Mainstreaming the diagnosis of Lynch syndrome (LS) in colorectal cancer (CRC) patients: The ItaLynch study.

10580 Background: International guidelines recommend universal screening for LS through somatic DNA mismatch repair deficiency (dMMR) testing in CRC. However, LS remains largely underdiagnosed, often due to inconsistent referrals from oncologists to genetic counseling and germline testing. We report preliminary results of the ItaLynch study, proposing a mainstream, oncologist-led diagnostic pathway for LS. Methods: ItaLynch is a prospective, observational, multicenter, multidisciplinary Italian study on pts with dMMR CRC. It started in May 2021, and is ongoing in 23 high-volume centers. The ItaLynch diagnostic pathway is based on three key steps. The first step is universal screening through dMMR testing by immunohistochemistry (IHC) in all CRC pts. The second step consists of reflex testing and a Lynch alert: MLH1-deficient (dMLH1) pts undergo reflex testing for BRAF V600E and, if wild-type, for MLH1 promoter methylation. A Lynch alert is added to the pathology report of all dMMR CRC pts. The alert is positive for pts with a high risk of LS as per reflex testing results or loss of non-MLH1 proteins; it is negative for pts not likely to have a hereditary predisposition (i.e. BRAF V600E mut or MLH1 promoter hypermethylated dMLH1). The third and most innovative step is the oncologist-led mainstreaming germline testing for pts with a positive Lynch alert. Carriers of a germline pathogenic variant (PV) as well as those who have non-informative test results but are clinically suspicious are then referred to post-test genetic counselling. Results: Up to Dec. 19 2024, we enrolled 1,146 pts with dMMR CRC. Among the 937 pts eligible for the current analysis, 714 (76%) were dMLH1, and 223 (24%) displayed loss of non-MLH1 proteins. Reflex testing was carried out in 653 (91%) of the dMLH1 pts and 271 (41%) were BRAF wt. Of these, 219 (80%) subsequently underwent MLH1 promoter methylation testing, and 98 (45%) were not hypermethylated. Of these, 60 (61%) underwent oncologist-led germline genetic testing, and 11 (18%) were carriers of an LS-associated PV. Among the 223 cases with loss of non-MLH1 proteins, 157 (70%) underwent genetic testing, and 86 (55%) were diagnosed with LS. At the time of writing, the overall proportion of LS cases is 10% (97/937 pts with data available for the current analysis). These 97 LS cases represent 45% of the 217 pts who were flagged with a positive Lynch alert and underwent oncologist-led genetic testing (60 of which with dMLH1 and 157 with non-MLH1 loss). Conclusions: Overall, our large cohort is representative of the population of pts with dMMR CRC. Our novel diagnostic algorithm, through the implementation of the Lynch Alert flagging system that identifies dMMR CRC pts with a high likelihood of LS and of an oncologist-led germline genetic testing, obtained a high diagnostic yield. Further analyses are ongoing on the entire cohort to evaluate the feasibility of the proposed diagnostic pathway.