Shickh Salma, Mighton Chloe, Clausen Marc, Sam Jordan, Hirjikaka Daena, Reble Emma, Graham Tracy, Panchal Seema, Eisen Andrea, Elser Christine, Schrader Kasmintan A, Baxter Nancy N, Laupacis Andreas, Lerner-Ellis Jordan, Kim Raymond H, Bombard Yvonne
Institute of Health Policy, Management & Evaluation, University of Toronto, Toronto, ON, Canada.
Genomics Health Services Research Program, Li Ka Shing Knowledge Institute of St Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
JCO Precis Oncol. 2024 Dec;8:e2400407. doi: 10.1200/PO-24-00407. Epub 2024 Dec 12.
Genomic sequencing (GS) is increasingly used to improve diagnoses and inform targeted therapies. GS can also be used to identify the 10% of cancer patients with an underlying hereditary cancer syndrome (HCS), who can benefit from surveillance and preventive surgery that reduce morbidity/mortality. However, the evidence on clinical utility of GS for HCS is limited: we aimed to fill this gap by assessing yield of all cancer results and associated recommendations for patients undergoing GS for HCS.
An observational chart review and survey were conducted for cancer patients with previous uninformative cancer gene panel results, who received GS as part of the Incidental Genomics Trial (ClinicalTrials.gov identifier: NCT03597165). Descriptive statistics were used to describe demographics and clinical history. Proportions were calculated to compare frequencies of result types and recommendations made and followed.
A total of 276 patients were eligible and included. Participants were mostly female (n = 240), European (n = 158), and with breast cancer history (n = 168). Yield: 25 patients (9.1%) received ≥1 pathogenic/likely pathogenic variant, 246 (89%) received ≥1 variant of uncertain significance (VUS), and 27 (10%) were negative. Most pathogenic variants (20/26) were in low/moderate cancer risk genes. The mean number of VUS was 2.7/patient and higher in non-Europeans versus Europeans (3.5 2.5, < .05). Recommendations: Pathogenic variants triggered 100 recommendations in 21/25 patients; most were for genetic counseling, communication to relatives, and cascade testing.
GS provided a modest increase in utility after first-tier cancer gene panels, at the cost of a high frequency of uncertain results. Furthermore, most positives were low/moderate cancer risk results that did not have corresponding evidence-based, management guidelines.
基因组测序（GS）越来越多地用于改善诊断并为靶向治疗提供依据。GS还可用于识别10%患有潜在遗传性癌症综合征（HCS）的癌症患者，这些患者可从降低发病率/死亡率的监测和预防性手术中获益。然而，关于GS对HCS临床效用的证据有限：我们旨在通过评估所有癌症检测结果的产出以及为接受HCS-GS检测的患者提供的相关建议来填补这一空白。
对既往癌症基因检测结果无诊断意义、接受GS检测作为偶然基因组学试验（ClinicalTrials.gov标识符：NCT03597165）一部分的癌症患者进行观察性图表回顾和调查。使用描述性统计来描述人口统计学和临床病史。计算比例以比较结果类型的频率以及所给出和遵循的建议。
共有276名患者符合条件并被纳入。参与者大多为女性（n = 240）、欧洲人（n = 158）且有乳腺癌病史（n = 168）。产出：25名患者（9.1%）获得≥1个致病/可能致病变异，246名（89%）获得≥1个意义未明的变异（VUS），27名（10%）检测结果为阴性。大多数致病变异（20/26）存在于低/中度癌症风险基因中。VUS的平均数量为2.7个/患者，非欧洲人高于欧洲人（3.5对2.5，P <.05）。建议：致病变异在21/25名患者中引发了100条建议；大多数建议涉及遗传咨询、告知亲属以及级联检测。
在一线癌症基因检测之后，GS的效用有适度提高，但代价是不确定结果的频率较高。此外，大多数阳性结果是低/中度癌症风险结果，尚无相应的循证管理指南。
