<i>ERBB2</i> Copy Number as a Quantitative Biomarker for Real-World Outcomes to Anti-Human Epidermal Growth Factor Receptor 2 Therapy in Advanced Gastroesophageal Adenocarcinoma.

Abstract

Human epidermal growth factor receptor 2 (HER2) overexpression or amplification (<i>ERBB2</i>amp) are biomarkers for approved anti-HER2 therapies. <i>ERBB2</i>amp may better predict response compared with immunohistochemistry or in situ hybridization, and quantitative copy number (CN) may further stratify patients. We characterized <i>ERBB2</i>amp in advanced gastroesophageal adenocarcinomas (GEA) and hypothesized that increased CN was associated with better outcome to trastuzumab. Comprehensive genomic profiling, including assessment of <i>ERBB2</i>amp, was performed for 12,905 GEA tissue cases. Clinical outcomes were assessed using a clinicogenomic database linking deidentified electronic health record-derived clinical data to genomic data. Multivariable Cox proportional hazard models were used for real-world progression-free survival (rwPFS) comparisons. <i>ERBB2</i>amp (CN ≥ 5) was detected in 15% (1,934 of 12,905) of GEA; median CN 22 (interquartile range 9-73). Median <i>ERBB2</i> amplicon size was 0.27 megabase (interquartile range 0.13-0.95), and smaller amplicons were associated with higher CN (<i>P</i> < .001). In the clinicogenomic database, of 101 evaluable first-line trastuzumab-treated patients, <i>ERBB2</i> CN was a significant predictor of rwPFS as a continuous variable (adjusted hazard ratio = 0.73; 95% CI, 0.60 to 0.89; <i>P</i> = .002), whereas <i>ERBB2</i> CN was not predictive of rwPFS on chemotherapy (adjusted hazard ratio = 0.93; 95% CI, 0.73 to 1.20; <i>P</i> = .59). Among trastuzumab-treated patients, no significant associations with <i>ERBB2</i> CN were observed for disease site, age, stage at advanced diagnosis, or most selected coalterations. <i>ERBB2</i>amp was detected in 15% of GEA tissue samples, with significant diversity in <i>ERBB2</i> CN and amplicon focality. <i>ERBB2</i> CN was predictive of rwPFS as a continuous variable for patients treated with trastuzumab. Further studies exploring the clinical utility of quantitative <i>ERBB2</i> CN, particularly in the setting of the evolving anti-HER2 landscape and combination therapies, are warranted.