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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Available from: Allison W Kurian
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    • "For women with HBOC, options for managing cancer risk present important and sometimes difficult decisions beginning in young adulthood regarding enhanced cancer screening, chemoprevention, and/or preventive surgeries ( " Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement, King et al. 2003; " NCCN Guidelines Version 1.2014: Breast and/or Ovarian Cancer Genetic Assessment, " 2014). The most widely used clinical management guidelines are those of the National Comprehensive Cancer Network, ( " NCCN Guidelines Version 1.2014: Hereditary Breast and/or Ovarian Cancer Syndrome, " 2014) briefly summarized below: Data from academic medical centers around the world show that these recommended strategies for risk reduction and early detection among high risk women can be effective in reducing cancer incidence and stage at diagnosis and, in the case of oophorectomy, can improve cancer-specific and overall survival, especially if offered prior to any cancer diagnosis (Croshaw et al. 2011; Kurian et al. 2010; Rebbeck et al. 2009). These data and increased awareness have resulted in dramatic increases in genetic testing for the two genes, BRCA1 and BRCA2, that have been found to account for a large percentage of HBOC (DeStefano et al. 2008). "
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    ABSTRACT: Research to date regarding identification and management of hereditary breast and ovarian cancer syndrome (HBOC) in the U.S. has been confined primarily to academic center-based studies with limited patient engagement. To begin to understand and address the current gaps and disparities in delivery of services for the appropriate identification and optimal risk management of individuals with HBOC, we designed and have initiated the American BRCA Outcomes and Utilization of Testing (ABOUT) Study. ABOUT relies on a collaborative patient advocacy, academic and industry partnership to recruit and engage U.S. individuals who are at increased risk for HBOC and investigate their experiences, decisions and outcomes. It utilizes an extensive research infrastructure, including an interactive web-based data system and electronic interfaces for secure online participation and automated data exchange. We describe the novel recruitment approach that was designed for collaboration with a national commercial health plan partner to identify all individuals for whom a healthcare provider orders a BRCA test and mail to each individual an invitation to participate and study packet. The study packet contains detailed information about the study, a baseline questionnaire and informed consent for participation in the study, for release of relevant medical and health plan records and for ongoing research engagement. This approach employs patient-reported, laboratory-reported and health plan-reported outcomes and facilitates longitudinal engagement. We believe that the type of innovative methodology and collaborative framework we have developed for ABOUT is an ideal foundation for a patient-powered research network. This approach can make substantial contributions to identifying current and best practices in HBOC, leading to improved strategies for clinical care and optimal health outcomes among individuals with high inherited risk for cancer.
    Full-text · Article · Sep 2014 · Journal of Genetic Counseling
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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.
    Full-text · Article · Apr 2014
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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.
    Full-text · Article · Jan 2014 · Breast Cancer Research and Treatment
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