ERBB2 Copy Number as a Quantitative Biomarker for Real-World Outcomes to Anti–Human Epidermal Growth Factor Receptor 2 Therapy in Advanced Gastroesophageal Adenocarcinoma. (20th January 2022)

• Record Type: Journal Article
• Authors: Zhang, Liangliang; Hamdani, Omar; Gjoerup, Ole; Cho-Phan, Cheryl; Snider, Jeremy; Castellanos, Emily; Nimeiri, Halla; Frampton, Garrett; Venstrom, Jeffrey M.; Oxnard, Geoffrey; Klempner, Samuel J.; Schrock, Alexa B.
• Is Part Of: JCO precision oncology. Volume 6(2022)
• Publication Date: 2022-01-20
• Subjects: Precision Medicine; Neoplasms; Pharmacogenetics; Molecular Targeted Therapy; Personalized medicine; Oncology; Pharmacogenomics; Periodical; Periodicals; 616.994
• DOI: 10.1200/PO.21.00330
• Languages: English
• ISSNs: 2473-4284

Abstract

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