Bilateral mastectomy

Breast cancer is the most common cancer in women [11]. Approximately 5% of new breast cancer diagnoses have been shown to occur in carriers of germline pathogenic variants [3]. The role of bilateral risk-reducing mastectomy (BRRM) has become widely accepted, and rates have increased in recent years, due to improved genetic testing and significant media attention with consequent increased awareness [12, 13]. Indications for bilateral mastectomy include GPVs in BRCA1, BRCA2, PALB2. It can also be indicated for other ‘high risk’ variants, including PTEN, TP53, CDH1 and STK11 [14]. BRRM is not currently indicated for breast cancer associated with neurofibromatosis type 1, except where there are additional risk factors [15].

Testing criteria

Testing criteria for inherited breast and ovarian cancer (BRCA1, BRCA2, PALB2, ATM, CHEK2, RAD51C and RAD51D truncating variants) are outlined in the NHS England National Genomic Test Directory which is updated twice per year (available at https://www.england.nhs.uk/publication/national-genomic-test-directories/) [16]. Testing is available for individuals with breast cancer, ovarian cancer, pancreatic cancer or prostate cancer, or unaffected relatives of deceased affected individuals with any of the aforementioned cancers, if they meet other prerequisites of testing. Guidelines utilise the pathology-adjusted Manchester Score [17] and the CanRisk tool [18,19,20] to calculate likelihood of a pathogenic variant being present, which is used to outline thresholds at which an individual living with cancer, a deceased individual who had cancer or an unaffected relative can be eligible for testing.

PTEN hamartoma-tumour syndrome (PHTS) is a multi-system disorder which predisposes an individual to an increased risk of breast, thyroid and renal cancers. It may also be associated with endometrial, colorectal, and skin cancer. It is caused by GPVs of the PTEN gene. For individuals with GPVs of the PTEN gene, there is a lifetime risk of developing breast cancer of between 67 and 85% [21,22,23,24,25]. Testing for PTEN GPVs is indicated in affected individuals with clinical features (such as macrocephaly) or in a deceased individual if appropriate tissue is available and no living affected individual is available for genetic testing [5].

GPVs in the TP53 gene cause a TP53-related cancer syndrome (Li Fraumeni syndrome). It is associated with increased risk of multiple cancers including bone and soft tissue sarcomas, early-onset breast cancer, adrenocortical cancers, and malignant tumours of the central nervous system. Women have a risk of developing breast cancer of up to 85% by 60 years of age, the majority of which is early-onset breast cancer, with median age at diagnosis of 34 years [26]. Testing is available for an affected individual if they meet any one of the criteria as set out by the national test directory. Testing can also be performed in a deceased individual if appropriate tissue is available, and no living affected individual is available for genetic testing [5].

GPVs of the CDH1 tumour suppressor gene are known to cause hereditary diffuse gastric cancer (HDGC) and hereditary lobular breast cancer (HLBC). HLBC is classified as the presence of a CDH1 GPV in either an affected individual or a family with one or more lobular breast cancer cases, but without any diffuse gastric cancer. In those with CDH1 GPV with a personal or familial history of diffuse gastric cancer, this is recategorized as HDGC [27]. For female carriers of CDH1 GPV, there is an estimated 39–55% risk of developing lobular breast cancer by age 80 [27, 28]. Genetic testing is available, as per the NHS England National Genomic Test Directory, for affected individuals who meet the clinical criteria whereby at least one cancer is histologically confirmed [27]. It can alternatively be performed for a deceased individual where appropriate tissue is available and no living affected individual is available [5].

Peutz–Jeghers syndrome (PJS) is a multi-system disorder caused by a STK11 (LKB1) GPV. It is associated with tumours of the gastrointestinal tract, female reproductive system (cervical and ovarian cancer), breast, pancreas, and biliary tract. There is a lifetime female breast cancer risk of 19.3–54% in PJS, making it borderline for being a high-risk gene especially where no family history of breast cancer [29]. Genetic testing is available for affected individuals who meet clinical criteria, or for deceased affected individuals where criteria are met, there is appropriate tissue available, and no living affected relative [5].

