Survival Analysis of Cancer Risk Reduction Strategies for BRCA1/2 Mutation Carriers

Department of Health Research and Policy, Stanford University, Palo Alto, California, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 12/2009; 28(2):222-31. DOI: 10.1200/JCO.2009.22.7991
Source: PubMed


Women with BRCA1/2 mutations inherit high risks of breast and ovarian cancer; options to reduce cancer mortality include prophylactic surgery or breast screening, but their efficacy has never been empirically compared. We used decision analysis to simulate risk-reducing strategies in BRCA1/2 mutation carriers and to compare resulting survival probability and causes of death.
We developed a Monte Carlo model of breast screening with annual mammography plus magnetic resonance imaging (MRI) from ages 25 to 69 years, prophylactic mastectomy (PM) at various ages, and/or prophylactic oophorectomy (PO) at ages 40 or 50 years in 25-year-old BRCA1/2 mutation carriers.
With no intervention, survival probability by age 70 is 53% for BRCA1 and 71% for BRCA2 mutation carriers. The most effective single intervention for BRCA1 mutation carriers is PO at age 40, yielding a 15% absolute survival gain; for BRCA2 mutation carriers, the most effective single intervention is PM, yielding a 7% survival gain if performed at age 40 years. The combination of PM and PO at age 40 improves survival more than any single intervention, yielding 24% survival gain for BRCA1 and 11% for BRCA2 mutation carriers. PM at age 25 instead of age 40 offers minimal incremental benefit (1% to 2%); substituting screening for PM yields a similarly minimal decrement in survival (2% to 3%).
Although PM at age 25 plus PO at age 40 years maximizes survival probability, substituting mammography plus MRI screening for PM seems to offer comparable survival. These results may guide women with BRCA1/2 mutations in their choices between prophylactic surgery and breast screening.

