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

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.