The NHS England National Genomic Test Directory allows testing outside of the criteria; however, it must be deemed appropriate by a specialist MDT [5].

NICE guidelines stratify breast cancer risk as ‘near population risk’, ‘moderate risk’ and ‘high risk’. These categories have slightly different definitions based upon lifetime risk from age 20 to risk between ages 40 and 50. High risk of breast cancer is defined as a lifetime risk from age 20 of greater than or equal to 30%, a risk between age 40 and 50 of greater than 8% or known carriers of BRCA1, BRCA2 and TP53 GPVs and carriers of PTEN, CDH1 and STK11 GPVs [14]. GPVs in ATM and CHEK2 confer a moderate risk of breast cancer.

Surgical interventions

NICE recommends that all women at high risk should be offered a discussion about BRRM. There are several prerequisites prior to this procedure taking place. All cases should be managed by a multidisciplinary team and should take into consideration individual risk factors including comorbidities, the woman’s current age and life expectancy. Women who are eligible for BRRM should have genetic counselling under the care of a specialist cancer genetic clinic including pre-operative counselling about psychosocial and sexual consequences of BRRM and directed towards support groups. BRRM should be carried out by a surgical team with specialist oncoplastic/breast reconstructive skills [14]. Breast reconstruction options, including skin and/or nipple-sparing mastectomy, should be discussed with the patient pre-operatively [30].

NICE guidelines for BRRM, do not detail the age threshold for performing risk-reducing surgery. US guidelines and Hanson et al. suggest that BRRM should be considered from age 20 for female carriers of TP53 GPVs [31]. Guidelines for the management of CDH1 carriers state BRRM can be considered in hereditary lobular breast cancer and hereditary diffuse gastric cancer, however it is not generally recommended for those aged under 30 years or over 60 years [27]. Risk-reducing mastectomy is not currently recommended for female PJS by the European Hereditary Tumour group [29], however, as it falls under the ‘high-risk’ category in NICE guidelines, it can be considered for those with STK11 GPVs in the UK [14].

Alternatives to BRRM

The current NHS England breast surveillance programme offers mammographic surveillance every 3 years to all women aged between 50 and 71 in England. For women at a higher than population risk of developing breast cancer additional surveillance is available. NICE guidelines outline breast imaging surveillance, including mammography, offered to women with a moderate- to high risk of breast cancer or those with a known BRCA1/2 or TP53 GPV. Annual MRI breast surveillance is available for young women (aged <50 years) with or at high risk of being a BRCA or TP53 carrier who meet set criteria. The PHTS guideline development group of the GENTURIS European Reference Network suggest screening in individuals with PTEN GPVs should ideally be with annual MRI surveillance, however, this is not NICE guidance [21].

Medication to reduce the risk of breast cancer is available for women at moderate-to-high risk of breast cancer for up to 5 years. Tamoxifen is a selective oestrogen receptor modulator which offers long period of prevention of breast cancer following 5 years daily use [32]. It is offered as chemoprevention for premenopausal women, however, is contraindicated in individuals with a personal history of thromboembolic disease or endometrial cancer. Anastrozole is a non-steroidal aromatase inhibitor which has been proven to result in long-term prevention of breast cancer in post-menopausal women at increased risk of developing breast cancer following 5 years of regular use [33]. It is offered to post-menopausal women at high-risk and considered for women at moderate risk of breast cancer in the UK. It is contraindicated in women with osteoporosis, alternatively, raloxifene or tamoxifen can be offered [14]. The IBIS trials were not designed for germline pathogenic variant carriers therefore further longitudinal studies are required. Importantly, no effect was noted for invasive oestrogen receptor-negative breast cancer, the most common type of breast cancer in BRCA1 female carriers [32, 33].

