A population-based virtual solution to reduce gaps in genetic risk evaluation and management in families at high risk for hereditary cancer syndromes: The Georgia-California GeneLINK Trial

项目摘要：越来越多的证据表明，针对遗传风险评估（GRE）的家庭， 癌症易感基因致病变异体（PV）已被确定可能是最具成本效益的 通过预防减少癌症对人口的负担。然而， 在遗传性癌症家族中成功实施级联遗传风险评估的挑战 综合征癌症诊断后GRE的临床背景越来越复杂：由于MGP测试 成为常态，指南组织已经聚集在一个>40个癌症易感基因的列表上，其中 PV在临床上是可行的，在癌症威胁和无数的预防和治疗策略中具有广泛的可变性。 早期检测一个令人生畏的挑战是，癌症患者负责沟通， 亲戚亲戚尽管风险亲属（ARR）之间存在共同的健康威胁， 影响家庭沟通的情境因素复杂。此外，ARR是分散的世界- 在不同的医疗保健实践中广泛接受护理。重要的是，激励措施很少， 临床医生与癌症患者亲属和遗传咨询服务的资源越来越多， 紧张由于缺乏对家庭的指导，这并不奇怪，大多数癌症患者的肺静脉ARR 不要参加GRE考试。我们在开发和优化直接面向家庭的虚拟遗传风险方面具有独特的优势 评估和测试解决方案提供给所有的风险亲属的人口为基础的样本的成年人最近 在格鲁吉亚和加州被诊断为癌症，临床相关PV检测呈阳性。我们将使用一个 我们开创了独特的数据基础设施，以识别和邀请具有临床症状的不同癌症患者群体。 相关PV及其家属参与我们的研究。我们提出了一个2 × 3析因随机试验的900 2018-2019年在这两个州诊断的患者，通过遗传学方法检测到临床显著PV 测试，将提供遗传风险评估和测试，所有第一和第二学位的亲属。我们将评估 两种干预设计特征对以患者和亲属为中心的结局的影响：1） 个性化的家庭遗传风险支持（一种技术辅助的个人定制的患者和家庭成员 名为家庭遗传健康计划（FGHP）的教育和沟通工具）与FGHP加直接 人类FGHP导航员的帮助）;以及2）提供给亲属进行基因测试的价格 （标准$200 vs. $100 vs. $50每次测试）。我们将确定这两种设计的独立效果 1）癌症患者对沟通的评价以及他们与亲属的接触， 遗传性癌症和GRE; 2）被邀请的亲属对基因检测决策和接受的评估; 3）在注册的亲属完成正式的GRE。我们还将探讨这些功能对 患者SES亚组的结局。这项研究的结果有巨大的潜力，以改善 在美国遗传性癌症综合征高风险家庭中的癌症预防和早期发现。

Project Abstract: There is growing evidence that targeting genetic risk evaluation (GRE) in families where a cancer susceptibility gene pathogenic variant (PV) has been identified may be the most cost-effective approach to reduce the population burden of cancer through prevention. However, there are enormous challenges to implementing successful cascade genetic risk evaluation in families with hereditary cancer syndromes. The clinical context of GRE after cancer diagnosis is increasingly complex: As MGP testing has become the norm, guideline organizations have converged on a list of >40 cancer susceptibility genes in which PVs are clinically actionable, with wide variability in cancer threat and a myriad of strategies for prevention and early detection. A daunting challenge is that the cancer patient is responsible for communication and engagement of relatives for GRE. Despite the shared health threat among at risk relatives (ARRs), the social and contextual factors that affect family communication are complex. Furthermore, ARRs are dispersed world- wide and receive care in disparate health care practices. Importantly, there is little incentive and limited resources for clinicians to engage cancer patients’ relatives and genetic counseling services are increasingly strained. Given the lack of guidance for families, it is not surprising that most ARRs of cancer patients with PVs do not undergo GRE. We are uniquely positioned to develop and optimize a direct-to-family virtual genetic risk evaluation and testing solution offered to all at risk relatives of a population-based sample of adults recently diagnosed with cancer in Georgia and California who tested positive for a clinically relevant PV. We will use a unique data infrastructure we pioneered to identify and invite a diverse cohort of cancer patients with clinically relevant PVs and their families to participate in our study. We propose a 2 x 3 factorial randomized trial of 900 patients diagnosed in 2018-2019 in the two states who had a clinically significant PV detected by genetic testing that will offer genetic risk evaluation and testing to all 1st and 2nd degree relatives. We will evaluate the effects of two intervention design features on patient- and relative-centered outcomes: 1) the level of personalized family genetic risk support (a technology assisted personally tailored patient and family member education and communication tool called the Family Genetic Health Program, FGHP) vs. the FGHP plus direct assistance from a human FGHP Navigator); and 2) the price offered to the relatives for the genetic test (standard $200 vs. $100 vs. $50 per test). We will determine the independent effects of the two design features on 1) the cancer patient’s appraisal of communication and their engagement with relatives about hereditary cancer and GRE; 2) the invited relative’s appraisal of decision-making and receipt of genetic testing; and 3) on the enrolled relative’s completion of formal GRE. We will also explore the effect of the features on the outcomes across patient SES subgroups. The findings of this study have enormous potential to improve cancer prevention and early detection in families at high risk of hereditary cancer syndromes in the US.