Prognostic impact of gain-of-function TP53 mutations on outcomes in HER2-negative advanced gastric cancer

Background: TP53 alterations are among the most prevalent genomic events across solid tumors, yet the biological and clinical heterogeneity of TP53 mutation types-particularly gain-of-function (GOF) variants-remains poorly defined in advanced gastric cancer (AGC). GOF mutations involving the DNA-binding domain can confer oncogenic properties beyond simple loss of tumor suppressor activity. We aimed to characterize the landscape of GOF and non-GOF TP53 mutations and evaluate their prognostic relevance in patients with HER2-negative AGC treated with first-line oxaliplatin-based chemotherapy. Methods: From 2017-2021, tumor tissues from 675 patients with AGC were sequenced. Among these, 409 patients with HER2-negative AGC receiving first-line FOLFOX (n=188) or XELOX (n=221) were included. Targeted sequencing was performed using CancerSCAN or K-MASTER v1.0/v1.1 NGS panels. GOF TP53 variants were prespecified (R175H, R248W, R248Q, R249S, R273H, R273L, R282W), with all remaining alterations classified as non-GOF. PFS and OS were assessed using Kaplan-Meier methods. Results: Among 675 patients, 409 patients with HER2-negative AGC were treated with first-line FOLFOX (n=188) or XELOX (n=221). TP53 mutation was identified in 115 (28.1%) of 409 patients; GOF (n=21, 5.1%) and non-GOF (n=94, 23.0%). The most common hotspot of GOF TP53 mutations was R175H (n=8), followed by R248W (n=7), R248Q (n=4), and R273H (n=2). With a median follow-up duration of 22.7 months, the median progression-free survival (PFS) with FOLFOX/XELOX and overall survival (OS) of 409 patients were 5.1 and 21.8 months, respectively. Patients with TP53 mutated AGC showed significantly shorter PFS than those with wild-type TP53 mutation (median 4.8 vs. 5.3 months, P =0.049). There were no significant differences in PFS between GOF TP53 and non-GOF TP53 mutated AGC (median 4.9 vs. 4.8 months, P =0.680). There were no significant differences in OS between TP53 mutated and wild-type AGC (18.4 vs. 22.0 months, P =0.261). Median OS seemed to be numerically shorter in patients with GOF TP53 mutated AGC compared to those with non-GOF TP53 mutated and wild-type AGC (15.7 vs. 19.3 vs. 22.0 months, P =0.442). Conclusions: TP53 mutations-including biologically aggressive GOF variants-were identified in nearly one-third of HER2-negative AGC patients. Although statistical significance was not achieved, GOF TP53 mutations demonstrated a consistent pattern toward inferior survival, suggesting their potential role as poor-prognostic genomic biomarkers in chemotherapy-treated AGC. Larger prospective analyses integrating molecular subtypes and immunologic signatures are warranted to clarify the therapeutic and biological relevance of TP53 functional subclasses.