Predictors of early cancer burden in CDH1 pathogenic variant carriers: a UK single-centre cohort study

Abstract

Background Hereditary diffuse gastric cancer (HDGC) with CDH1 germline pathogenic variants carries a high lifetime risk of signet ring cell carcinoma (SRCC). There is limited data to inform decision between endoscopic surveillance and prophylactic total gastrectomy (PTG) in patients with early SRCC, which could have indolent behaviour. We hypothesize patients with few early SRCC lesions can be monitored endoscopically. Therefore, we aimed to identify clinical predictors early SRCC burden and evaluate the natural histoary of early cancer lesions in HDGC. Methods This is a single centre longitudinal cohort study of CDH1 germline variant carriers recruited at Cambridge University Hospitals (United Kingdom) between 2005 and 2024. We analysed two cohorts: 53 patients who underwent endoscopic evaluation followed by PTG and 93 individuals received longitudinal surveillance. We excluded patients with advanced cancer at baseline endoscopy. Participants received high-resolution endoscopy with targeted and systematic random biopsies following Cambridge protocol. Multivariable negative binomial regression, logistic regression, and linear mixed-effects models were applied to assess predictors of SRCC burden and temporal dynamics of SRCC detection. Findings In PTG cohort, 89% individuals had early-stage cancer (pT1aN0M0) and 11% had no evidence of carcinoma (pT0N0M0). SRCC foci ranged from 0-273 (median 14, IQR 2-37). The number of positive targeted and random biopsies independently predicted SRCC burden on gastrectomy (P<0.001), whereas age, CDH1 mutation type, number of affected relatives were not significantly associated. In the surveillance cohort, the number of positive biopsies remained largely stable over time, with no significant temporal increase detected (Incidence rate ratio: 1.026 per six months, 95%CI: 0.985-1.068, P=0.214). Interpretation Endoscopic surveillance using systematic biopsies reliably estimates SRCC burden on gastrectomy in HDGC. Individuals few pale SRCC lesions showed stable findings during long-term surveillance, supporting the safety of endoscopic monitoring extended surveillance intervals. Future research should clarify the clinical significance of high SRCC burden. Funding Medical Research Council and Cancer Research UK.