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Background: Genomic profiling through paired tumor/non-tumor analysis can identify pathogenic germline variants (PGV) responsible for inherited cancer syndromes. This can benefit patients and their relatives through cascade testing (CT), preventing many cancer-related deaths. We explored the impact of this strategy for tumor profiling on cancer syndrome diagnosis. Methods: The Tumor Profiling Lab (TPL) sequences cancer specimens and matched normal tissue using the Oncomine Comprehensive Assay (ThermoFisher). A protocol was implemented between the TPL and the Cancer Genetics and Prevention Program (CGPP) by which a notification was sent to oncologists and the CGPP when a PGV was identified. The notification highlights the finding and facilitates referral to CGPP. Our analysis includes data from 1/2018 to 7/2021. Primary outcome: identification of PGV. Secondary outcomes: patients referred and seen by CGPP, and advised for CT. Results: A total of 123 (6.35%) patients with over 20 cancer types had a PGV; for 85 (69.1%) this was a new finding. 36 of the 85 (42.4%) were referred to CGPP and of those, 24 (66.7%) were seen and advised for CT. 4 patients with newly diagnosed PGV had already been seen by CGPP, but either had not undergone genetic testing or had not been tested for the gene in which a PGV was later found. Of the 123 patients with PGV, 74 were not seen by CGPP. 33 (44%) were advised by their oncologist regarding CT for relatives. In total, among patients with newly diagnosed PGV, 51 (60%) were advised for CT. Conclusion: 2/3 of cancer patients in whom paired tumor/normal sequencing analysis identified a PGV had not been previously diagnosed with an inherited cancer syndrome by standard of care approaches. Identification of a PGV resulted in CT advice for 60% of these patients, with hundreds of family members potentially benefitting from preventive measures. Creating more streamlined systems for notifying relatives can result even in greater benefit by reaching more individuals. Baseline demographics Table 1 N = 123 Age at tumor testing, mean (range) 60.4 (10-90) Gender, n (%) Female 62 (50.4) Male 61 (49.6) Stage at tumor testing, n (%) Stage IV 103 (83.7) Stage I-III 20 (16.3) Known PGV, n (%) Known 38 (30.9) New 85 (69.1) Referral to CGPP, n (%) Referred 37 (30.1) Not Referred 61 (49.6) N/A (known to a cancer genetics program*) 25 (20.3) *22 known to CGPP; 3 known to outside programs Seen by CGPP, n (%) Seen 49 (39.8) Not Seen 74 (60.2) Days from referral to visit, median (range) 17 (1-217) Advised for CT (including seen by CGPP)**, n (%) Advised 81 (65.9) Not advised 42 (34.1) ** One patient seen before tumor testing; no identifiable mutation at that visit. After testing, new PGV found, but was not counseled on it. Advised for CT (if not seen by CGPP), n (%) N = 75 Advised 33 (44.0) Not advised 42 (56.0) Citation Format: Christina N. Dimopoulos, Karina Brierley, Joanna Gibson, Zenta Walther, Xavier Llor. Paired tumor/normal clinical sequencing enables identification of patients with pathogenic germline variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5897.

Background: Lynch syndrome (LS) affects 1/279 individuals and accounts for 3-5% of all colorectal cancers (CRC). LS is due to germline mutations in mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. Tumors exhibit MMR deficiency, expressed as loss of MMR protein expression on immunohistochemistry (IHC). A subset of sporadic tumors also has MMR deficiency due to inactivation of MLH1 via promoter methylation and about 2/3 have BRAFV600E mutations. Increased surveillance and chemoprevention reduce cancer incidence and mortality in LS. LS is largely underdiagnosed, particularly among minorities. Universal screening of CRC tumors through IHC is recommended in order to help identify patients for LS genetic testing. Nevertheless, even in programs that have implemented this, minority patients with MMR deficient tumors were found to be consistently under-referred mostly due to referral bias. We set up a strategy to increase LS and tackle disparities in cancer genetics (CG). Methods: This study reports on the analysis of universal CRC IHC testing for MMR expression, initially followed by BRAF V600E and later by MLH1 testing for loss of MLH1/PMS2 expression, from implementation (1/1012) until 1/1021. In 6/2015, a system was established where a designated Pathologist reviewed all results and a list of identified candidates for germline LS testing (abnormal MMR expression/wild type BRAF or methylation of MLH1) was sent to the CG program. After a two-week period, if no referral had been placed, a genetic counselor (GC) messaged the provider requesting a referral. The pathology side was fully automated in 9/2018 through the monitoring engine Repetitive Tasks Scheduling Engine (RTSE) that pulls data stored in the underlying relational database-Adaptive Server Enterprise, which is accessible to RTSE via a Java Database Connectivity API. This process automatically generates weekly emails that report all cases with suspicion criteria for LS to CG. Results: Since 1-2012, 1,433 patients with CRC underwent tumor testing and were included in this study: 78.5% non-Hispanic white (NHW); 12.2% African American (AA); 6.77% Hispanic (H). Prior to the interventions 25% of eligible patients were referred to CG and none among AA. Once the interventions were established, appropriate referrals prior to messaging the provider were 39.5% for NHW, 35.7% for AA, and 42.8% for H. As a result of the messages, referral rates increased to 80.5% (p=0.00) in NHW, 85.7% in AA (p=0.05), and 71.5% in H (ns). The total number of patients diagnosed with LS since universal testing started was 19: 2 prior to the interventions (0.8% of all CRC); 17 during the interventions (1.5% of all CRC). Conclusion: A systematic, automated, multi-system approach, that includes a targeted message to providers can double the number of appropriate referrals for genetic testing to rule out Lynch syndrome and resulted in almost twice the percentage of LS diagnosis with equal success among AA, H, and NHW. Citation Format: Vinit Singh, Amanda Ganzak, Peter Gershkovich, Joanna Gibson, Rosa M. Xicola, Xavier Llor. A multisystem approach doubles the number of patients referred for genetic testing and diagnosed with Lynch syndrome with equally success among ethnic/racial groups [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-052.