Molecular Divergence upon EGFR-TKI Resistance Could Be Dependent on the Exon Location of the Original EGFR-Sensitizing Mutation

SIMPLE SUMMARY: In this study, we report that the exon location of the original EGFR-sensitizing mutation could drive resistance mechanisms underlying tumor progression in advanced EGFR-positive NSCLC patients under targeted therapies. In our study, plasma detection of the p.T790M EGFR resistance mutation, upon disease progression, was more frequent in tumors with an EGFR exon 19 deletion (p = 0.0028). Furthermore, oncogenic mutations of KRAS, arising upon disease progression in 5.6% of the cases, were always detected in patients with tumors harboring EGFR exon 18 or 21-sensitizing mutations (p < 0.001). ABSTRACT: Tumor molecular profiling upon disease progression enables investigations of the tumor evolution. Next-generation sequencing (NGS) of liquid biopsies constitutes a noninvasive readily available source of tumor molecular information. In this study, 124 plasma samples from advanced EGFR-positive NSCLC patients, treated with a first-line EGFR tyrosine kinase inhibitor (EGFR-TKI) were collected upon disease progression. The circulating cell-free DNA (cfDNA) was sequenced using the Oncomine Pan-Cancer Cell-Free Assay™. Excluding EGFR mutations, the most frequently mutated gene was TP53 (57.3%), followed by APC (11.3%), FGFR3 (7.3%), and KRAS (5.6%). Different molecular alterations were observed upon disease progression depending on the location of the original EGFR-sensitizing mutation. Specifically, the detection of the p.T790M mutation was significantly associated with the presence of exon 19 mutations in EGFR (Fisher p-value: 0.028). All KRAS activating mutations (n = 8) were detected in tumors with EGFR mutations in exons 18 and 21 (Fisher p-value < 0.001). Similarly, mutations in NRAS and HRAS were more frequently detected in samples from tumors harboring mutations in exons 18 or 21 (Fisher p-value: 0.050 and Fisher p-value: 0.099, respectively). In conclusion, our data suggest that the mechanisms underlying EGFR-TKI resistance could be dependent on the exon location of the original EGFR-sensitizing mutation.