Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
University of Maryland, College Park.
JAMA Netw Open. 2022 Nov 1;5(11):e2242370. doi: 10.1001/jamanetworkopen.2022.42370.
The recent successes of poly-ADP ribose polymerase (PARP) inhibitors and belzutifan support germline genetic data as an exciting, accessible source for biomarkers in cancer treatment. This study hypothesizes, however, that most oncology clinical trials using germline data largely prioritize BRCA1/2 as biomarkers and PARP inhibitors as therapy.
To characterize past and ongoing oncology trials that use germline data.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study of oncology trials used the Informa Trialtrove database to evaluate trial attributes. Trials using germline information (including the terms germline, hereditary, or inherited in the title, treatment plan, interventions, end points, objectives, results, or notes) and conducted globally between December 1, 1990, and April 4, 2022 (data freeze date), were included.
Trials by cancer type, phase, participants, sponsor type, end points, outcomes, and locations were described. Associated biomarkers and mechanisms of action for studied therapeutic interventions were counted. How germline data in trial inclusion and exclusion criteria are associated with end points, outcomes, and enrollment were also examined.
A total of 887 of 84 297 (1.1%) oncology clinical trials in the Trialtrove database that use germline data were identified. Most trials were conducted in cancer types where PARP inhibitors are already approved. A total of 74.8% (672) of trials were performed in the phase 2 setting or above. Trials were primarily sponsored by industry (523 trials [59.0%]), academia (382 trials [43.1%]), and the government (274 trials [30.9%]), where trials may have multiple sponsor types. Among 343 trials using germline data with outcomes in Trialtrove, 180 (52.5%) reported meeting primary end points. Although BRCA1/2 are the most frequent biomarkers seen (BRCA1, 224 trials [25.3%]; BRCA2, 228 trials [25.7%]), trials also examine pharmacogenomic variants and germline mediators of somatic biomarkers. PARP inhibitors or immunotherapy were tested in 69.9% of trials; PARP inhibition was the most frequently studied mechanism (367 trials [41.4%]). An overwhelming number of trials using germline data were conducted in the US, Canada, and Europe vs other countries, mirroring disparities in cancer genetics data. Germline data in inclusion and exclusion criteria are associated with altered end point, outcomes, and enrollment compared with oncology trials with no germline data use. Examples of inclusion and exclusion criteria regarding germline data that may unintentionally exclude patients were identified.
These findings suggest that for germline biomarkers to gain clinical relevance, trials must expand biomarkers, therapies, and populations under study.
聚 ADP 核糖聚合酶 (PARP) 抑制剂和贝鲁替尼的最近成功支持将种系遗传数据作为癌症治疗中生物标志物的一个令人兴奋且易于获取的来源。然而，本研究假设，使用种系数据的大多数肿瘤学临床试验主要将 BRCA1/2 作为生物标志物，并将 PARP 抑制剂作为治疗方法。
描述过去和正在进行的使用种系数据的肿瘤学试验。
设计、设置和参与者：本研究使用 Informa Trialtrove 数据库对肿瘤学试验进行回顾性横断面研究，以评估试验属性。纳入了使用种系信息（标题、治疗计划、干预措施、终点、目标、结果或注释中包含术语“种系”、“遗传性”或“遗传”）且在全球范围内进行的试验（包括美国、加拿大和欧洲），时间为 1990 年 12 月 1 日至 2022 年 4 月 4 日（数据冻结日期）。
描述了按癌症类型、阶段、参与者、赞助商类型、终点、结果和地点进行的试验。还计算了研究治疗干预措施的相关生物标志物和作用机制。还研究了试验纳入和排除标准中种系数据与终点、结果和入组的关联。
在 Trialtrove 数据库中，共确定了 887 项（1.1%）使用种系数据的肿瘤学临床试验。大多数试验都在已经批准 PARP 抑制剂的癌症类型中进行。共有 74.8%（672 项）的试验在 2 期或更高阶段进行。试验主要由行业（523 项试验[59.0%]）、学术机构（382 项试验[43.1%]）和政府（274 项试验[30.9%]）赞助，其中试验可能有多种赞助类型。在 343 项有 Trialtrove 结局的使用种系数据的试验中，有 180 项（52.5%）报告达到了主要终点。尽管 BRCA1/2 是最常见的生物标志物（BRCA1，224 项试验[25.3%]；BRCA2，228 项试验[25.7%]），但试验还研究了药物基因组学变异和种系介导的体细胞生物标志物。69.9%的试验检测了 PARP 抑制剂或免疫疗法；PARP 抑制是研究最多的机制（367 项试验[41.4%]）。使用种系数据的试验绝大多数都在美国、加拿大和欧洲进行，而在其他国家进行的试验较少，这反映了癌症遗传学数据的差异。与未使用种系数据的肿瘤学试验相比，纳入和排除标准中的种系数据与改变的终点、结果和入组相关。确定了与种系数据相关的纳入和排除标准的示例，这些标准可能会无意中排除患者。
这些发现表明，为了使种系生物标志物具有临床相关性，试验必须扩大生物标志物、治疗方法和研究人群。