Bilateral salpingo-oophorectomy

Ovarian cancer can form part of an inherited cancer syndrome with or without association with breast cancer. GPVs which are associated with both ovarian and breast cancer include BRCA1, BRCA2, RAD51C, RAD51D and PALB2. Meanwhile, GPVs associated with ovarian cancer but not associated with breast cancer include those found in LS (MLH1, MSH2, MSH6), and BRIP1 [34]. The European Society for Medical Oncology has published guidelines on the management of hereditary breast-ovarian cancer syndromes [35].

Small cell carcinoma of the ovary, hypercalcaemic type, is a rare and extremely aggressive subtype of ovarian cancer associated with somatic and germline deleterious variants of SMARCA4 [36, 37]. Somatic SMARCA4 testing is outlined in the national genomic test directory, but germline testing is not routinely available [5]. Given the prevalence of this condition, there currently is not enough evidence to make recommendations for genetic testing or the role of RRBSO in this population, and it is not outlined in the current RCOG recommendations. There is a strong argument for early RRBSO given the early-onset and aggressive nature of this condition [36].

Testing criteria

The NHS England National genomic test directory outlines testing that is appropriate for the affected individual if they have high-grade non-mucinous epithelial ovarian cancer (EOC) at any age or EOC with a family history of EOC (at least one first or second-degree relative or greater than two second- or third-degree relatives). Testing can also be performed on a deceased affected individual if appropriate tissue is available and no affected living relative is available for testing. In inherited ovarian cancer which is associated with breast cancer, this is extended to living unaffected individuals in certain circumstances [5].

Surgical interventions

Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is the gold standard for the prevention of ovarian cancer with an 80–96% risk reduction in patients with BRCA1/2 GPVs [38]. RRBSO does not reduce the risk of developing primary peritoneal carcinoma [38,39,40]. Concomitant hysterectomy is justified in LS due to increased risk of endometrial cancer, however, it may also be appropriate for a small number of women with other GPVs undergoing RRBSO for additional gynaecological indications such as fibroids or other benign conditions [34].

The Royal College of Obstetrics and Gynaecology (RCOG) has produced a summary of guidelines in conjunction with the British Journal of Obstetrics and Gynaecology regarding the role of RRBSO in individuals below the age of natural menopause [34]. RRBSO can be offered to women with moderate-to-high-risk GPVs. Moderate risk is classified a 4–10%, while high risk is classified as greater than 10% lifetime risk of developing ovarian cancer [41]. GPVs are associated with varying estimated lifetime risk of developing ovarian cancer: BRCA1 44% (95% CI, 36–53%), BRCA2 17% (11–25%) [42], RAD51C 11% (6–21%), RAD51D 13% (7–23%) [43], MLH1, MSH2 and MSH6 (LS) 11% (7.4–19.7%), 17.4% (11.8–31.2%) and 10.8% (3.7–38.6%), respectively [34], PALB2 ~5% (2–10%) and BRIP1 5.8% (3.6–9.1%) [34, 44]. The recommended timing of RRBSO varies dependent on the risk. The timing of RRBSO is individualised, and is based upon the risk of the GPV, fertility considerations and personal preferences. RRBSO can be considered between ages 35 and 40 years for carriers of BRCA1 GPVs and those with LS, between 40 and 45 years for those with BRCA2 GPVs, 40 and 50 years for RAD51C or RAD51D carriers and delayed to 45 and 50 years for carriers of BRIP1 or PALB2 [34].

