Abstract
BackgroundMolecular profiling of advanced EGFR mutated NSCLC has recently demonstrated the co-existence of multiple genetic alterations. Specifically, co-existing KRAS-mutations in EGFR NSCLCs have been described, despite their prevalence at progression and their role in the response to EGFR tyrosine kinase inhibitors (TKIs) remain marginally explored. Aim of our study was to investigate the prevalence of co-existing KRAS mutations at the time of progressive disease and explore their impact on clinical outcome.Materials and MethodsWe retrospectively analyzed by digital droplet PCR prevalence of KRAS co-mutations in 106 plasma samples of EGFR mutated NSCLC patients, in progressive disease after EGFR TKI treatment as first-line therapy.Results KRAS co-mutations (codon 12 and 13) were identified in 3 patients (2.8% of analyzed samples), with low allelic frequency (<0.2%), and had a negative impact on clinical outcome to first-line EGFR TKI.ConclusionDetection of KRAS mutations in cell-free DNA of EGFR mutant NSCLC patients at progression after first or second generation EGFR TKI is a rare event. Due to their low abundance, the negative impact of KRAS mutations on the response to EGFR TKI remains to be confirmed in larger studies.
Highlights
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide with five-year survival rate less than 10% among patients with advanced disease [1]
From 2016 to 2019, 122 patients with advanced epidermal growth factor receptor (EGFR) mutated NSCLC referring to our Institution received treatment with a first- or second -EGFR-tyrosine kinase inhibitors (TKIs) as first-line therapy and underwent Cell Free DNA (cfDNA) genotyping for assessment of EGFR mutations at progression
We report a retrospective evaluation of the prevalence of codon 12 and 13 KRAS co-mutations in EGFR mutated NSCLC patients in progressive disease after EGFR TKI treatment as first-line therapy, with the aim to establish their prevalence and explore their impact on clinical outcome
Summary
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide with five-year survival rate less than 10% among patients with advanced disease [1]. Activating mutations in the epidermal growth factor receptor (EGFR) gene occur as early cancer-driving clonal event [2] in a subset of NSCLC patients (approximately 15% of Caucasian patients) and predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) [3]. Other less common EGFR- independent mechanisms of resistance include activation of bypassing pathways and histologic transformation to small-cell lung cancer (10–15% of cases) [9,10,11]. Co-existing KRAS-mutations in EGFR NSCLCs have been described, despite their prevalence at progression and their role in the response to EGFR tyrosine kinase inhibitors (TKIs) remain marginally explored. Aim of our study was to investigate the prevalence of co-existing KRAS mutations at the time of progressive disease and explore their impact on clinical outcome
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