Pathway Mutation Accumulate Perturbation Score: A prognostic and predictive biomarker for immunotherapy in advanced...

Gastric cancer (GC) remains highly lethal, with limited available biomarkers. The Pathway Mutation Accumulation Perturbation Score (PMAPscore), which leverages pathway-level mutations, provides a novel approach to predicting immunotherapy response and survival outcomes.

To evaluate the prognostic and predictive value of the PMAPscore in patients with advanced GC undergoing immunotherapy.

Three cohorts of patients with GC treated with immunotherapy were analyzed: PUCH (Peking University Cancer Hospital; n = 39, training cohort), MSK (Memorial Sloan Kettering; n = 19, validation cohort) and SMC (Samsung Medical Center; n = 43, validation cohort). A PMAPscore-based risk model was developed and validated for survival outcomes. Immune mechanisms in highand low-risk groups were explored using The Cancer Genome Atlas (TCGA) GC data (n = 431).

Low-risk patients identified by the PMAPscore model exhibited significantly better progression-free survival (PFS), overall survival (OS) and durable clinical benefit (DCB). In the PUCH cohort, low-risk patients had higher DCB rates (85.7% vs 44.0%, p = 0.02), longer PFS (p < 0.001), and longer OS (p < 0.001). Similar trends were observed in the MSK and SMC cohorts. Multivariate analysis confirmed low-risk status as an independent predictor of improved PFS and OS, outperforming tumor mutation burden (TMB), programmed death-ligand 1 (PD-L1) expression, microsatellite instability (MSI) status, and the gastrointestinal immune prognostic signature (GIPS). The TCGA data indicated enhanced antitumor immune activity in low-risk tumors, with increased human leukocyte antigen (HLA)-related gene expression and greater B-cell and natural killer (NK) cell infiltration.

The PMAPscore-based risk model is a robust tool for predicting survival and immunotherapy responses in patients with advanced GC, supporting its clinical application for treatment stratification.