Feasibility of a novel oncologist-led diagnostic algorithm for Lynch syndrome in colorectal cancer patients: The ItaLynch study.

10618 Background: International guidelines recommend universal Lynch syndrome (LS) screening in colorectal cancer (CRC) using tumor mismatch repair deficiency (dMMR) testing. However, LS remains underdiagnosed worldwide, largely due to inconsistent referral for genetic counseling and germline testing. We report the final feasibility results of a novel, mainstreamed, oncologist-led diagnostic algorithm for LS. Methods: ItaLynch is a prospective, observational, multicenter Italian study on patients with dMMR CRC (May 2021–Dec 2025; 23 high-volume centers). The pathway includes: (1) universal dMMR screening by immunohistochemistry (IHC) in all CRC; (2) reflex testing and “Lynch alert”: MLH1-deficient (dMLH1) tumors undergo BRAFV600E testing and, if wild-type, MLH1 promoter methylation; a Lynch alert is added to all dMMR pathology reports (positive for high LS risk based on reflex testing or non-MLH1 loss; negative for BRAFV600E-mutated or MLH1-hypermethylated cases); (3) oncologist-led mainstream germline testing for patients with positive alert, followed by post-test genetic counseling for carriers of pathogenic variants (PV) or clinically suspicious cases. Results: Up to Dec. 31 2025, we enrolled 1,482 pts with dMMR CRC. Overall, 1,316 were eligible for analysis (14 not eligible; 152 not yet filled out). Excluding 104 cases with incomplete data, 1,212 patients were evaluable from somatic to germline testing. Overall, 1033 (85%) completed the ItaLynch diagnostic pathway, demonstrating the strong feasibility of this this algorithm. Of patients with IHC data, 975 (78%) were dMLH1 and 281 (22%) had non-MLH1 loss. BRAF testing was performed in 904/975 (93%) dMLH1 cases; 386/904 (43%) were BRAFwt. MLH1 methylation testing was done in 329/386 (86%); 146/329 (44%) were not hypermethylated. Germline testing was performed in 108/146 (74%), identifying 21 LS-associated PV (19%). Among non-MLH1 loss, 232/281 (83%) underwent germline testing and 115 (50%) were diagnosed with LS. Overall, germline testing was performed in 361/1,033 adherent patients (35%), identifying 143 PV (40% of tests) and 24 VUS; PV prevalence was 14% (143/1,033). Mainstreaming reduced genetic pre-test counseling visits by 54% (196/361 avoided) and, compared with universal germline testing, avoided 672/1,033 tests (65%). Post-test counseling uptake was 83% among PV carriers. Median turnaround time from somatic to germline diagnosis was 217 days for dMLH1 and 73 days for non-MLH1. Among non-adherent patients, 67 underwent germline testing (14 PV, 3 VUS). In the full cohort, 157 PV were identified (MLH1 37, MSH2 57, MSH6 43, PMS2 20). Conclusions: This oncologist-led, mainstreamed diagnostic pathway for LS is feasible and optimized use of healthcare resources. Analyses of pathway deviations (15%), cost-effectiveness, and clinical/translational outcomes are ongoing.