Upfront Multigene Panel Testing for Cancer Susceptibility in Newly Diagnosed Endometrial Cancer Patients: A Prospective Cohort Study

Background: Lynch syndrome (LS) is the most common cause of hereditary endometrial cancer (EC). Screening EC patients for LS varies by institution and current strategies employ tumor testing and/or family history approaches. Ultimately a LS diagnosis is made by genetic testing. In this study, we evaluated upfront multi-gene panel testing (MGPT) in unselected ECs for improved identification of LS and to determine the frequency of pathogenic variants (PVs) in other cancer susceptibility genes (CSGs).  Methods: EC patients were prospectively enrolled at nine Ohio institutions, 10/1/2017 - 12/31/2020. All patients had clinical germline testing for forty-seven CSGs. Mismatch repair (MMR) immunohistochemistry (IHC), MLH1 methylation and clinicopathologic data were abstracted from patients’ records. Detailed family history data were obtained for all subjects.  Findings: 29 of 961 EC patients (3·1%, 95% CI 2·1 – 4·3%) were found to have LS. PMS2 PVs were most frequent (11/29), followed by MSH6 (10/29), MSH2 (6/29), and  MLH1 (2/29). Tumor IHC was concordant for all MLH1 and  MSH2, and 9/10 MSH6 heterozygotes. For  PMS2, tumor IHC and germline status concordance was 80% and family history was not predictive of LS. An additional 68 (7·1%) women had likely pathogenic (LP) or PVs in 16 other CSGs. Twenty-one patients had LP/PVs in high penetrance CSGs. Of note, 10 patients (1·04%) had PVs in BRCA1 or BRCA2, with a significant excess of type-II ECs among  BRCA heterozygotes.    Interpretation: Prospective MGPT in a large, unselected EC cohort revealed that a majority of LS diagnoses are attributable to low-penetrance genes. MGPT substantially increased LS diagnoses by capturing patients who had equivocal IHC findings or for whom tumor screening was not performed. The finding that 97/961 (10%) women in this cohort have actionable CSG variants supports a role for upfront MGPT for all women with EC.  Funding: This research was funded by an Ohio State University James Comprehensive Cancer Center Statewide Pelotonia Cancer Impact Award. Declaration of Interest: HH is on the scientific advisory boards for Invitae Genetics, Promega, and Genome Medical. HH has stock/stock options in Genome Medical and GI OnDemand, outside of the submitted work. DC is a COVID response consultant for Kane Logistics, he receives honoraria as Deputy Editor of Gynecologic Oncology and as an author for Up to Date, and he also holds patents: 1) “MicroRNA-based methods and compositions for the diagnosis, prognosis and treatment of ovarian cancer using a real-time PCR platform” Patent number 9,499,869 B2, issued November 22, 2016 Cohn DE, Alder HJ, Croce C, Resnick KE; 2) “Chimeric VEGF peptides” Patent number 8,080,253 B2, issued December 20, 2011 Kaumaya PTP, Cohn DE, all outside of the submitted work. JMs wife is employed by Pfizer Inc. JN declares consulting roles for AstraZeneca, Curio, and Clovis Oncology; speakers’ bureau for Clovis oncology and Merck; and has received a research grant from Zodus Medical Inc, all outside of the submitted work. CB has received honoraria as a speaker for OncLive and for an oral boards review course by Perinatal services, outside of the submitted work. SS reports speakers’ bureaus for AstraZeneca and Merck, outside of the submitted work. KR’s partner is SS with previously listed disclosures. PJG received an award from Promega, outside of the submitted work. MDL, RP, CC, AC, AS, DB, SW, SA, EJ, AC, and RN declare no competing interests. Ethical Approval: The study was approved by the Institutional Review Boards (IRBs) at each participating center with OSU serving as IRB of record.