Special requirements

RRBSO is usually undertaken once a woman’s family is complete, although this is considered in the context of her personal circumstances and risk. It is possible to consider the option of fertility preservation with IVF or oocyte freezing, as embryos can be implanted after RRBSO to enable the woman the potential option of completing her family later. For many women RRBSO is performed prior to the age of the natural menopause, resulting in an iatrogenic ‘surgical’ menopause. Consequently, immediate menopausal symptoms are often experienced which may include vasomotor symptoms, mood changes, sleep disturbance, vaginal dryness, and sexual dysfunction. Longer-term consequences of an early menopause include increased risk of cardiovascular disease, osteoporosis, and neurocognitive effects. Hormone replacement therapy (HRT) up to 51 years of age is recommended, in the absence of any contraindication including personal history of breast cancer or venous thromboembolism. It can result in symptom relief and minimises the long-term effect of early menopause; however, it may not completely ameliorate the effects of surgery on sexual function [34]. The impact of the menopause, and the option of HRT should be discussed prior to surgery and commenced immediately after RRBSO. For women who are not having a hysterectomy, oestrogen must be used in combination with a progestogen to protect against endometrial cancer. The progestogen can be delivered directly into the uterus, with fewer adverse effects than systemic progestogen. The intra-uterine system can be placed at the time of RRBSO provided this has been discussed and agreed with the woman during the pre-operative consultation. NICE guidance recommends that HRT usage should be confined to women younger than the age of the expected natural menopause if at moderate or high risk of breast cancer [14]. Continuing beyond this will require a discussion and consideration of BRRM status.

Alternatives to RRBSO

The combined oral contraceptive pill (COCP) is a strong protective factor for ovarian cancer in the general population and has been demonstrated to substantially reduce the risk of ovarian cancer in women with GPVs in BRCA1/2 GPVs (compared with less than 5 years COCP, >10 years COCP, HR 0.37, 95% CI 0.19–0.73) [45, 46]. Women should be counselled on the use of COCP and small increased risk of breast cancer [45]. There is currently no effective tool which has been developed for population-wide surveillance for the early detection of ovarian cancer. NICE guidelines for the identification and management familial and genetic risk of ovarian cancer are currently in development and due for publication March 2024 [47].

Hysterectomy

Lynch syndrome (LS) is associated with GPVs in DNA mismatch repair (MMR) genes including GPVs of MLH1, MSH2, MSH6, PMS2 [8, 48]. GPVs in these genes are associated with different risks for cancers including colorectal, small bowel, endometrial, ovarian, and pancreatic cancers. In women with LS, gynaecological cancers are twice as common as gastrointestinal cancers [49].

Testing criteria

In the UK, all new diagnoses of endometrial and colorectal cancer are eligible for tumour immunohistochemistry to identify MMR-deficient or microsatellite instability tumours that may be suggestive of LS. Germline testing can subsequently confirm the presence of GPVs in LS genes. Germline testing is also appropriate for affected individuals or unaffected individuals with family history of LS-related cancer where no affected living individual is available for testing [5].

The risk of endometrial cancer in LS varies as the genes associated with LS have different penetrance. Cumulative incidence of endometrial cancer at 75 years of age is 37% in MLH1, 48.9% in MSH2, 41.1% in MSH6 and 12.8% in PMS2 mutation carriers [48, 50].

Surgical interventions

Risk-reducing hysterectomy (RRH), often performed with bilateral salpingo-oophorectomy (BSO), is an option for patients with LS. RRH at age 40 years has been demonstrated to prevent endometrial cancer by age 50 years in carriers of MLH1 (13%), MSH2 (16%)| and MSH6 (11%) GPVs who would have been expected to develop endometrial cancer [49]. Current guidelines, from the Manchester International Consensus Group, recommends that all women at risk of LS should be offered RRH with BSO at “a time appropriate to them”. This is recommended at no earlier than age 35–40 years, following completion of childbearing, and suggested from around age 35 years for carriers of GPVs of MSH2 or MLH1 and after age 40 years for MSH6. There is insufficient evidence for recommending risk-reducing gynaecological surgery for carriers of PMS2 GPVs, however patient representatives have expressed that they should be offered RRS [51]. The British Gynaecological Cancer Society (BGCS) Uterine Cancer Guidelines support offering surgery to these women after the age of 50, as their risk prior to menopause is low [52]. The BGCS recommend post-operative HRT to women following premenopausal oophorectomy for women with LS, due to its protective effect on colorectal cancer risk [52]. For women with MSH6 GPVs, the risk of developing ovarian cancer only starts to increase in the post-menopausal years, in contrast to an earlier onset risk for endometrial cancer. In these women, a two-stage RRS approach may be adopted, after counselling, with RRH offered from 40 years, and delayed RRSBO until after 50 years, in circumstances where the woman wishes to avoid surgical menopause and prefers to avoid taking HRT.

