shown to reduce the risk by 80%–90% and to reduce mortality [24.Domchek S.M. Friebel T.M. Singer C.F. et al.Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.JAMA. 2010; 304: 967-973Google Scholar, 35.Rebbeck T.R. Kauff N.D. Domchek S.M. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers.J Natl Cancer Inst. 2009; 101: 80-87Google Scholar, 40.Finch A.P. Lubinski J. Moller P. et al.Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation.J Clin Oncol. 2014; 32: 1547-1553Google Scholar, 41.Marchetti C. De Felice F. Palaia I. et al.Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers.BMC Womens Health. 2014; 14: 150Google Scholar]. Mutation type, the patient's preferences and family history should be taken into consideration when deciding on the age for RRSO. Among BRCA1 carriers, the incidence of occult ovarian cancer at the time of RRSO was 1.5% before the age of 40 and 3.8% for 40- to 49-year olds [40.Finch A.P. Lubinski J. Moller P. et al.Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation.J Clin Oncol. 2014; 32: 1547-1553Google Scholar]. Among BRCA2 carriers, the risk of ovarian cancer before the age of 50 is only 1%. RRSO should be carried out at age 35–40 [II, B]. There is an increasing body of evidence suggesting that ovarian cancer originates in the fimbria or fallopian tubes [42.Swanson C.L. Bakkum-Gamez J.N. Options in prophylactic surgery to prevent ovarian cancer in high-risk women: how new hypotheses of fallopian tube origin influence recommendations.Curr Treat Options Oncol. 2016; 17: 20Google Scholar]. This, combined with epidemiological data demonstrating that tubal ligation and salpingectomy are associated with a lower incidence of ovarian cancer, has resulted in a growing interest in risk-reducing salpingectomy in the high-risk population. Risk-reducing salpingectomy alone cannot yet be recommended, outside the setting of a clinical trial [V, C] [42.Swanson C.L. Bakkum-Gamez J.N. Options in prophylactic surgery to prevent ovarian cancer in high-risk women: how new hypotheses of fallopian tube origin influence recommendations.Curr Treat Options Oncol. 2016; 17: 20Google Scholar]. Following RRS, the residual annual risk of breast and/or ovarian/peritoneal cancer is often at levels lower than the general population risk. No validated data are available from prospective, long-term follow-up studies to support offering screening schedules after RRS. It is not clear whether any surveillance regimen is necessary, effective or cost-beneficial; thus, there is no currently recommended surveillance schedule after RRS [V, C]. Following NSM in which there is more residual breast tissue, continued screening with annual breast MRI or ultrasound may be considered. Screening recommendations are not different for a woman who has a previous diagnosis of cancer. A multitude of fertility-related issues face female carriers. BRCA1/2 carriers can be reassured that there is no convincing evidence that mutation carriers have reduced ovarian reserve or fertility [IV, C] [43.Shapira M. Raanani H. Feldman B. et al.BRCA mutation carriers show normal ovarian response in in vitro fertilization cycles.Fert Steril. 2015; 104: 1162-1167Google Scholar]. All women harbouring a BRCA1/2 mutation should be encouraged to complete childbearing before planned RRSO [V, C]. For women who wish to undergo RRSO and have not yet completed childbearing, fertility preservation options such as oocyte and embryo cryopreservation should be discussed [V, C]. Women harbouring a BRCA1/2 mutation who have been diagnosed with a malignancy should be counselled about options for fertility preservation before the commencement of oncology treatment [V, B]. For a full discussion of fertility preservation options, the reader is referred to the ESMO guidelines [44.Peccatori F.A. Azim Jr, H.A. Orecchia R. et al.Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2013; 24: vi160-vi170Google Scholar]. BRCA1/2 mutation carriers (male and female) planning to conceive should be made aware of the options of prenatal diagnosis (via chorio-villous or amniotic fluid sampling in weeks 11–20 of gestation) and pre-implantation genetic diagnosis (PGD) [V, C]. The risks and benefits of both approaches need to be carefully outlined and the need for in vitro fertilisation (IVF), irrespective of fertility status, if PGD is chosen must be clearly stated. A multitude of factors, including religious, cultural, ethical and socioeconomic factors, can influence an individual's choice to utilise prenatal diagnosis or PGD, and any decision should be respected. Of note, these technologies are not available everywhere. Following RRSO, many women will suffer from menopausal symptoms including vasomotor symptoms, altered libido and vaginal dryness. Many of these will further compound psychological distress as a result of changes in body image and sexuality. Appropriate counselling should be available and vaginal moisturisers and lubricants should be prescribed to all women following RRS [V, C]. With respect to menopausal symptoms, several studies have indicated that short-term use of HRT to alleviate menopausal symptoms following RRSO is safe among healthy BRCA1/2 mutation carriers [III, B] [45.Rebbeck T.R. Friebel T. Wagner T. et al.Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group.J Clin Onco