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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

Authors :
Kaori Hino
Tomohiro Nishina
Takeshi Kajiwara
Hideaki Bando
Maho Nakamura
Shigenori Kadowaki
Keiko Minashi
Satoshi Yuki
Takashi Ohta
Hiroki Hara
Takuro Mizukami
Toshikazu Moriwaki
Koushiro Ohtsubo
Masato Komoda
Seiichiro Mitani
Fumio Nagashima
Ken Kato
Takanobu Yamada
Hiroko Hasegawa
Kentaro Yamazaki
Takayuki Yoshino
Ichinosuke Hyodo
Source :
JCO Precision Oncology.
Publication Year :
2022
Publisher :
American Society of Clinical Oncology (ASCO), 2022.

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.

Subjects

Subjects :
Cancer Research
Oncology

Details

ISSN :
24734284
Database :
OpenAIRE
Journal :
JCO Precision Oncology
Accession number :
edsair.doi...........e214c6707c4a7723cb7413e729f775c1
Full Text :
https://doi.org/10.1200/po.22.00135