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，靶向遗传风险评估(GRE)在一个家庭中 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 通过预防减少癌症人口负担的方法。然而，有大量的 在遗传性癌症家族中实施成功的级联遗传风险评估面临的挑战 综合症。癌症诊断后GRE的临床背景越来越复杂：就像MGP检测一样 成为标准，指南组织已经聚集在一份&gt；40癌症易感基因清单上，其中 PVS在临床上是可操作的，在癌症威胁方面有很大的变异性，有无数的预防和治疗策略 及早发现。一个令人生畏的挑战是，癌症患者负责沟通和 GRE的亲属订婚。尽管高危亲属(ARR)之间存在共同的健康威胁，但社会 而影响家庭沟通的语境因素也是复杂的。此外，ARR分散在世界各地- 范围广泛，并在不同的医疗保健实践中接受护理。重要的是，几乎没有激励措施，而且是有限的。 临床医生接触癌症患者亲属和遗传咨询服务的资源越来越多 太紧张了。鉴于缺乏对家庭的指导，难怪大多数患有静脉曲张的癌症患者的ARR 不要进行GRE。我们在开发和优化直接遗传给家庭的虚拟遗传风险方面处于独特的地位 最近为以人群为基础的成年人样本的所有高危亲属提供的评估和测试解决方案 在佐治亚州和加利福尼亚州被诊断患有癌症，临床相关的PV检测呈阳性。我们将使用 我们率先开发了独特的数据基础架构，以识别和邀请具有临床症状的不同癌症患者群 相关PVS及其家属参与本研究。我们建议采用2×3因子随机试验，共900例。 2018-2019年在这两个州被诊断患有临床上有意义的PV的患者 将为所有一级和二级亲属提供遗传风险评估和检测的检测。我们将评估 两种干预设计特征对以患者为中心和相对以患者为中心的结果的影响：1) 个性化家庭遗传风险支持(一种技术辅助的个人定制的患者和家庭成员 教育和交流工具，称为家庭遗传健康计划(FGHP)与FGHP+DIRECT 人类FGHP导航器的帮助)；以及2)提供给亲属进行基因测试的价格 (标准200美元对100美元对50美元每个测试)。我们将确定这两个设计的独立效果 特点：1)癌症患者对沟通的评价以及他们与亲属关于 遗传性癌症和GRE；2)受邀亲属对决策和接受基因检测的评价； 3)登记亲属完成正式的GRE考试。我们还将探讨这些功能对以下方面的影响 不同患者SES亚组的结果。这项研究的发现有巨大的改进潜力。 在美国，遗传性癌症综合征高危家庭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.