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.

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

“…ERBB2 CN as a continuous value showed a significant association with PFS in this study, as well as in two recent studies using the nationwide (US-based) deidentified Flartiron Health-Foundation clinic genomic database and Foundation Medicine genomic database for gastroesophageal adenocarcinoma. 7,13 The former study demonstrated significant differences in the time to trastuzumab discontinuation and OS between patients with HER2 concordance (HER2+ and ERBB2 amplification+) and those with discordance (HER2+ and ERBB2 amplification-) and between patients with high ERBB2 CN (≥ median value, 25) and those with low ERBB2 CN. 7 The latter showed that the association of ERBB2 CN with PFS was not observed in HER2-positive patients who were treated with chemotherapy without trastuzumab.…”

“… 7 The latter showed that the association of ERBB2 CN with PFS was not observed in HER2-positive patients who were treated with chemotherapy without trastuzumab. 13 Taken together, ERBB2 CN is a robust efficacy predictor of trastuzumab treatment in patients with HER2-positive AGC. Setting a common optimal cutoff value for ERBB2 CN seemed to be difficult, because the trastuzumab effect continuously emerged as the ERBB2 CN increased, and the NGS methods differed across studies.…”

“…In recent years, high ERBB2 CN has been reported to be an independent predictor of longer real-world PFS in patients with AGC treated with trastuzumab using next-generation sequencing (NGS) technology, and a significant association of continuous ERBB2 CN with survival was also demonstrated. [12][13][14] Currently, commercial comprehensive genomic profiling can be used to investigate the relevance of gene alterations to the clinical benefits of chemotherapies in clinical practice. Thus, there is a growing need to clarify how information on gene alterations obtained by NGS can be used to better identify biomarker-selected patients uniquely poised to benefit from precision-guided therapies.…”

HER2 Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial

“…From a translational perspective, retrospective studies showed the impact of HER2 "hyperamplification" (i.e. higher HER2 CNV or its values greater than a specific cut-off) on better outcomes of trastuzumab or even long-term response in patients with HER2-positive metastatic GC/GEJC, since higher level of HER2 amplification assessed by ISH or NGS may be a surrogate of HER2 addiction [8,9,[14][15][16]. Also, patients with higher amounts of HER2 in their tumors assessed by IHC or mass spectrometry derive greater benefit from trastuzumab-based therapy [1,10,11].…”

“…Long-term benefit from trastuzumab-based first-line therapy is observed in a minority (about 15%) of patients and the potential biological explanations are multiple. First, research showed that higher HER2 copy number variation (CNV) in tumor cells is associated with superior outcomes after HER2 targeting treatments [8,9], since HER2 "hyper-amplification" may be a surrogate of HER2 addiction and is clearly associated with long-term responses to trastuzumab. Similar results have been reported for HER2 overexpression assessed by immunohistochemistry (IHC) or mass spectrometry [1,10,11].…”