Cost-Effectiveness of Preventive Strategies for Women with a BRCA1 or a BRCA2 Mutation

Context Recent research has provided more precise estimates of the age-specific incidence of ovarian and breast cancer in carriers of BRCA mutations. These data will help define the value of prophylactic surgery for these women. Content For BRCA2 carriers, the authors' decision model shows that combined prophylactic surgery (mastectomy and bilateral salpingo-oophorectomy) was very cost-effective relative to oophorectomy alone. Both strategies dominated (were less costly and were more effective) surveillance, prophylactic mastectomy alone, or chemoprevention. For BRCA1 carriers, oophorectomy dominated all other strategies. Limitations The model uses observational study data and expert opinion. Implications Oophorectomy alone or in combination with mastectomy is the most cost-effective strategy for BRCA mutation carriers. The Editors Germline mutations account for 5% to 10% of breast cancer diagnosed in the United States each year (1). Because women who develop cancer associated with such mutations do so at a relatively young age, these mutations account for a disproportionate share of life-years lost due to cancer. Genetic testing is expensive, but so is cancer. Hence, cost-effective policies on testing and preventive treatment options may save up to $800 million of the more than $8 billion or more spent each year on breast cancer diagnosis, prevention, and treatment (2-4). In a recent decision analysis of preventive strategies, we reported that prophylactic surgery or chemoprevention could lead to better survival and quality-adjusted survival than surveillance alone for women with a positive test result for BRCA1 or BRCA2 mutations (5). We showed that the survival benefit for women who had prophylactic mastectomy with bilateral oophorectomy at 30 years of age was 4.9 years, but it increased to 7.8 years if the penetrance rates of breast and ovarian cancer were 85% and 63%, respectively. These results are similar to those found in other decision analyses (6-10), although the outcomes for women treated with prophylactic surgery, especially prophylactic oophorectomy, have improved in more recent observational data (11-13). Recently, King and colleagues (13) published findings on breast and ovarian cancer penetrance in a cohort of unaffected women who received a positive test result for a specific BRCA1 or BRCA2 mutation. To assist policymakers and those who pay for medical care, using a societal perspective, we have incorporated these findings (6) into our mathematical model to estimate the cost-effectiveness of each strategy given a BRCA1 or a BRCA2 mutation. In light of questions raised about the penetrance data (14-16) and other factors, we have also conducted sensitivity analyses in which we varied our assumptions about mutation penetrance; cancer mortality; and the timing, efficacy, costs, and preference ratings of preventive interventions to identify threshold values for these strategies. Methods We developed a Markov process (17) and used 25000 Monte Carlo simulations with TreeAge DATA Pro software (TreeAge Software Inc., Williamstown, Massachusetts) to estimate the cost-effectiveness of the following preventive strategies for women with a positive test result for BRCA1 or BRCA2 mutations: chemoprevention (tamoxifen for breast cancer and oral contraceptives for ovarian cancer), prophylactic surgery (bilateral mastectomy for breast cancer and bilateral salpingo-oophorectomy for ovarian cancer; oophorectomy also reduces the risk for breast cancer), or both surgical procedures for breast and ovarian cancer, and surveillance alone. For surveillance, we assumed that women with a positive test result would follow the guidelines outlined by Burke and colleagues (18) and the National Comprehensive Cancer Network (19), which include annual mammography; breast ultrasonography, if necessary; clinical breast examinations; and semi-annual gynecology examinations, including pelvic examinations, ultrasonography, and CA-125 studies. We focused on 8 health outcomes: good health; death; breast cancer; ovarian cancer; both breast cancer and ovarian cancer; and side effects of oral contraceptives and tamoxifen, such as cataracts, endometrial cancer, and thrombophlebitis or pulmonary emboli (Table 1). We used 25000 simulations for our base case, in which women initiate their preventive strategy at 35 years of age, with up to 70 years of follow-up (Markov cycles). For each year and each strategy, we calculated the age-dependent probabilities of developing breast cancer, developing ovarian cancer, developing side effects, dying of breast or ovarian cancer, dying of any cause, or remaining well. The Figure depicts the preventive strategies, the health outcomes, and further health outcomes included in the model. For our base case, we ranked our preventive strategies by cost and determined which strategy had the most favorable cost-effectiveness ratio with and without quality adjustment. Table 