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

Q: What does the study investigate about ERBB2 in HER2-positive gastric cancer?

It evaluates how ERBB2 copy number relates to the molecular traits of HER2-positive gastric cancer and to treatment efficacy.

Q: How were tumors classified as “ERBB2 dominant” or “non-ERBB2 dominant”?

Tumors where ERBB2 had the highest copy number among co-amplified oncogenes were defined as “ERBB2 dominant”; the rest were “non-ERBB2 dominant”.

Q: What clinical differences were observed between ERBB2-dominant and non-ERBB2-dominant tumors?

ERBB2-dominant tumors showed longer progression-free survival and overall survival and a higher response rate than non-ERBB2-dominant tumors.

Sep 22, 2026

Uploaded by Jake

Background Oncogene co-amplification is commonly observed, but its clinical relevance is still unclear, especially regarding links to copy number patterns. Objective This study clarifies molecular features of HER2-positive gastric cancer by analyzing copy numbers of ERBB2 and other oncogenes and assessing associations with treatment efficacy. Methods The HIGHSOX-trial collaborative design evaluates trastuzumab plus S-1 and oxaliplatin, using next-generation sequencing. Tumors with the highest ERBB2 copy number among co-amplified oncogenes were classified as “ERBB2 dominant”. Results 32 patients enrolled; median PFS was 11.8 months and OS 28.8 months. ERBB2 amplification occurred in 84.4%, with most showing co-amplification or amplification of other oncogenes alone. ERBB2-dominant tumors demonstrated better outcomes than non-ERBB2-dominant tumors. Conclusions Copy number-based oncogene dominance may indicate tumor dependence and inform response to HER2-targeted therapy, supporting a potential novel biomarker in HER2-positive gastric cancer.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Background

Objective

Methods

Results

Conclusions

Introduction

HER2 and ERBB2 biology

Clinical context of trastuzumab and related trials

Key Points

Targeted Oncology (2026) 21:269–283 [https://doi.org/10.1007/s1](https://doi.org/10.1007/s1) 1523-026-01204-5 Copy Number‑Based Oncogene Dominance May SuggestERBB2 Dependence and Trastuzumab Response in HER2‑Positive Gastric Cancer Takeru Wakatsuki1 · Noriko Yamamoto2 · Naoki Ishizuka3 · Shuichi Hironaka4 · Keiko Minashi5 · Shigenori Kadowaki6 · Hidekazu Hirano7 · Hirokazu Shoji7 · Toshifumi Yamaguchi8 · Keisho Chin1 · Mariko Ogura1 · Izuma Nakayama1,9 · Hiroki Osumi1 · Arisa Ueki10 · Shigehisa Kitano11,12 · Narikazu Boku13 · Kensei Yamaguchi1 · Daisuke Takahari1,14 Received: 17 November 2025 / Accepted: 5 February 2026 / Published online: 15 March 2026 © The Author(s) 2026 Abstract Background While oncogene co-amplification is frequently observed, its clinical significance remains unclear, particularly with regard to its association with copy number. Objective 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. Methods 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”. Results 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) . Conclusions 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. 1 Introduction Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase (RTK) belonging to the epidermal growth factor receptor family [1] . It is encoded by the ERBB2 gene located on chromosome 17q12, and amplification of ERBB2 leads to HER2 overexpression, promoting proliferation, survival, and differentiation of tumor cells [2] . The incidence of HER2-positive breast and gastric cancers has been reported to be up to 20%, with lower frequencies in other cancers [3] . It is recognized that HER2 is a critical Extended author information available on the last page of the article driver oncogene and a promising treatment target in various HER2-positive cancers. Trastuzumab, a humanized monoclonal anti-HER2 antibody, has been initially developed for HER2-positive breast cancer [4, 5] . In gastric cancer, the ToGA trial showed significant clinical benefits by adding trastuzumab to standard chemotherapy for HER2-positive advanced gastric cancer [6] . Subsequently, trastuzumab deruxtecan, an antibodydrug conjugate consisting of trastuzumab covalently linked to a topoisomerase I inhibitor, has been approved as a third or later line treatment [7] . Recently, the KEYNOTE 811 trial demonstrated significant benefit

FAQs

What does the study investigate about ERBB2 in HER2-positive gastric cancer?

It evaluates how ERBB2 copy number relates to the molecular traits of HER2-positive gastric cancer and to treatment efficacy.

How were tumors classified as “ERBB2 dominant” or “non-ERBB2 dominant”?

Tumors where ERBB2 had the highest copy number among co-amplified oncogenes were defined as “ERBB2 dominant”; the rest were “non-ERBB2 dominant”.

What clinical differences were observed between ERBB2-dominant and non-ERBB2-dominant tumors?

ERBB2-dominant tumors showed longer progression-free survival and overall survival and a higher response rate than non-ERBB2-dominant tumors.

Sep 22, 2026

Uploaded by Jake