Women in families with multiple cases of female breast +/- ovarian cancer are at increased risk of developing breast cancer. In the absence of a known germline pathogenic variant in a breast cancer predisposition gene, the exact levels of risk are difficult to determine. Risk models such as CanRisk, IBIS and iPrevent can calculate individual cancer risks.
Breast cancer risks can be low under age 40, even with family history, for women who do NOT carry a high-risk pathogenic variant. Potential harms of screening may outweigh benefits at this age, and an individual discussion is advised, based on the woman’s 10-year breast cancer risk assessment.
Bilateral risk reducing mastectomy reduces absolute breast cancer risk to <2%.
Mammography has been shown to reduce mortality for women at population risk of developing breast cancer. Annual mammography in an observational study of women aged 40-49 with a family history of risk of breast cancer (3% absolute risk during this time period) detected breast cancers at lower stages (smaller, fewer positive lymph nodes and lower grade) than in women who are not involved in a screening program.r
The sensitivity of mammography has been reported to be lower (50%) for women with high breast density, and limited evidence supports adding breast MRI, breast ultrasound or tomosynthesis to increase sensitivity. A systematic review of mammography with digital breast tomosynthesis use for breast cancer screening found lower false positive rates, recall rates and increased cancer detection when compared to standard 2D mammography, adding support for its use in screening.rr
Screening with use of MRI in addition to mammography has been shown to have a significant increase in sensitivity for women with a high risk of breast cancer based on family history (55% with mammography alone increasing to 98% with the addition of MRI). Cancers detected have also been earlier stage, required less adjuvant therapy and had a lower rate of metastatic disease.r However, false positive findings increased and specificity decreased with use of MRI.r
Five years of treatment with selective oestrogen receptor modulators (SERM), such as tamoxifen and raloxifene, or aromatase inhibitors (AIs), such as anastrozole or exemestane, have been shown to reduce the risk of oestrogen receptor-positive breast cancer in women identified to be at increased risk. A meta-analysis showed that tamoxifen reduced breast cancer incidence by 32% compared with placebo in women at increased risk. Tamoxifen was more effective at reducing breast cancer risk than raloxifene but had greater toxicity. AIs (for post-menopausal women only) reduced breast cancer risk by 53% compared with placebo.r After cessation of therapy, persistent breast cancer risk reduction has been shown for tamoxifen and anastrazole.rr None of the medications have proven mortality benefit.
Ovarian cancer risk estimates vary according to several factors including the number of relatives with ovarian cancer, their age(s) at diagnosis, the tumour subtype of their cancers and the degree of relationship between those affected and the consultand. Different types of ovarian cancer have different risks for relatives (when BRCA pathogenic variants are excluded). There is a lower risk of ovarian cancer for women with a family history of clear cell or mucinous ovarian cancer and higher risks for family history of high grade serous or endometrioid histology. Serous histology increases the risk two- to four-fold for relatives, with higher risks for young onset (age <50 years). Families with high grade serous or endometrioid ovarian/fallopian tube/primary peritoneal cancer are more likely to have BRCA pathogenic variants, and testing is now advised for most women with ovarian type cancer with high grade non-mucinous pathology especially if there is additional family history of breast and ovarian cancer. Residual risk is also dependent on current age.
Ovarian cancer risk is lower in families where BRCA pathogenic variants have been excluded. The CanRisk Web Tool (which uses BOADICEA version 5) uses an ovarian cancer risk assessment model that includes the effects of pathogenic variants in BRCA1, BRCA2, RAD51D, RAD51C and BRIP1, polygenic risk scores, residual family history and personal lifestyle/hormonal/reproductive risk factors. However, this tool has not been independently validated for ovarian cancer risk.
Decisions about RRBSO should be individualised based on the empiric residual lifetime risk, current health status, cancer anxiety and personal preference. Women with one first degree relative with high grade serous or endometrioid ovarian cancer have an estimated lifetime ovarian cancer risk of 2-5%.r Women with two first degree relatives with high grade serous or endometrioid ovarian cancer have a predicted lifetime ovarian cancer risk of 8% provided a BRCA1 or BRCA2 pathogenic variant has been excluded in a relevant family member.r In some families with a strong history of both breast and ovarian cancer, the ovarian cancer risk may be as high as BRCA pathogenic variant carriers.
RRBSO for ovarian cancer risk
There is no effective ovarian cancer screening program, so management relies on risk-reducing removal of the ovaries and fallopian tubes (RRBSO). Individual discussion is required regarding acceptable levels of ovarian cancer lifetime risk. If a woman does not have a known BRCA, PALB2, RAD51 or BRIP1 pathogenic variant, then her lifetime risk is likely to be below 5%, unless she has two close relatives with ovarian cancer.
RRBSO reduces the risk of ovarian cancer to below an absolute level of 5% in BRCA carriers and is expected to do likewise in breast-ovarian non-BRCA families. RRBSO is predicted to increase survival in women at high ovarian cancer risk but optimal management of early menopause, which may include referral to menopause clinics, is important in providing the best long-term health outcomes for women. Discussion with a clinician with relevant expertise is advised when making decisions about the role (if any) of RRBSO for an individual woman.