Germline Cancer Predisposition Results From The National Cancer Institute - Children'S Oncology Group (Nci-Cog) Pediatric Match Trial.

Abstract Background: Although genomic changes identified by clinical tumor sequencing may be present in the germline, precision oncology trials have generally not incorporated germline testing and reporting. We describe our experience with clinical reporting of matched tumor and germline results from the NCI-COG Pediatric Molecular Analysis for Therapy Choice (MATCH) trial (NCT03155620). Design/Method: Patients age 1 to 21 years old with treatment-refractory solid tumors, non-Hodgkin lymphomas, or histiocytic disorders were eligible. DNA and RNA extracted from FFPE tumors were sequenced using Oncomine Assay v.3 with reporting of potentially actionable fusions, amplifications, and mutations, including loss of function variants in tumor suppressor genes. Germline reporting focused on 36 genes from the same DNA panel that convey adult or pediatric cancer susceptibility but does not include all cancer susceptibility genes (e.g. APC, DICER1). Deletions and splice site variants were not reported. Results: As of June 2020, 1009 patients had been enrolled from 132 COG sites, with tumor and germline testing complete for 868 patients to date. Overall, 62 (7.1%) germline reports included a pathogenic or likely pathogenic germline variant (termed germline findings) in 18 cancer susceptibility genes. This frequency was similar in patients with solid tumors (46/633, 7.3%), CNS tumors (14/204, 6.9%), and lymphomas/histiocytoses (2/31, 6.5%). Variant(s) of potential germline significance were identified in 25% of tumor reports; of these, 74% (163/221) had no germline findings. The proportion of germline findings for genes with >10 reported tumor variants varied: 32% (7/22) in NF1, 25% (3/12) in RB1, 16% (17/108) in TP53 and 0% in ALK (0/21) and PTEN (0/12). Of note, 82% (14/17) of tumor variants in breast cancer susceptibility genes (BRCA1/2, CHEK2 and PALB2) had germline findings. On study intake forms, 25% of patients with germline findings had a “known genetic disease” reported. Oncologists caring for patients with a germline finding were then queried about prior knowledge of a genetic diagnosis. Of 24 respondents, 13 (54%) reported no prior molecular diagnosis of the identified condition. Conclusions: Coordinated germline and tumor testing revealed clinically relevant cancer susceptibility variants across a spectrum of genes in 7% of pediatric patients with treatment-refractory cancers. This is likely an underestimate of germline findings given test limitations. The parallel tumor/normal reporting approach minimized the need for targeted reflex genetic testing in 19% of study participants and provided new information on cancer susceptibility in germline positive patients to half of the responding oncologists. The NCI-COG Pediatric MATCH trial reporting process can serve as a model for precision oncology trials and clinical tumor profiling. Citation Format: Sarah Scollon, Sharon E. Plon, Steven Joffe, Jaclyn A. Biegel, Shashikant Kulkarni, George Miles, David Patton, Brent Coffey, Paul M. Williams, Gregory J. Tsongalis, Mark J. Routbort, Julie M. Gastier-Foster, Lauren Saguilig, Jin Piao, Todd A. Alonzo, Katherine A. Janeway, Peter C. Adamson, Margaret Mooney, James V. Tricoli, Nita L. Seibel, Donald W. Parsons. Germline cancer predisposition results from the National Cancer Institute - Children's Oncology Group (NCI-COG) Pediatric MATCH Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 631.