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Case series of EGFR C797S mutations in non-small cell lung cancer identified with cell-free circulating tumor DNA next generation sequencing.
Background: In non-small cell lung cancer (NSCLC), targeted treatment with first line tyrosine kinase inhibitors (TKIs) selects for the evolution of resistance at EGFR T790M in 50% of cases. To address this clinical challenge, third-generation pyrimidine-based EGFR TKIs with selectivity for EGFR T790M over wild-type EGFR have been developed. These drugs form a covalent bond with cysteine 797 in the adenosine triphosphate–binding pocket. Here we report a case series of EGFR C797S mutations identified with cell-free circulating tumor DNA (cfDNA) next generation sequencing (NGS). Methods: Guardant360 utilizes cfDNA NGS to target 70 genes for single nucleotide variants (SNVs), including all 28 exons and partial introns in EGFR. EGFR C797S SNVs were identified in the Guardant Health database of 13,987 cfDNA samples (12,086 patients) from June 2014 through January 2016 and phased with the neighboring T790M mutation to determine if these mutations occurred in cis or trans. Results: T790M mutation was identified in 311 NSCLC patients (352 samples) and 8 of whom had C797S mutations (11 samples). EGFR exon 19 deletions were the primary EGFR driver, with a median mutant allele fraction (MAF) of 6.55% (range 0.4% to 64.1%). T790M mutations in samples with C797S mutations had a median MAF of 1.42% (range 0.58% to 37.61%). C797S mutations were observed in cis with T790M in 8 cases and had an initial median MAF of 0.33% (range 0.14% to 33.01%), which composed 12%-100% (median 45.21%) of the T790M fraction. Five patients with C797S mutations had samples collected prior to the emergence of T790M. The average time from T790M detection to C797S detection was 77 days. Five patients’ tumors evolved two simultaneous C797S mutations, consistent with convergent sub-clonal evolution after third generation TKI treatment. Conclusions: The detection of drug resistance mutations in NSCLC patients with cfDNA NGS demonstrates that cfDNA NGS can identify and quantify resistance mutations that arise under selective treatment pressure without the need for invasive biopsy and assist clinicians in determining the timing and selection of next line therapy.