Potential for bias in studies on efficacy of prophylactic surgery for BRCA1 and BRCA2 mutation.

Women who carry a germline mutation in the BRCA1 or BRCA2 (BRCA1/2) gene have a 50%–80% lifetime risk of developing breast cancer and a 10%–40% lifetime risk of developing ovarian cancer (1–4). These high-risk women are being offered various preventive measures, including surveillance, chemoprevention, and prophylactic surgery to reduce their risk of cancer. During a prophylactic bilateral mastectomy or a prophylactic bilateral salpingo-oophorectomy, healthy breast or ovarian tissue, respectively, is removed to prevent the development of a malignancy. However, these procedures do not completely eradicate cancer risk because, often, not all tissue at risk is taken away (5–9). Because of the invasive and irreversible nature of prophylactic surgery, knowledge of its efficacy and the extent of risk reduction are crucial for women considering the procedure. Several groups have investigated the efficacy of bilateral prophylactic surgery in women with a family history of breast and/ or ovarian cancer or in known BRCA1/2 mutation carriers (Table 1). For BRCA1/2 mutation carriers, prophylactic bilateral mastectomy was associated with an 85%–100% risk reduction for breast cancer (10,11), and a prophylactic salpingo-oophorectomy was associated with an 85%–96% risk reduction for ovarian cancer and a 53%–68% risk reduction for breast cancer (12,13). There are, however, specific methodologic problems associated with research evaluating the efficacy of prophylactic surgery. For example, was ovarian cancer more prevalent in families of women who opted for a prophylactic oophorectomy than it was in families of the comparison group? Might cancer events be overselected because women elected BRCA mutation testing after their cancer diagnosis? Might cancer events be overselected because a woman’s cancer diagnosis was the reason for prophylactic surgery in one of her relatives, while both of them are included in the study? The aim of this commentary is to discuss various biases that may occur in studies that estimate the risk reduction after prophylactic surgery. These insights may help evaluate previous investigations and help plan future efficacy studies.