Abstract A016: Cascade Failure in Lynch Syndrome Diagnosis: A Single-Institution Analysis

Abstract Early-onset colorectal cancer (EOCRC) and endometrial cancer (EC) are defining malignancies for Lynch syndrome (LS). Universal tumor screening with mismatch repair (MMR) immunohistochemistry (IHC) is now standard practice in these malignancies. Despite this, many patients still fail to complete genetic testing after abnormal MMR results. We reviewed deidentified data from 772 patients with CRC (n=565) and EC (n=207) from the Emory Lynch Syndrome Screening Network (LSSN) database (2013 to 2023). We evaluated age specific cascade performance and COVID-19 era changes. All patients underwent IHC for MLH1, MSH2, MSH6, and PMS2, with reflex BRAF V600E and MLH1 methylation testing performed as indicated. Outcomes included deficient MMR (dMMR) rates, germline testing referral, germline testing completion, and pathogenic variant detection by age (50 vs ≥50 years) and COVID era (pre-2020 vs ≥2020). Among 119 EOCRC cases, IHC completion was 99% (99/100) with dMMR identified in 15% (15/99). For early-onset EC (n=19), IHC completion was 100% with dMMR in 21% (4/19). For CRC, dMMR rates increased from 12% (59/482) pre-COVID to 51% (41/80) post-COVID. This is likely due to case selection bias post COVID rather than true biologic shifts. EOCRC patients with dMMR had better cascade completion compared to older patients. Referral rates for germline testing were 73% (11/15) in EOCRC vs 17% (14/83) in older patients and germline testing 53% (8/15) in EOCRC vs 11% (9/83) in older patients. Pathogenic variants were detected in 63% (5/8) of tested EOCRC patients vs 44. 4% (4/9) of older patients. Post COVID, CRC referrals increased to 36. 6% vs 20. 3% pre-COVID, but testing completion was largely unchanged (22% vs 17%). Among early-onset EC patients with dMMR, 75% (3/4) completed testing with no pathogenic variants identified. In contrast, older EC patients had 20% (15/74) referral rate and 8% (6/74) completed germline testing with no pathogenic findings. Overall, 84. 4% (151 of 179) of dMMR patients across groups never completed germline testing. This is a major implementation gap given the high pathogenic yield among those tested. Systematic interventions are urgently needed to address cascade failures and ensure universal genetic evaluation for all dMMR patients. Citation Format: Gideon T. Dosunmu, Fabienne Ehivet, LePaige R. Godfrey, Hasiya E. Yusuf, Kim Nguyen, Mosunmoluwa Oyenuga, Oluwadunni E. Emiloju, Lindsay Hannan, Patrick S. Sullivan, Christine Stanislaw, Olatunji Alese. Cascade Failure in Lynch Syndrome Diagnosis: A Single-Institution Analysis abstract. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31 (23Suppl): Abstract nr A016.