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.

Lay abstract

Trastuzumab is a drug that has been shown to prolong survival in some patients with advanced esophagogastric cancer whose tumor expresses a protein biomarker called HER2. There are different methods for assessing whether a patient’s tumor expresses HER2, including but not limited to traditional methods such as immunohistochemistry and in situ hybridization and novel methods such as next-generation sequencing, which detects alterations in the gene (ERBB2) that encodes the HER2 protein. In our study, we assessed concordance between HER2 status (HER2-positive or HER2-negative) measured by traditional methods and ERBB2 amplification measured by next-generation sequencing, to determine whether there was an association between concordance and clinical benefit in patients with advanced esophagogastric cancer treated with trastuzumab. Our results suggest that, when HER2 positivity is detected through traditional methods, both ERBB2 concordance (i.e., agreement that a patient’s tumor had the biomarker) and a higher ERBB2 copy number (the amount of the ERBB2 gene expressed by the tumor) were associated with longer time to treatment discontinuation and overall survival in patients with advanced esophagogastric cancer treated with first-line trastuzumab.

Keywords:

• comprehensive genomic profiling
• gastrointestinal/esophageal cancer
• HER2
• immunohistochemistry
• in situ hybridization
• molecular alteration
• next-generation sequencing
• real-world evidence
• trastuzumab

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/fon-2021-0203

Author contributions

Study design (literature, background search): J Snider, M McCusker, S Ali, E Castellanos, S Stein. Data collection: Flatiron Health, Inc. and Foundation Medicine, Inc. Data analysis (and figures as applicable): A Schrock, J Snider, M McCusker, S Stein, R Miksad. All authors contributed to data interpretation and to writing and review of the manuscript.

Acknowledgments

The authors would like to thank C Patton (Flatiron Health, Inc) for medical writing and publication management support. This study was sponsored by Flatiron Health, Inc., which is an independent subsidiary of the Roche Group.

Financial & competing interests disclosure

This study was sponsored by Flatiron Health, Inc., which is an independent subsidiary of the Roche Group. During the study period, J Snider, M McCusker, R Miksad, E Castellanos and A Swaminathan report employment at Flatiron Health, Inc., which is an independent subsidiary of the Roche Group. B Alexander, A Schrock, R Madison, S Ali and J Venstrom report employment at Foundation Medicine Inc., a wholly owned subsidiary of Roche. J Snider, M McCusker, R Miksad, E Castellanos, R Madison, B Alexander, A Schrock and A Swaminathan report stock ownership in Roche. J Snider, R Miksad and E Castellanos report equity ownership in Flatiron Health, Inc. In addition, S Ali reports employment at EQRx, advisory positions at Incysus and Elevation Oncology, and patent interests. S Stein reports con sulting/advisory roles in Genentech/Roche, Eisai, QED, Exelixis and Merck. R Miksad reports a consulting/advisory role in the De Luca Foundation. B Alexander reports consulting/advisory roles in Abbvie and Precision Health Economics, and research funding from Eli Lilly, Puma and Celgene. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance was utilized in the production of this manuscript. Identify funding for such assistance.

Data sharing statement

The data that support the findings of this study have been originated by Flatiron Health, Inc. and Foundation Medicine, Inc. These deidentified data may be made available upon request, and are subject to a license agreement with Flatiron Health and Foundation Medicine; interested researchers should contact [email protected] to determine licensing terms.

Ethical conduct of research

Institutional Review Board approval was obtained prior to study conduct, and included a waiver of informed consent.

Additional information

Funding

The authors would like to thank C Patton (Flatiron Health, Inc) for medical writing and publication management support. This study was sponsored by Flatiron Health, Inc., which is an independent subsidiary of the Roche Group