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 mutation in a breast cancer predisposition gene, the exact levels of risk are difficult to determine. Risk models such as BRCAPRO and BOADICEA can calculate individual cancer risks and empirical data from cohort studies can contribute to an estimation of individuals risks.
Bilateral risk reducing mastectomy reduces absolute breast cancer risk to <2%
RRBSO for breast cancer risk
Premenopausal RRBSO has been reported to approximately halve breast cancer risk in BRCA mutation carriers although prospective data are still awaited and the impact in other (non-BRCA) high risk women has not been described. There are competing health risks from surgical menopause particularly before age 45 in women who do not use hormone supplementation. Risk reducing medication is an alternative means of breast cancer risk reduction (see below).
Annual screening for women age 50-69 with a family history of breast cancer detects cancers at an earlier stage than women with a family history having two yearly screening. For women with at least two close relatives with breast cancer where one relative is diagnosed under age 50, the most cost-effective time interval is predicted to be annual screening.
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 programme and 80% of cancers were screen detected. Projected mortality reduction was 20% at 10 years.
For women at increased risk of breast cancer the addition of ultrasound to mammography slightly improves detection of breast cancer but increases the number of false positives so is not recommended.
MRI is more sensitive (62-88%) but less specific (75-99%) than mammography, therefore increases recalls (8-17%) and biopsies (3-15%) compared to mammograms alone. In the prospective EVA trial,r MRI detected all cancers during annual screening; no interval cancer occurred and no cancer was identified during half-yearly ultrasound. Early data suggest cancer detection by MRI alone is not significantly improved by the addition of mammography or ultrasound.r
Further studies on the cost effectiveness of MRI screening in high risk women are needed.
Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer in high risk women. Five years of tamoxifen reduces the risk of ER (oestrogen receptor) positive invasive breast cancer by almost half for high risk women. This equates to a risk reduction of about one third in overall breast cancer risk, with effects lasting for 20 years, although overall mortality benefit is not yet seen.
For post menopausal women, 5 years of raloxifene has lower efficacy than tamoxifen but fewer side effects. Alternatives in postmenopausal women include anastrozole and exemestane which also reduce the risk of invasive ER-positive breast cancer (reduced overall invasive breast cancer risk by half [anastrozole] and two thirds [exemestane] compared to placebo in separate trials). Medications should be discussed with an experienced medical professional to determine the balance of relevant risks and benefits of each in an individual.
Ovarian cancer risk estimates vary according to a number of factors including the number of relatives with ovarian cancer, their age(s) at diagnosis, the histology of the cancers and the degree of relationship between those affected and the consultand. Residual risk is also dependant on current age.
Ovarian cancer risk is lower in families where BRCA mutations have been excluded. Only 3/37 ovarian cancers occurring in the UKFOCCS screening trial were in individuals without known mutations. Rates of occult cancer at RRBSO in the international study of ovarian cancer screening and surgery, GOG-0199, were only 0.5% in individuals who did not have a BRCA mutation compared to 4.6% in BRCA1 carriers and 3.5% in BRCA2. If a BRCA1/2 mutation has been excluded by testing of a relevant relative, current computer models eg. BOADICEA or BRCAPRO do NOT accurately estimate ovarian cancer risk.
Decisions about RRBSO should be individualised based on the empiric residual life time risk, current health status, cancer anxiety and personal preference. Women with one first degree relative with ovarian cancer have an estimated lifetime ovarian cancer risk of 2-5%.r Women with two first-degree relatives have a predicted lifetime ovarian cancer risk of 8% provided a BRCA1 or BRCA2 mutation 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 mutation carriers. Discussion with a clinician with relevant expertise is advised when making decisions about the role (if any) of RRBSO for an individual woman.
RRBSO for ovarian cancer risk
There is no effective ovarian cancer screening programme, 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 mutation, then her lifetime risk is likely to be below 5%, unless she has two close relatives with ovarian cancer.
If family history includes only postmenopausal ovarian cancers, then a rationale for pre-menopausal RRBSO could be the possibility of breast cancer risk reduction. An alternative option would be to use breast cancer risk-reducing medication prior to age 50, followed by RRBSO.
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.