Copy Number-Based Oncogene Dominance May Suggest ERBB2 Dependence and Trastuzumab Response in HER2-Positive Gastric...

While oncogene co-amplification is frequently observed, its clinical significance remains unclear, particularly with regard to its association with copy number.

The aim of this study was to elucidate the molecular traits of human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, focusing on copy numbers of ERBB2 and other oncogenes, and to investigate their association with treatment efficacy.

This is a collaborative study associated with the HIGHSOX trial investigating the efficacy of trastuzumab combined with S-1 and oxaliplatin in HER2-positive gastric cancer, and next-generation sequencing was performed. Tumors in which ERBB2 was the highest copy number among co-amplified oncogenes were defined as "ERBB2 dominant". The others were defined as "non-ERBB2 dominant".

A total of 32 patients were enrolled, and the median progression-free survival and overall survival were 11.8 and 28.8 months, respectively. ERBB2 amplification was present in 84.4%, with the majority (88%) exhibiting either co-amplification of ERBB2 with other oncogenes (75%) or amplification of other oncogenes alone (13%), including KRAS, MET, FGFR2, and CCNE1. A potential inverse relationship in copy number between ERBB2 and other oncogenes (ρ = - 0.345, p = 0.058) was observed. The ERBB2 copy number was significantly higher than that of other oncogenes in ERBB2-dominant tumors, whereas the opposite pattern was observed in non-ERBB2-dominant tumors (both p < 0.001). Non-ERBB2-dominant tumors showed significantly shorter progression-free survival (median progression-free survival: 6.9 vs 17.0 months, hazard ratio, 6.40, p = 0.001), overall survival (median overall survival 14.8 vs 35.5 months, hazard ratio, 2.72, p = 0.016), and a numerically lower response rate (63.6% vs 90.0%, p = 0.151).

Copy number-based oncogene dominance may suggest tumor dependence and response to HER2-targeted therapy, highlighting a potential novel biomarker in HER2-positive gastric cancer.