Revisiting Epidermal Growth Factor Receptor (EGFR) Amplification as a Target for Anti-EGFR Therapy: Analysis of Cell-Free Circulating Tumor DNA in Patients With Advanced Malignancies.

Shumei Kato,Peter Vu,Paul T Fanta,Aaron Goodman,Razelle Kurzrock,Scott M Lippman,Richard B Schwab,Ryosuke Okamura,Sandip P Patel,Victoria M Raymond,Richard B Lanman,Manvita Mareboina,Jason K Sicklick,Suzanna Lee

doi:10.1200/po.18.00180

Abstract

PurposeTo date, evidence for tissue epidermal growth factor receptor (EGFR) overexpression as a biomarker for anti-EGFR therapies has been weak. We investigated the genomic landscape of EGFR amplification in blood-derived cell-free tumor DNA (cfDNA) across diverse cancers and the role of anti-EGFR therapies in achieving response.MethodsWe assessed EGFR amplification status among 28,584 patients with malignancies evaluated by clinical-grade next-generation sequencing (NGS) of blood-derived cfDNA (54- to 73-gene panel). Furthermore, we curated the clinical characteristics of 1,434 patients at the University of California San Diego who had cfDNA testing by this NGS test.ResultsOverall, EGFR amplification was detected in cfDNA from 8.5% of patients (2,423 of 28,584), most commonly in colorectal (16.3% [458 of 2,807]), non–small-cell lung (9.0% [1,096 of 12,197]), and genitourinary cancers (8.1% [170 of 2,104]). Most patients had genomic coalterations (96.9% [95 of 98]), frequently involving genes affecting other tyrosine kinases (72.4% [71 of 98]), mitogen-activated protein kinase cascades (56.1% [55 of 98]), cell-cycle–associated signals (52.0% [51 of 98]), and the phosphoinositide 3-kinase pathway (35.7% [35 of 98]). EGFR amplification emerged in serial cfDNA after various anticancer therapies (n = 6), including checkpoint inhibitors (n = 4), suggesting a possible role for these amplifications in acquired resistance. Nine evaluable patients with EGFR amplification were treated with anti-EGFR–based regimens; five (55.6%) achieved partial responses, including three patients whose tissue NGS lacked EGFR amplification.ConclusionEGFR amplification was detected in cfDNA among 8.5% of 28,584 diverse cancers. Most patients had coexisting alterations. Responses were observed in five of nine patients who received EGFR inhibitors. Incorporating EGFR inhibitors into the treatment regimens of patients harboring EGFR amplification in cfDNA merits additional study.

Highlights

Epidermal growth factor receptor (EGFR), known as human epidermal growth factor receptor 1 (HER1) or ErbB1, is a receptor tyrosine kinase that belongs to the ErbB family proteins
Among 28,584 patients with diverse solid malignancies whose cell-free tumor DNA (cfDNA) was evaluated at a central laboratory, 8.5% (n = 2,423) had EGFR amplification
The most common cogenomic alterations associated with EGFR amplification was TP53 (65.3% [64 of 98]), MET CDK6 PIK3CA

Summary

Introduction

Epidermal growth factor receptor (EGFR), known as human epidermal growth factor receptor 1 (HER1) or ErbB1, is a receptor tyrosine kinase that belongs to the ErbB family proteins. Along with EGFR, the ErbB family includes. Functional activation of EGFR via mutation or amplification/overexpression has been identified in many tumor types, including lung, head and neck, gastroesophageal, and colorectal cancers, and has been associated with proliferation, invasion, and metastasis.[3,4] Alterations in EGFR have been linked to primary resistance and accelerated tumor growth (designated as hyperprogression) from immune checkpoint inhibitors.[5,6,7] Because of its critical role in tumor aggressiveness, EGFR has been an attractive target for anticancer therapy.[1] To date, there are various anti-EGFR therapies that are US Food and Drug Administration approved, including erlotinib, gefitinib, afatinib, and osimertinib for non–small-cell lung cancer (NSCLC) with specific activating EGFR mutations,[8] cetuximab and panitumumab for colorectal cancer without KRAS or NRAS mutations,[9] cetuximab for head and neck cancer,[10] and necitumumab for squamous cell carcinoma of lung.[11]

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