Returning genetic research panel results for breast cancer susceptibility

描述（由申请人提供）：癌症易感性（例如BRCA 1/2）的遗传筛查已成为癌症预防的标准循证实践，并已证明可降低乳腺癌发病率和死亡率。然而，大多数被怀疑具有遗传易感性的个体和家庭并没有BRCA 1/2突变。采用下一代测序的研究表明，其他基因（如PALB 2、CHEK 2和ATM）的突变与乳腺癌风险升高有关。因此，已经开发了多重面板，以有效地同时筛选大量基因，包括具有不同突变率和癌症谱的基因，并对知情同意和遗传咨询提出了挑战。尽管没有明确的证据表明这些基因中的许多基因具有临床实用性，但这些基因组现在可商购获得并越来越多地使用。随着使用库DNA的大型前瞻性队列研究越来越多地用于评估基因、环境和生活方式的影响，人们一直在争论是否有义务与研究参与者分享个人研究结果（IRR）。作为多重检测板， 乳腺癌的易感性表明，一些遗传研究结果将与健康结果和/或可用于临床测试。然而，随着这些测试在临床上的应用，是否、如何、何时以及应该向研究参与者返回哪些信息还没有达成共识。此外，归还内部回报率的相关费用尚不清楚，谁应承担这些活动的费用也没有解决。拟议的纵向多中心研究的总体目标是评估以下方面的风险、获益、效用和成本： 将乳腺癌易感性的多重遗传研究结果返回给地理和社会人口统计学上不同的研究人群。我们的理论模型基于健康行为的自我调节理论，旨在为选择短期和纵向结果以及这些结果的潜在中介者和调节者提供信息，以告知关于返回IRR的风险，益处和效用的辩论。此外，我们包括一个扩大的概念化的“实际”效用的基因组测试结果。在目标1中，我们将评估研究参与者对IRR的吸收（目标1a），以及与吸收相关的因素（目标1b）。在目标2中，我们将评估短期（目标2a）和纵向（目标2b）风险和获益（即患者对基因组治疗的理解、反应、使用和感知效用）。 返回多重基因研究结果的信息）。我们还将评估这些结局的调节因素（例如，IRR的回报或多或少有益的亚组）。同样重要的是，我们将研究短期和纵向参与者成本，研究团队成本和医疗保健利用率和成本与回报或IRR（目标3a）和这些成本的调节因素（目标3b）。我们希望这项研究能够为正在进行的辩论提供信息，并最终为个人基因组研究结果的回报提供基于证据的指导方针。

DESCRIPTION (provided by applicant): Genetic screening for cancer susceptibility (e.g. BRCA1/2) has become a standard evidence-based practice in cancer prevention and has proven to reduce breast cancer morbidity and mortality. Yet, most individuals and families in whom genetic susceptibility is suspected do not have a BRCA1/2 mutation. Research employing next generation sequencing has revealed that mutations in other genes, such as PALB2, CHEK2 and ATM are associated with elevated risks of breast cancer. Thus, multiplex panels have been developed to efficiently screen a large number of genes simultaneously, including genes of varied penetrance and cancer spectrum and presenting challenges to informed consent and genetic counseling. Despite no clear evidence of clinical utility for many of these genes, these gene panels are now commercially available and increasingly utilized. As large prospective cohort studies with banked DNA have become increasingly utilized to evaluate the effects of genes, the environment and lifestyle, there has been debate over the obligations, if any, to share individual research results (IRR) with research participants. As multiplex panels for breast cancer susceptibility illustrate, some genetic research findings will be associated with health outcomes and/or become available for clinical testing. Yet, there is no consensus on if, how, when and what information should be returned to research participants as these tests become clinically available. Further, the associated costs of returning IRR are unknown, and who should bear the costs of these activities has not been resolved. The overall goal of the proposed longitudinal multi-center study is to evaluate the risks, benefits, utilities and costs of returning multiplex genetic research results for breast cancer susceptibility to geographically and sociodemographically diverse research populations. Our theoretical model grounded in the Self- Regulation Theory of Health Behavior was developed to inform the selection of the short-term and longitudinal outcomes and potential mediators and moderators of these outcomes to inform the debate over risks, benefits and utility of returning IRR. Additionally, we include a broadened conceptualization of the "actual" utility of genomic test results. In Aim 1, we will evaluate uptake of IRR among research participants (Aim 1a), and factors associated with uptake (Aim 1b). In Aim 2, we will evaluate the short-term (Aim 2a) and longitudinal (Aim 2b) risks and benefits (i.e. patients understanding, reactions to, use and perceived utility of genomic information) of returning multiplex genetic research results. We will also evaluate the moderators of these outcomes (e.g. subgroups for whom the return of IRR is more or less beneficial). Equally important we will examine the short-term and longitudinal participant costs, research team costs and medical care utilization and costs with return or IRR (Aim 3a) and moderators of these costs (Aim 3b). We expect this research to inform the ongoing debate and ultimately evidence based guidelines for return of individual genomic research results.