1. Incidence, Preventive Strategy, and Mortality Assumptions Used in the Markov Model Figure. Preventive strategies and health states (outcomes) used in the Markov model and probabilisitic sensitivity analysis. Health Parameters The model used King and colleagues' estimates of the cumulative incidence (penetrance) of breast cancer and ovarian cancer among BRCA1- and BRCA2-positive women (13) in each decade of age up to 100 years. We converted these 10-year risks to annual conditional probabilities of cancer by assuming constant instantaneous rates of disease per year within each decade. We assumed that the risks for developing the 2 types of cancer were independent. Therefore, among BRCA1- or BRCA2-positive women, those with breast cancer had the same conditional probability of developing ovarian cancer as those who were well. For patients who developed breast cancer, we calculated the annual risks for death, ovarian cancer, or survival with breast cancer. We took into account both the age when the patient received the diagnosis and the time from diagnosis. Because intensive surveillance may influence stage at diagnosis, we assumed that BRCA1- or BRCA2-positive women, given a choice of preventive measures at 35 years of age and subsequently receiving a diagnosis of breast cancer, would be similar in stage distribution to the participants in the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 Study, known as the Breast Cancer Prevention Trial (BCPT) (25). Of these participants, 70% had localized (node-negative) and 30% had regional (node-positive) disease (25). We assumed that BRCA1- or BRCA2-positive women who developed cancer would have the same conditional probability of death as women with cancer in the general population. Therefore, we used the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program data issued in 2001 (20) to calculate the probabilities of death. We did not adjust for screening for ovarian cancer because screening does not seem to alter the prognosis of this type of cancer (26, 27). We based our estimates of the health effects of preventive strategies on findings that bilateral prophylactic oophorectomy and salpingo-oophorectomy may reduce the risk for ovarian cancer and breast cancer by 96% (11, 23, 28) and 53% (11), respectively, among BRCA1- and BRCA2-positive women. Other recent studies suggest that bilateral prophylactic mastectomy may reduce the risk for breast cancer by 90% (12, 21, 29), tamoxifen (taken for 5 years) may reduce the risk for breast cancer by 49% (25, 30), and oral contraceptives may reduce the risk for ovarian cancer by 54% (31, 32). For our base case, we assumed that the risk reductions associated with these strategies lasted indefinitely. We assumed that women 35 years of age who were given estrogen replacement therapy until 50 years of age after prophylactic oophorectomy would not have an increased risk for breast cancer more than that conferred by BRCA1 or BRCA2 (8, 33). We also assumed that they would have the same risk for cardiovascular disease and osteoporosis as that of the general population. We calculated the incremental mean years of survival that each preventive measure would yield by subtracting that value from the mean life expectancy associated with surveillance. We assumed that women who experienced serious side effects from tamoxifen or oral contraceptives would discontinue those treatments and thereafter use only surveillance as a strategy. Cost Parameters We included the costs of genetic testing and screening in our model (34). We obtained age-stratified data on cancer care costs from Kaiser Permanente (Table 2) (35). We based our estimates of the costs of treating complications, such as endometrial cancer, thrombophlebitis with pulmonary embolism, and cataracts (Table 2), on Medicare payments from the Health Care Financing Administration (now the Centers for Medicare & Medicaid Services) (38, 40). We based our estimates of the costs of care for those dying with and without cancer on analyses of these data by Riley and colleagues (36) and Lubitz and Riley (37). We obtained drug cost data from the 2004 Drug Topics Red Book (39). We adjusted all costs for increases in the medical care component of the Consumer Price Index (4) and provided the values in 2004 U.S. dollars. Table 2. Medical Costs Used in the Markov Model We did not determine indirect costs, such as those due to time off from work, travel, and other out-of-pocket expenses, and we assumed them to be inconsequential compared with direct medical costs (41). Quality-of-Life Adjustment We used preference ratings of cancer treatmentrelated and preventive treatment-related states obtained from our study (24, 42) by using time-tradeoff ratings among women 33 to 50 years of age with a family history of breast cancer (at least 1 first-degree relative diagnosed before 50 years of age) or with a personal history of several breast biopsies (Table 3). We obtained preference ratings of

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