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

Abstract

To 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 <i>EGFR</i> amplification in blood-derived cell-free tumor DNA (cfDNA) across diverse cancers and the role of anti-EGFR therapies in achieving response. We assessed <i>EGFR</i> 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. Overall, <i>EGFR</i> 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]). <i>EGFR</i> 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 <i>EGFR</i> amplification were treated with anti-EGFR-based regimens; five (55.6%) achieved partial responses, including three patients whose tissue NGS lacked <i>EGFR</i> amplification. <i>EGFR</i> 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 <i>EGFR</i> amplification in cfDNA merits additional study.