HER2/ERBB2 and Genomic Alterations in Patients with Gallbladder Cancer from Argentina

Background/Objectives: Gallbladder cancer (GBC) is highly prevalent in Western Argentina, where the frequency and clinical significance of HER2/ERBB2 abnormalities remain unknown. We investigated the prevalence, prognostic impact, and genomic co-occurrence of HER2/ERBB2 alterations in Argentine patients with GBC. Methods: We retrospectively analyzed patients with GBC from the Latin American Intergroup of Gastrointestinal Oncology (ILOGI) database. HER2 protein expression was assessed by immunohistochemistry, and sequence variants in ERBB2 and 213 other cancer-related genes by next-generation sequencing. Overall survival (OS) was analyzed using Kaplan–Meier curves, the log-rank test, and univariate Cox proportional hazards regression. Genomic co-occurrences were evaluated using Fisher’s exact test. Results: Thirty patients were included in the study. Most were women with gallstones and advanced-stage disease. HER2 overexpression was detected in five patients (17%), with ERBB2 variants in three other tumors, yielding an overall HER2/ERBB2 alteration rate of 27% (8/30). Among patients with stage III–IV disease, HER2/ERBB2 abnormalities were not associated with a statistically significant difference in OS (HR, 0.40; 95% CI, 0.11–1.45; p = 0.162). Similarly, HER2 overexpression alone had no significant prognostic impact. Exploratory analysis identified potential co-occurrence of HER2/ERBB2 abnormalities with sequence variants in 16 genes involved in chemotherapy sensitivity and the PI3K/AKT/mTOR and VEGF signaling pathways, although these associations were not statistically significant after correction for multiple comparisons. Conclusions: HER2/ERBB2 abnormalities are frequent among Argentine patients with GBC and do not appear to be associated with poorer OS. Our findings provide a biologic rationale for further investigation of the potential synergistic effects of combining anti-HER2 therapies with PI3K/AKT/mTOR or VEGF pathway inhibitors.