Association of ERBB2 Copy Number and Gene Coalterations With Trastuzumab Efficacy and Resistance in Human Epidermal Growth Factor Receptor 2–Positive Esophagogastric and Gastric Cancer

Abstract

PURPOSE ERBB2 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 ERBB2 amplification and gene coalterations with response and resistance to trastuzumab-combined chemotherapy. METHODS 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 ERBB2 amplification (CN ≥ 4.0) and who received first-line trastuzumab-combined chemotherapy were selected, and ERBB2 CN and gene coalterations were assessed. RESULTS ERBB2 CN did not differ in tumor response to trastuzumab-combined chemotherapy (one-way analysis of variance test, P = .37). Multivariate analysis using the Cox proportional hazard model revealed that ERBB2 CN (continuous log2-converted CN, hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P < .01) and receptor/oncogene amplifications in the HER2 signaling pathway (hazard ratio, 2.5; 95% CI, 1.2 to 5.3; P = .01) were significant predictors for progression-free survival (PFS). ERBB2 variants coexisted in five patients (7%) and were missense mutations. Two patients with low variant allele frequencies (VAFs; 8%, 12%) showed high ERBB2 CN (55, 80) and durable response (≥ 20 months), whereas three patients with high VAFs (66%–90%) showed low ERBB2 CN (8-11) and no response with short PFS (1-10 months). CONCLUSION ERBB2 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 ERBB2 showed poor outcomes and may need HER2 tyrosine kinase inhibitors and trastuzumab deruxtecan.

Comprehensive biomarker analysis of long-term response to trastuzumab in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma

“…Studies have used the median ERBB2 CN or calculation of the receiver operating characteristic curve to set a threshold for identification of patients with long-term benefit. However, there is no consensus about the best threshold defining a high ERBB2 amplification in NGS data [10,12]. In our cohort, the anticipated ERBB2 amplification could only be confirmed by using NGS in 68% of the patient.…”

“…To date, positive HER2 status by IHC or ISH is the prerequisite for the administration of trastuzumab in mGC/mGEJC patients. Besides that, a higher amplification level of ERBB2 was tended to be associated with improved survival under trastuzumab treatment [9][10][11][12]. NGS is an emerging technology with the potential to detect the absolute ERBB2 copy number.…”

“…A high level of HER2 gene amplification was proposed as improved predictor of sensitivity to trastuzumab treatment, but the studies defined different thresholds [9][10][11][12]. Furthermore, a tumor mutational burden (TMB) of more than 10 mutations per Mb was indicated to be a potential biomarker for trastuzumab efficacy [13].…”

“…Furthermore, a tumor mutational burden (TMB) of more than 10 mutations per Mb was indicated to be a potential biomarker for trastuzumab efficacy [13]. Moreover, initial resistance to trastuzumab or impaired treatment response was associated with the presence of co-amplifications and mutations of oncogenes or genes related to the HER2 signaling pathway such as EGFR and KRAS [10,14,15]. In addition, intratumoral heterogeneity of HER2 protein expression, frequently found in GC and GEJC, was associated with poor prognosis [16][17][18].…”

PD-L1 gene amplification and focality: relationship with protein expression

“…For ERBB2 , information about CN and gene co-amplification can be predictive of trastuzumab clinical efficacy. 20 21 Mesenchymal Epithelial Transition ( MET) gene amplifications can be found in multiple tumors types and, at least in lung cancer, focality of amplification is correlated with responses to MET inhibitors. 22 23 Herein, we described this interplay between an additional genomic layer (focality) and protein expression of PD-L1, which could also be explored for other cancer genes.…”