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    • "The solution of our MDP model yields cost and QALYs-optimal intervention strategies for healthy BRCA1/2 mutation carriers of age 30 to 65 and with all possible prior intervention status. In our model, the screening decision choice is considered each year as opposed to a one-time decision made at age 25 (as in [11]) or age 35 (as in [13]). In [13], Markov modeling with Monte Carlo simulation was implemented to find the cost-effective strategies for 35 to 50 year old BRCA1/2 mutation carriers. "
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    ABSTRACT: Purpose: Women with BRCA1/2 mutations have higher risk for breast and ovarian cancers. Available intervention actions include prophylactic surgeries and breast screening, which vary significantly in cost, cancer prevention, and in resulting death from other causes. We present a model designed to yield optimal intervention strategies for mutation carriers between the ages of 30 and 65 and any prior intervention history. Methods: A Markov decision process (MDP) model is developed that considers yearly state transitions for the mutation carriers and state dependent intervention actions. State is defined as a vector comprising mutation type, health states, prior intervention actions, and age. A discounted value iteration algorithm is used to obtain optimal strategies from the MDP model using both cost and quality-adjusted life years (QALYs) as rewards. Results: The results from MDP model show that for 30-year-old women with BRCA1 mutation and no prior intervention history, the cost-optimal strategy is a combination of prophylactic mastectomy (PM) and prophylactic oophorectomy (PO) at age 30 with no screening afterwards. Whereas, the QALYs-optimal strategy suggests PO at age 30 and PM at age 50 with screening afterwards. For BRCA2 mutation carriers at age 30, the cost-optimal strategy is PO at age 30, PM at age 40, and yearly screening only after age 56. Corresponding QALYs-optimal strategy is PM at age 40 with screening. Strategies for all other ages (31 to 65) are obtained and presented. It is also demonstrated that the cost-optimal strategies offer near maximum survival rate and near minimum cancer incidence rates by age 70, when compared to other ad hoc strategies.
    04/2014; 19(2). DOI:10.1109/JBHI.2014.2319246
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    • "However, despite the availability of modern treatment regimens and more extensive use of chemotherapy, endocrine, and targeted therapy, the prognosis for young women with breast cancer still remains unsatisfactorily poor. In the case of BRCA1/2-associated breast and ovarian cancer, identification of a mutation in the family makes presymptomatic testing, surveillance, and prophylactic surgery possible; these measures have a positive effect on the life expectancy that is superior to the improvement in breast and ovarian cancer prognosis that we have seen over the last decades [10]. It is therefore very important to identify mutation carriers. "
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    ABSTRACT: All women in the South Sweden Health Care Region with breast cancer diagnosed aged less than 41 during the period between 1990 and 1995 were contacted in 1996 and offered germline mutation analysis of the BRCA1 and BRCA2 genes. Mutation carriers (n = 20) were compared with noncarriers (n = 201) for overall survival (OS) and risk of contralateral breast cancer (CBC). Mutation carriers were younger at diagnosis and more likely to have ER-negative, PgR-negative and grade III tumors. Median follow-up was 19 years. The 5-, 10-, 15-, and 20-year OS were 60, 45, 39, and 39 % for mutation carriers and 82, 70, 59, and 53 % for noncarriers, respectively (5-year log-rank P = 0.013; 10-year P = 0.008; 15-year P = 0.020; and 20-year P = 0.046). In univariable analysis, there was a trend for an inferior OS for mutation carriers (HR 1.8; 95 % CI 1.0-3.3). When stratified for use of (neo)adjuvant chemotherapy, an inferior OS was significant only for the subgroup of patients who did not receive chemotherapy (HR 3.0; 95 % CI 1.2-7.7). In multivarible analysis, BRCA1/2 mutation status was a significant predictor of OS when adjusting for tumor stage, age, and use of chemotherapy, but not when ER status was also included in the model. The 15-year cumulative risk of CBC was 53 % for mutation carriers and 10 % for noncarriers (HR 5.9; 95 % CI 1.9-18.6); among the noncarriers the risks were 5, 22, and 30 % for patients without close relatives having breast cancer, with second-degree relatives having breast cancer, and with firstdegree relatives with breast cancer, respectively. In conclusion, the poor prognosis of young BRCA1/2 mutation carriers with breast cancer is mainly explained by the prevalent occurrence of negative prognostic factors rather than mutation status per se, and can to at least some extent be abrogated by the use of chemotherapy.
    Breast Cancer Research and Treatment 01/2014; 144(1). DOI:10.1007/s10549-014-2842-9 · 3.94 Impact Factor
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    • "Specifically, current data suggests breast cancer risk reduction of over 90% with prophylactic mastectomy [8–12, 56, 57] and reduction in ovarian cancer of approximately 80% with prophylactic oophorectomy [13, 14]. As for breast surveillance, although MRI is the most sensitive screening option, current evidence supports the benefits of both mammography and breast MRI annually in BRCA mutation carriers [7, 58–61]. Finally, ovarian cancer surveillance remains a challenge and has not been shown to be effective in detecting early stage ovarian cancers [62]. "
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    ABSTRACT: Recognizing the importance of identifying patients at high risk for inherited cancer predisposition, the United States Preventive Services Task Force (USPSTF) has outlined specific family history patterns associated with an increased risk for BRCA mutations. However, national data indicate a need to facilitate the ability of primary care providers to appropriately identify high risk patients. Once a patient is identified as high risk, it is necessary for the patient to undergo a detailed genetics evaluation to generate a differential diagnosis, determine a cost-effective genetic testing strategy, and interpret results of testing. With identification of inherited predisposition, risk management strategies in line with national guidelines can be implemented to improve patient outcomes through cancer risk reduction and early detection. As use of genetic testing increasingly impacts patient outcomes, the role of primary care providers in the identification and care of individuals at high risk for hereditary cancer becomes even more important. Nevertheless it should be acknowledged that primary care providers face many competing demands and challenges to identify high risk patients. Therefore initiatives which promote multidisciplinary and coordinated care, potentially through academic-community partnerships, may provide an opportunity to enhance care of these patients.
    12/2013; 2013:260847. DOI:10.1155/2013/260847
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