Esplin, Edward D.

e16783 Background: PARP inhibitor (PARPi) treatment was recently approved for pancreatic cancer (PaCa) patients with germline mutations in 2 DNA damage repair (DDR) genes. Despite criteria recommending germline multigene panel testing for all PaCa patients, barriers to testing remain, including among underserved populations, which limit access to precision therapies. We initiated a sponsored testing program that increases access to germline genetic testing for PaCa in two ways: 1) offering a comprehensive multigene panel, and 2) removing the barrier of cost. Here we present initial results from this program, including the diagnostic yield in patients across stages of PaCa and clinical utility of the findings. Methods: We retrospectively analyzed de-identified data from 966 PaCa patients tested on an 84 gene panel as part of the program to date. The only inclusion criterion was a willingness to participate in the sponsored program by the patient and the provider who ordered the testing. Data included likely pathogenic (LP) and pathogenic (P) mutations, disease stage and ethnicity. Results: In total, 166 (17%) patients were positive for P/LP germline mutations in 30 genes. Mutation rate by ethnicity was: Caucasian 17%, African American 12%, Hispanic 16%, Ashkenazi Jewish 20%, Asian 3%. Only 25% of patients with P/LP variants reported a family history of cancer. There was no statistical difference in mutation rates by stage (p = 0.11) [Table]. In positive patients, 83 (78%) had mutations conferring potential eligibility for DDR gene-specific precision therapies or clinical treatment trials. 28 (26%) were potentially eligible for olaparib due to BRCA1/2 mutations, 8 (7%) were potentially eligible for pembrolizumab, and 47 (44%) for PARPi clinical trials. Conclusions: This study found 8.5% of all PaCa patients tested are potentially eligible for germline-based precision therapies and/or clinical treatment trials. Of mutation positive patients, 75% did not report a family history of cancer. The positive rate was not statistically different between patients with stage I and stage IV PaCa, underscoring the recommendation to test all patients with PaCa. This program had a 1.5% increased relative uptake among African American patients compared to a standard insurance reimbursement delivery model. These data suggest reducing barriers improves PaCa patient access to genetic information that enables precision therapy. [Table: see text]

236 Background: Hepatobiliary cancer (HBC), including cholangiocarcinoma, affects over 40,000 people in the U.S. each year, and results in over 30,000 cancer deaths annually. Despite continuing advances in next-generation sequencing (NGS), the understanding of germline genetic risk as it relates to these malignancies remains limited, and guidelines for the germline testing of these patients are lacking. We report the spectrum of pathogenic/likely pathogenic (P/LP) germline genetic variants observed in patients with HBC, and the clinical utility related to germline genetic test results. Methods: We retrospectively studied a consecutive series of 267 patients referred to Invitae for germline genetic testing based on a personal history of HBC, per an IRB approved protocol. Patients were evaluated with a multigene panel of up to 135 genes chosen by the ordering providers. De-identified clinical and family history information were reviewed as provided by clinicians. Results: Among 267 HBC patients 15% (n = 41) had P/LP variants identified in genes including MUTYH, ATM, CHEK2, BAP1, BRCA1, MLH1, BRCA2, PALB2, TP53, APC, CDH1, MSH6, and PMS2 (12% excluding MUTYH heterozygotes). Amongst patients with a family history (FH) of HBC, P/LP rate was 13%; for patients with a FH of cancers other than HBC, P/LP rate was 16%; for patients with no reported FH, P/LP rate was 13%. Conclusions: In this study, 15% of HBC patients had P/LP variants in cancer-risk genes. The clinical utility of these germline P/LP variants includes 32% of patients who were eligible for ongoing clinical treatment trials based on their germline test results (NCT02286687), 60% with clinical management recommendations per current NCCN guidelines, and cascade testing of at risk family members. These data justify comprehensive germline multigene panel testing in all HBC patients, in view of the potential impact on clinical management for a substantial fraction of positive patients as well as facilitating cascade testing for risk assessment of family members.