Association of <i>ERBB2</i> Copy Number and Gene Coalterations With Trastuzumab Efficacy and Resistance in Human Epidermal Growth Factor Receptor 2-Positive Esophagogastric and Gastric Cancer.

Abstract

<i>ERBB2</i> copy number (CN), measured using next-generation sequencing, is a predictive biomarker for trastuzumab efficacy in human epidermal growth factor receptor 2 (HER2)-positive advanced esophagogastric and gastric cancer (AGC). We aimed to investigate the association of <i>ERBB2</i> amplification and gene coalterations with response and resistance to trastuzumab-combined chemotherapy. The SCRUM-Japan GI-SCREEN was a comprehensive genomic profiling project of GI cancer tissues using Oncomine Cancer Research Panel and Oncomine Comprehensive Assay. From 885 patients with AGC who successfully underwent gene profiling, 74 with <i>ERBB2</i> amplification (CN ≥ 4.0) and who received first-line trastuzumab-combined chemotherapy were selected, and <i>ERBB2</i> CN and gene coalterations were assessed. <i>ERBB2</i> CN did not differ in tumor response to trastuzumab-combined chemotherapy (one-way analysis of variance test, <i>P</i> = .37). Multivariate analysis using the Cox proportional hazard model revealed that <i>ERBB2</i> CN (continuous log₂-converted CN, hazard ratio, 0.76; 95% CI, 0.62 to 0.93; <i>P</i> < .01) and receptor/oncogene amplifications in the HER2 signaling pathway (hazard ratio, 2.5; 95% CI, 1.2 to 5.3; <i>P</i> = .01) were significant predictors for progression-free survival (PFS). <i>ERBB2</i> variants coexisted in five patients (7%) and were missense mutations. Two patients with low variant allele frequencies (VAFs; 8%, 12%) showed high <i>ERBB2</i> CN (55, 80) and durable response (≥ 20 months), whereas three patients with high VAFs (66%-90%) showed low <i>ERBB2</i> CN (8-11) and no response with short PFS (1-10 months). <i>ERBB2</i> CN and gene coamplification in the HER2 signaling pathway were positive and negative predictors of PFS in trastuzumab-treated HER2-positive AGC patients, respectively. HER2-positive AGC patients with a high VAF of <i>ERBB2</i> showed poor outcomes and may need HER2 tyrosine kinase inhibitors and trastuzumab deruxtecan.