Hereditary Breast and Ovarian Cancer

Posted by • February 5th, 2016

2-1-2016 1-50-03 PMHereditary breast and ovarian cancer is a syndrome that involves an increased predisposition to breast cancer, ovarian cancer, or both and an autosomal dominant pattern of transmission. Risk-reducing mastectomy and risk-reducing salpingo-oophorectomy are options for the primary prevention of breast and ovarian cancers, and they have been shown in multiple studies to have efficacy.

The risk of breast and ovarian cancer among women with mutations such as BRCA1 and BRCA2 can be mitigated by operations to remove the organs at greatest risk. Data are presented to assist in deciding what operation should be performed and when it should occur. A new Review Article summarizes.

Clinical Pearl

• What are the estimated cancer risks among carriers of the BRCA1 and BRCA2 mutations?

Among female BRCA1 carriers, the average cumulative risk of breast cancer by 80 years of age is 67% and the average cumulative risk of ovarian cancer is 45%. Among BRCA2 carriers, these risks are 66% and 12%, respectively. By 70 years of age, the cumulative risk of breast cancer is approximately 1% among men with BRCA1 mutations and approximately 7% among men with BRCA2 mutations. The lifetime risk in the general male population is 0.1%.

Figure 1. Cumulative Risk of Breast and Ovarian Cancer.

Clinical Pearl

• How effective are prophylactic mastectomy and salpingo-oophorectomy in reducing the cancer risk in BRCA1/2 carriers?

From 1999 through 2004, the results of four retrospective and prospective observational studies were published. These studies compared breast-cancer outcomes in women who underwent prophylactic mastectomy with outcomes in women at similar risk who did not undergo surgery. Four studies showed a reduction of 90% or more in the risk of subsequent breast cancer among women who underwent prophylactic mastectomy. Updated reports and additional studies have confirmed these initial results; only one small study did not show a significant reduction in the risk of subsequent breast cancer after bilateral mastectomy. Seven efficacy studies of risk-reducing salpingo-oophorectomy for prevention of ovarian cancer and one meta-analysis showed a significant risk reduction of approximately 80% among BRCA1 and BRAC2 carriers. Follow-up times were relatively short, averaging approximately 4 years. Current guidelines recommend risk-reducing salpingo-oophorectomy for both BRCA1 and BRCA2 carriers between the ages of 35 and 40 years who have completed their childbearing.

Morning Report Questions

Q: Is salpingectomy with delayed oophorectomy an effective risk-reducing procedure for women with BRCA1/2 mutations?

A: The discovery that many pelvic serous cancers originate in the fallopian tubes raises the question of whether bilateral salpingectomy with delayed oophorectomy may be an option for premenopausal women who want to delay surgical menopause. Anecdotal reports indicate that this option is being used occasionally. However, data regarding the efficacy of this investigational approach are lacking.

Q: Can tamoxifen be used as an alternative to prophylactic mastectomy in BRCA1/2 carriers?

A: Currently, data on the use of tamoxifen for primary prevention of breast cancer in BRCA1 and BRAC2 carriers are very limited. To the authors’ knowledge, the only prospective data derive from the National Surgical Adjuvant Breast and Bowel Project P1 trial, in which mutation status was determined in the 288 women in whom breast cancer developed. The hazard ratios for the development of breast cancer among women who received tamoxifen were 1.67 (95% CI, 0.32 to 10.7) among BRCA1 carriers and 0.38 (95% CI, 0.06 to 1.56) among BRCA2 carriers. Although these results are limited by small sample sizes, they are consistent with an effect in BRCA2 carriers; approximately 77% of breast cancers in BRCA2 carriers are ER-positive. These results are uninformative for BRCA1 carriers. The major question is whether tamoxifen can provide primary prevention of breast cancer in BRCA1 carriers, in whom 75 to 80% of breast cancers are ER-negative. Currently, the authors think that the data are inadequate to support the use of tamoxifen for primary prevention of breast cancer in BRCA1 carriers. However, given the predominance of ER-positive disease that develops in BRCA2 carriers, tamoxifen is an option for this group.

Table 3. Suggested Approaches to Care of Patients with Hereditary Breast and Ovarian Cancer Syndrome.

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