Recently, a few studies have reported an increased risk of serous endometrial cancer in BRCA1 carriers estimated as 3% lifetime risk [53, 54]. This is not currently an indication of RRS [51].

Alternatives to RRH

There is no population-wide surveillance tool for endometrial cancer in the UK. Current international guidelines do not recommend invasive screening for carriers of MMR GPVs, however there is a recommendation that they may wish to consider the option of annual clinician review from the age of 25 to discuss red flag features of endometrial and ovarian cancer [51]. The BGCS guidelines recommend that women with LS could be offered annual surveillance with a transvaginal ultrasound scan (TVS), hysteroscopy and/or endometrial sampling from the age of 35 years after counselling about the risks, benefits and limitations of surveillance, acknowledging that there is no current high-quality evidence that surveillance improves outcomes [52]. Surveillance is not a substitute for risk-reducing surgery, but is considered an option for women who have yet to complete their families. Aspirin has been proven to reduce the risk of colorectal cancer in the LS population, however there is little evidence to support this for reducing endometrial cancer risk [55].

There is strong evidence to show that obesity is associated with a significantly increased risk of endometrial cancer in the general population, whilst use of progestogen-containing hormonal contraceptives, oral or intra-uterine, is potentially associated with a decreased risk [52]. The BGCS guidelines fall short of recommending their use as a risk reduction strategy for women with LS but acknowledge that further studies are warranted. Women with LS can be advised that maintaining a healthy weight and using progestogen-containing contraceptives may reduce their risk, although LS-specific evidence is not yet available.

Polypectomy and colectomy

Several syndromes are associated with a predisposition to colorectal cancer. This includes LS, APC-associated polyposis, Peutz–Jeghers Syndrome (PJS), Juvenile Polyposis Syndrome (JPS) and MUTYH-associated polyposis. The British Society of Gastroenterology (BSG), Association of Coloproctology of Great Britain and Ireland (ACPGBI), and the UKCGG have produced extensive guidelines developed in accordance with the BSG NICE-compliant guideline process regarding the management of hereditary colorectal cancer [56]. They recommend colonoscopy as the gold-standard diagnostic and preventative method of surveillance for people with a hereditary risk of colorectal cancer [56]. This can guide the timing of and type of risk-reducing surgery if required.

Testing criteria

LS is the most common heritable cause of colorectal cancer and is associated with 10-48% cumulative risk of developing colorectal cancer by the age of 75 years dependent on the mutated MMR gene (MLH1 48.3%, MSH2 46.6%, MSH6 20.3%, PMS2 10.4%) [48]. In the UK, all new diagnoses of colorectal cancer are eligible for tumour immunohistochemistry to identify MMR-deficient tumours. Germline testing is also appropriate for affected individuals or unaffected individuals with family history of LS-related cancer where no affected living individual is available for testing [5].

Familial adenomatous polyposis (FAP) is defined by the presence of GPVs in the APC gene which predisposes an individual to colorectal and upper GI polyposis. The lifetime risk of malignancy in FAP is 100% [57]. Genetic testing for FAP is available for children or young adults who may not have developed bowel polyps but have the presence of one of the APC-associated clinical features outlined by the NHS England National Genomic Test Directory [