HER2 Amplification and PD-L1 Expression in Advanced Gastric Cancer: Correlations, Clinical Implications, and Molecular Characteristics

Abstract Epidermal growth factor receptor 2 (HER2) and programmed cell death ligand 1 (PD-L1) are pivotal therapeutic targets in advanced gastric cancer (GC). Nevertheless, the correlation between them, along with the clinical and genomic characteristics, and prognosis differences across distinct molecular subtypes, remains elusive. In this retrospective study, 390 advanced GC patients provided both tumor tissue and paired blood samples for Next-Generation Sequencing (NGS) of 639 tumor-related genes, along with PD-L1 immunohistochemical staining. HER2 amplification was further validated using FISH testing in 254 patients. We analyzed the clinical and molecular characteristics among subgroups based on HER2 amplification and PD-L1 CPS score. The highest consistency with FISH for HER2 amplification was observed when the positive threshold for NGS detection was set at 2.5. TP53 mutation rate peaked at 59%, significantly higher in cases with HER2 amplification (P < 0.01). Patients with both HER2 amplification and TP53 mutations exhibited notably shorter survival compared to cases with only TP53 mutations (P < 0.05). Furthermore, HER2 amplification did not correlate with PD-L1 expression levels. Stratified analysis of PD-L1 expression revealed distinct clinical and molecular features. Patients with higher PD-L1 expression levels (CPS ≥ 5) showed a higher tumor mutational burden (TMB) and microsatellite instability-high (MSI-H) status. Additionally, these patients exhibited enriched mutations in key signaling pathways such as PI3K, TGFβ, and Wnt/β-catenin. In conclusion, our study highlights the prognostic significance of HER2 amplification and TP53 mutations in advanced GC. Stratified analysis of PD-L1 expression may help identify candidates for targeted and immunotherapy in this patient population.