Precision Assessment and Delivery of Cancer Risks in BRCA 1/2 Mutation Cancers

项目摘要 在目前的风险评估和咨询实践中，所有检测出a 有害的BRCA 1/2突变与卵巢癌风险的一般范围相同， 在使用降低输卵管风险方面给予相同的建议- 卵巢切除术（RRSO）和其他预防措施。我们最近发布了一个模型 报告了根据具体的 一个女人遗传的突变特别是，我们最近发现， 乳腺癌或卵巢癌的风险增加或发病年龄提前， 对任何BRCA 1/2突变进行一般风险评估。此外，风险评估考虑到 先前暴露于重要的风险因素（例如，生育史，口服避孕药使用，或 预防性手术使用）可能对该人群的癌症风险估计有很大影响。 更准确的风险信息对于以下妇女的最佳决策至关重要： 考虑癌症预防策略。 基于这些初步观察，我们建议开发精确绝对风险 将突变风险组的信息纳入模型，以应用体外方法， 确定新的临床相关BRCA 1/2突变并验证其致病能力， 并更好地了解个人价值观如何影响个体女性对 并根据风险估计采取行动，用于未来的决策辅助干预。因此，该提案将 开发一种针对BRCA 1/2相关癌症风险的“精确预防”方法， 女性死于卵巢癌的可能性，并将对卵巢癌产生直接的转化影响。 BRCA 1/2突变的女性

Project Summary In current risk assessment and counseling practices, all women who test positive for a deleterious BRCA1/2 mutation are quoted the same general range of ovarian cancer risk and are given the same recommendation regarding utilization of risk reducing salpingo- oophorectomy (RRSO) and other preventive measures. We have recently published a model that reports substantial and clinically relevant differences in risk depending on the specific mutation a woman has inherited. In particular, we have recently shown that specific mutations confer an increased risk or earlier age of onset for breast or ovarian cancer compared with the generic risk estimates made for any BRCA1/2 mutation. In addition, risk estimates that consider previous exposure to important risk factors (e.g., reproductive history, oral contraceptive use, or preventive surgery use) may have a large impact on cancer risk estimates in this population. More precise risk information could be critical for optimal decision-making for women who are considering cancer prevention strategies. Based on these initial observations, we propose to develop precision absolute risk models that incorporate information about mutation risk group, to apply in vitro methods to identify new clinically relevant BRCA1/2 mutations and validate their capacity to cause disease, and to gain a better understanding of how personal values affect how individual women interpret and act on risk estimates, for use in a future decision aid intervention. Thus, this proposal will develop a “precision prevention” approach to BRCA1/2-associated cancer risk to lower the chances a woman will die from ovarian cancer, and will have immediate translational impact for women with BRCA1/2 mutations.