Detection of Low-Frequency KRAS Mutations in cfDNA From EGFR-Mutated NSCLC Patients After First-Line EGFR Tyrosine Kinase Inhibitors

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.ResultsKRAS 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.

Delaying Emergence of Resistance to KRAS Inhibitors with Adaptive Therapy: “Treatment-to-Contain” Instead of “Treatment-to-Cure”

“…The percentage of KRAS mutant alleles detected in the resistant tumours ranged from 0.4% to 17% [19]. Aside from that, KRAS mutations have been designated to be a driver mutation in cancer, with several publications demonstrating a low allelic frequency of KRAS concomitantly existing alongside other driver mutations such as EGFR [20,21], and it was found that de novo KRAS G12C mutation was present ranging from 0.2% [22] to 1.17% of detected samples (n = 6) [23,24]. Detecting de novo KRAS mutation requires high sensitivity and specificity technology, and it was found that KRAS mutation was absent using droplet digital PCR.…”

Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges

“…Of note, a KRAS mutation is a negative predictor of response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs; e.g., cetuximab, gefitinib, or erlotinib) (Table 2) [33][34][35][36], but a positive predictor of response to immune checkpoint inhibitors (ICIs; including anti-PD-1 and anti-PD-L1) (Table 3) [37][38][39]. However, response rates are variable and dissenting reports suggest that KRAS mutations cannot guide the therapeutic choice between TKIs and ICIs in NSCLC patients [40,41]. In PDAC, patients with KRAS-G12D mutations (but not total KRAS mutations) have a worse prognosis than patients with wild-type KRAS [42][43][44].…”

Non-Small Cell Lung Cancer Harboring Concurrent EGFR Genomic Alterations: A Systematic Review and Critical Appraisal of the Double Dilemma

“…Notably, their PFS was significantly shorter compared to EGFR mutations (2.42 months vs. 11.09 months; p = 0.0081), and also the ORR was poorer (16.7% vs. 57.1%). Additionally, Nardo et al analyzed the prevalence of concurrent KRAS mutations on 106 patients with EGFR-mutant NSCLC focusing on their impact on clinical outcome [32]. Indeed, KRAS co-alterations were detected in 3 patients with a VAF of less than 0.2%, which showed poor clinical outcome to first-line EGFR-TKI, in terms of time to treatment failure (TTF), OS and PFS (five, six and five months, respectively).…”