Contribution of KRAS mutations and c.2369C > T (p.T790M) EGFR to acquired resistance to EGFR-TKIs in EGFR mutant NSCLC: a study on circulating tumor DNA

Abstract

IntroductionKRAS oncogene mutations (MUTKRAS) drive resistance to EGFR inhibition by providing alternative signaling as demonstrated in colo-rectal cancer. In non-small cell lung cancer (NSCLC), the efficacy of treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) depends on activating EGFR mutations (MUTEGFR). However, inhibition of EGFR may select resistant cells displaying alternative signaling, i.e., KRAS, or restoration of EGFR activity due to additional MUTEGFR, i.e., the c.2369C > T (p.T790MEGFR).AimThe aim of this study was to investigate the appearance of MUTKRAS during EGFR-TKI treatment and their contribution to drug resistance.MethodsThis study used cell-free circulating tumor DNA (cftDNA) to evaluate the appearance of codon 12 MUTKRAS and p.T790MEGFR mutations in 33 advanced NSCLC patients progressing after an EGFR-TKI.Resultsp.T790MEGFR was detected in 11 (33.3%) patients, MUTKRAS at codon 12 in 3 (9.1%) while both p.T790MEGFR and MUTKRAS codon 12 were found in 13 (39.4%) patients. Six patients (18.2%) were KRAS wild-type (WTKRAS) and negative for p.T790MEGFR. In 8 subjects paired tumor re-biopsy/plasma samples were available; the percent concordance of tissue/plasma was 62.5% for p.T790MEGFR and 37.5% for MUTKRAS. The analysis of time to progression (TTP) and overall survival (OS) in WTKRAS vs. MUTKRAS were not statistically different, even if there was a better survival with WTKRAS vs. MUTKRAS, i.e., TTP 14.4 vs. 11.4 months (p = 0.97) and OS 40.2 vs. 35.0 months (p = 0.56), respectively.ConclusionsMUTKRAS could be an additional mechanism of escape from EGFR-TKI inhibition and cftDNA is a feasible approach to monitor the molecular development of drug resistance.

Utility of Genomic Assessment of Blood-Derived Circulating Tumor DNA (ctDNA) in Patients with Advanced Lung Adenocarcinoma

“…Lastly, our study demonstrated that patients with at least one alteration with a percentage of ctDNA ≥ 5% had a shorter overall survival (median 4.2 months versus not reached at a median follow up of 7.5 months, P=0.012) (Figure 4), consistent with a prior study performed on diverse cancer types (48) and various other studies describing the prognostic value of ctDNA including in patients with lung cancer (33,46–49). …”

Heterogeneity of resistance mutations detectable by next-generation sequencing in TKI-treated lung adenocarcinoma

“…To our knowledge, this is the first convincing example of a KRAS mutation acquired following TKI therapy, presumably as a resistance mechanism. The role of KRAS mutations in acquired TKI resistance was also supported by a recent study demonstrating a high incidence of KRAS mutations in the cell-free circulating tumor DNA from TKI-resistant NSCLC patients [47]. Further studies are needed to evaluate the analytic specificity (or background noise) of an assay with relatively high analytic sensitivity and to confirm the clinical specificity of an assay in circulating tumor DNA detecting a mutation commonly seen in other neoplasms.…”

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

“…The emergence of KRAS activating mutation in patients treated with first-generation EGFR-TKIs was previously described and postulated as a potential mechanism of escape from EGFR-TKI inhibition (39). Ortiz-Cuaran and colleagues described a patient treated with osimertinib that presented p.C797S in a plasma sample with corresponding re-biopsy C797S and T790M-negative but KRAS G12S-positive (13).…”