Genetically determined heterogeneous treatment effects of Helicobacter pylori eradication for targeted gastric cancer prevention

Population-based Helicobacter pylori screen-and-treat is a priority for gastric cancer (GC) prevention, yet the preventive effect varies across individuals and the determinants of this heterogeneity remain insufficiently understood. As large-scale prevention efforts expand globally, identifying individuals most likely to benefit is increasingly important. We analyzed two randomized trials, the Mass Intervention Trial in Linqu, Shandong Province (MITS; ChiCTR-TRC-10000979; n=1740) and the Shandong Intervention Trial (SIT; NCT00339768; n=1811), to characterize genetically determined heterogeneous treatment effects of H. pylori eradication for GC prevention. We identified 11 genetic variants that modified the preventive efficacy of eradication and integrated their genotype-specific conditional average treatment effects into a polygenic treatment benefit score. We further compared a benefit-based strategy prioritizing individuals predicted to derive greater benefit for GC prevention, with a risk-based strategy defined by a polygenic risk score, and assessed whether benefit-based subgroups exhibited differential residual GC risk post-eradication. With PTBS, targeting the high-treatment-benefit individuals conferred stronger protection against GC (MITS: hazard ratio [HR]=0.44, 95% confidence interval [CI]: 0.35-0.54; number needed to treat [NNT]=56; SIT: HR=0.25, 95% CI: 0.08-0.76; NNT=26) than treating all H. pylori-positive participants or those of high-genetic-risk. PTBS further stratified residual GC risk among individuals post-treatment (MITS: HR=0.65, 95% CI: 0.52-0.81; SIT: HR=0.27, 95% CI: 0.13-0.56, for high-treatment-benefit individuals) and was associated with slower precancerous lesion progression. Our findings suggest that host genetic factors modulate the preventive efficacy of H. pylori eradication, and that incorporating genotype-specific heterogeneous treatment effects provides a framework for enhancing the precision of population-based screen-and-treat programs while supporting post-eradication risk management.