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

Abstract

Purpose: Human epidermal growth factor receptor 2 (HER2) overexpression or amplification (ERBB2amp) are biomarkers for approved anti-HER2 therapies. ERBB2amp may better predict response compared with immunohistochemistry or in situ hybridization, and quantitative copy number (CN) may further stratify patients. We characterized ERBB2amp in advanced gastroesophageal adenocarcinomas (GEA) and hypothesized that increased CN was associated with better outcome to trastuzumab.

Methods: Comprehensive genomic profiling, including assessment of ERBB2amp, 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: ERBB2amp (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: ERBB2amp 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.

FIG 1.

ERBB2 amplification frequencies, CN distribution, and amplicon size across GEA samples. (A) Frequency of ERBB2 amplification detected in all GEA tissue samples as well as in esophageal/GEJ and gastric subsets and breast cancer samples in the Foundation Medicine Genomic Database. (B) Similar ERBB2 CN distribution was observed in ERBB2-amplified esophageal/GEJ, gastric, and breast subsets. (C) ERBB2 CN distribution in ERBB2-amplified GEA and breast cancer samples bucketed by ERBB2 amplicon size. For amplicons > 0.16 Mbp, increased focality significantly correlated with higher ERBB2 CN (P < .001). CN, copy number; GEA, gastroesophageal adenocarcinoma; GEJ, gastroesophageal junction; Mbp, megabase pairs.

FIG 2.

Treatment patterns for patients with GEA with ERBB2 amplification or ERBB2 wild-type tumors. Sankey diagrams showing treatment patterns for patients with GEA receiving first-line therapy post-CGP report. (A) Patients with GEA with ERBB2 amplification detected by CGP commonly received anti–HER2-containing regimens. (B) Patients with GEA without ERBB2 amplification or other ERBB2 alterations detected by CGP rarely received anti-HER2 therapy. Therapies grouped as others include immunotherapy, non–HER2-targeted therapies, and unknown clinical study drugs. CGP, comprehensive genomic profiling; chemo, chemotherapy; GEA, gastroesophageal adenocarcinoma; HER2, human epidermal growth factor receptor 2.

FIG 3.

ERBB2 CN as a predictor of rwPFS in patients with advanced GEA treated with anti-HER2 therapy in the first-line setting. Association of ERBB2 CN with rwPFS in patients with GEA treated with first-line trastuzumab in the CGDB. ERBB2 CN was predictive as a continuous variable, and no single CN cutoff was identified as an optimal predictor of rwPFS. To visualize Kaplan-Meier rwPFS curves, the cohort was split into ERBB2 CN quintiles. Curves are truncated at 30 months as the number at risk was reduced to one in the entire ERBB2amp cohort. Median and IQR rwPFS for each CN quintile is shown. CGDB, clinicogenomic database; CN, copy number; GEA, gastroesophageal adenocarcinoma; HER2, human epidermal growth factor receptor 2; IQR, interquartile range; rwPFS, real-world progression-free survival.