Bilateral risk-reducing mastectomy reduces cancer risk by at least 90%r in BRCA1 and BRCA2 pathogenic variant carriers (depending on the operation performed). Statistically significant survival benefit associated with bilateral risk-reducing mastectomy compared with surveillance is yet to be demonstrated.
Although early studies suggested pre-menopausal RRSO reduced breast cancer risk in BRCA1 and BRCA2 pathogenic variant carriers, they were subject to several biases that tended to overestimate benefit. Contemporary studies, designed to minimise bias, have yielded contradictory findings but overall there is no clear and consistent evidence for a role of RRSO in reducing breast cancer risk and it should not be used specifically for that purpose.r
The estimated breast cancer risk under age 30 years for BRCA1 and BRCA2 carriers is 4% (95% CI 2-7 and 2-9, respectively).r Personal lifestyle and family history factors, such as the presence of young onset cancer, may affect the risk trajectory and can be personalised using the validated risk prediction tools specified (e.g. CanRisk or iPrevent). A decision to commence breast screening at the younger end of the 25-30 year age range may therefore be considered when an individual’s estimated risk is greater than 4% by age 30 years or based on patient perception and preferences regarding risk.
Magnetic resonance imaging (MRI) is the preferred screening technique due to its high sensitivity compared with mammogram (MMG) or ultrasound (US). The addition of MMG is limited and does not lead to a significant increase in sensitivity compared with MRI alone.r There is no added value of US or clinical breast exam in women undergoing MRI for screening.r MRI detects tumours which are smaller and more likely to be node-negative than MMG. MRI has a recall rate (requiring further investigation and/or biopsy) of 15% for initial screening, which decreases with subsequent rounds of screening to <10%.
MMG screening is not recommended before age 40 years in BRCA1 and BRCA2 pathogenic variant carriers. The sensitivity of MRI is not influenced by age or breast density, being similar in women aged over 50 years to those aged under 50 years.
The rate of cancers occurring between annual screening (interval cancers) is higher in BRCA1 pathogenic variant carriers than other high risk populations.
Tamoxifen, raloxifene, anastrozole and exemestane have been shown to reduce the relative risk of breast cancer in high risk women by 30%-60%. Five years of daily tamoxifen (20mg) or anastrozole (1mg) reduces risk for at least 20 and 10 years, respectively. Lower dose, shorter-duration tamoxifen (e.g. 5mg daily for 3 years) is an option if the 20mg dose is not tolerated.r
To date studies have not included enough BRCA1 or BRCA2 pathogenic variant carriers to determine efficacy for primary prevention in this population. Tamoxifen use is associated with a reduction in contralateral breast cancer risk in BRCA1 and BRCA2 pathogenic variant carriers with breast cancer.r Risk-reducing medications can be offered to BRCA1 and BRCA2 pathogenic variant carriers who postpone or do not undergo bilateral mastectomy. As with all interventions, discussion of risks and benefits should occur. See COSA - Medications to lower the risk of breast cancer: clinician guide
Ovarian and fallopian tube cancer
The estimated ovarian cancer risk for BRCA1 carriers under age 40 years is 2% (95% CI 1-3) and for BRCA2 carriers under age 50 years is 0% (95% CI 0-2).r Personal lifestyle and family history factors, such as the presence of young onset cancer, may affect the risk trajectory and can be personalised using the validated risk prediction tools specified (e.g. CanRisk). A decision to perform RRSO at the younger end of the age range may therefore be considered when an individual’s estimated risk is at the upper end of the confidence interval or based on patient perception and preferences regarding risk.
Bilateral risk-reducing salpingo-oophorectomy (RRSO) significantly reduces the risk of ovarian and fallopian tube cancer in BRCA1 and BRCA2 pathogenic variant carriers. Careful examination of the resected tubes and ovaries using the SEE-FIM protocol is essential.r Those with serous tubal intraepithelial carcinoma (STIC) found in their RRSO specimen are at very high risk for subsequent peritoneal cancer (27.5% at 10 years post RRSO) whereas those with no STIC at RRSO have a low risk (10 year risk <1%).r
The effectiveness and safety of risk-reducing bilateral salpingectomy followed by delayed bilateral oophorectomy has not been established. It is not recommended for ovarian cancer risk management unless part of a clinical trial.
The decision to perform hysterectomy at the time of RRSO should be individualised. The absolute risk of uterine cancers in BRCA1 and BRCA2 carriers is relatively low.r Hysterectomy may simplify subsequent menopausal hormone therapy, or the use of tamoxifen for breast cancer risk or as adjuvant treatment of breast cancer, but may not be justified for endometrial cancer prevention alone.
For asymptomatic women annual transvaginal ultrasound (TVU) and serum CA125 levels have poor sensitivity and specificity for ovarian cancer. They do not reliably detect ovarian cancers at an early stage, nor do they affect outcomes. This is true of women in the general population and women at high risk of hereditary ovarian cancer. Effective ovarian cancer risk management relies on RRSO.
Although there is evidence the combined oral contraceptive pill can reduce the ovarian cancer risk, it is significantly less effective than RRSO and it is not recommended for cancer prevention.
Some studies suggest offering surveillance from age 50 years in BRCA1 or BRCA2 germline pathogenic variant carriers with a first- or second-degree relative with pancreatic cancer. Studies suggest surveillance can achieve ‘downstaging’ at diagnosis, although advanced interval cancers are common, and there is no evidence for improved survival. However, in one recently published screening study of patients at high risk of developing pancreatic cancer, most screen-detected pancreatic cancers were stage I with favourable long-term outcomes.r
If surveillance is offered it should be undertaken in an experienced high-volume centre after detailed discussion regarding limitations of screening including cost, high incidence of benign or indeterminate pancreatic abnormalities and uncertainties about the benefit. Most small cystic lesions found on screening will not warrant biopsy, surgical resection, or any other intervention.