Prophylactic total gastrectomy in germline CDH1 carriers: results across 25 years from a systematic review and meta-analysis.

BACKGROUND: Prophylactic total gastrectomy (PTG) is a risk-reducing strategy considered in individuals at high risk for diffuse gastric cancer (DGC) associated with germline CDH1 pathogenic variants. METHODS: A systematic literature search (PubMed, Scopus) was conducted to identify studies that performed PTGs in CDH1 carriers. Data were analysed using a random-effects generalised linear mixed model. Cochran's Q test was used to assess the heterogeneity between studies. Forest plots were used to display study-specific estimates, and the pooled estimates were calculated within three subsequent cohort periods (2001-2010; 2011-2020; 2021-2025). Statistical analyses were performed using R software. RESULTS: A total of 21 studies were considered out of 302 originally identified, including a total of 967 CDH1 carriers. PTG was performed in 62.9% of CDH1 pathogenic variant carriers. Advanced DGC (>pT1a) was detected in 1.1% and ≤pT1a in 79% in postoperative PTG specimens. The majority of PTGs were reported from North America (58.9%). The pooled proportion of PTG decreased from 83.2% (95% CI 61.0% to 94.0%) in 2001-2010 to 71.0% (95% CI 59.0% to 80.7%) in 2011-2020 and to 67.5% (95% CI 48.9% to 81.8%) in 2021-2025 (p for trend=0.12). CONCLUSION: About 60% of PTGs were reported from North America. The majority of the lesions were classified as pT1a. PTG indication has been progressively and constantly decreasing during the last years considered. This can be related to the recent genetic analyses reporting a lower DGC risk in CDH1 carriers and with the improvement in detection of early lesions during endoscopy. PROSPERO REGISTRATION NUMBER: CRD420261368873.