Real-World Association of HER2/ ERBB2 Concordance with Trastuzumab Clinical Benefit in Advanced Esophagogastric Cancer

Abstract

Aim: To assess concordance between HER2 status measured by traditional methods and ERBB2 amplification measured by next-generation sequencing and its association with first-line trastuzumab clinical benefit in patients with advanced esophagogastric cancer. Methods: Retrospective analysis of HER2/ ERBB2 concordance using a deidentified USA-based clinicogenomic database. Clinical outcomes were assessed for patients with HER2+ advanced esophagogastric cancer who received first-line trastuzumab. Results: Overall HER2/ ERBB2 concordance was 87.5%. Among patients who received first-line trastuzumab, concordant HER2/ ERBB2 was associated with longer time to treatment discontinuation (adjusted hazard ratio [aHR]: 0.63; 95% CI: 0.43–0.90) and overall survival (aHR: 0.51; 95% CI: 0.33–0.79). ERBB2 copy number ≥25 (median) was associated with longer time to treatment discontinuation (aHR: 0.56; 95% CI: 0.35–0.88) and overall survival (aHR: 0.52; 95% CI: 0.30–0.91). Conclusion: HER2/ ERBB2 concordance and higher ERBB2 copy number predicted clinical benefit from trastuzumab.

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

“…We did observe longer rwOS for patients with advGEA positive for HER2 by IHC or FISH treated with first-line trastuzumab with ERBB2 amplification detected by NGS versus those negative for amplification by NGS (Data Supplement), consistent with existing literature. 15 …”

“… 15 Further exploratory analysis using median ERBB2 CN as a cutoff suggested that ERBB2 CN can be used effectively to further stratify best responders to anti-HER2 therapy, suggesting additional utility for quantitative NGS testing. 15 , 16 …”

“…We also observed that a small subset of patients without ERBB2 amp detected on CGP received chemotherapy in combination with anti-HER2 therapy following CGP report, and in the majority of these cases, the patient had a prior positive HER2 IHC and/or ISH result, despite the generally high reported concordance between IHC and ISH testing for HER2 expression and the CGP methodology used for ERBB2 amplification detection in this study (88%-98%). 14 , 15 …”

“…We also observed that a small subset of patients without ERBB2amp detected on CGP received chemotherapy in combination with anti-HER2 therapy following CGP report, and in the majority of these cases, the patient had a prior positive HER2 IHC and/or ISH result, despite the generally high reported concordance between IHC and ISH testing for HER2 expression and the CGP methodology used for ERBB2 amplification detection in this study (88%-98%). 14,15 Historically, IHC testing for HER2 overexpression has been considered the gold standard and remains so according to published guidelines. However, many testing modalities including NGS for ERBB2amp are now clinically available as validated US Food and Drug Administration-approved assays and studies correlating testing results with clinical outcomes to anti-HER2 therapies are needed.…”

“… 15 Stein et al and others have also presented data suggesting that higher ERBB2 copy number (CN) gain as quantified by NGS is associated with better efficacy outcomes to anti-HER2 therapy compared with lower levels of ERBB2 amp in GEA. 15 , 16 Earlier studies have also presented data showing that higher ERBB2 CN by ISH is predictive of better response to anti-HER2 therapy. 17 The NCCN guidelines for esophageal and esophagogastric junction cancer and for gastric cancer (version 2.2021) recommend IHC or ISH for adenocarcinomas as the gold standard for selection of anti-HER2 therapy and NGS as an alternative subsequent option; however, these studies suggest a role for ERBB2 amp detection by NGS, including CN quantification, as a further predictive marker of HER2 therapy benefit.…”