Presence of the minor EGFR T790M mutation is associated with drug-sensitive EGFR mutations in lung adenocarcinoma patients

Abstract

Abstract. The T790M mutation in the epidermal growth factor receptor (EGFR) gene is known to be associated with the acquired resistance of lung adenocarcinoma patients to EGFRtyrosine kinase inhibitors (EGFR-TKIs). The minor T790M mutant allele is occasionally detected in EGFR-TKI-naive tumor samples, yet findings concerning the clinical impact of the minor T790M mutation vary among previous studies. In the present study, we assessed the clinical impact of the minor T790M mutation using a novel, highly sensitive assay combining high-resolution melting (HRM), mutant-enriched PCR and co-amplification at a lower denaturation temperature (COLD)-PCR. We determined the T790M mutational status in 146 surgically resected lung adenocarcinomas without a history of EGFR-TKI treatment using mutant-enriched COLD-HRM (MEC-HRM) and standard HRM assays. The sensitivities of the MEC-HRM and standard HRM assays for the detection of T790M-mutant alleles among wild-type alleles were 0.01 and 10%, respectively. Although the T790M mutation was not detected using a standard HRM assay, we identified 19 (13%) T790M mutations using the MEC-HRM assay and defined these 19 mutations as minor T790M mutations. The proportion of T790M alleles was <0.1% in 17 (84%) of the 19 samples. Multivariate analyses revealed that a minor T790M mutation was significantly associated with the presence of EGFR exon 19 deletions or the L858R mutation (both of which are drug-sensitive EGFR mutations) (P=0.04). In conclusion, the minor EGFR T790M mutations were present in 13% of EGFR-TKI-naive surgically resected lung adenocarcinomas and were associated with drug-sensitive EGFR mutations.

Different characteristics and survival in non‐small cell lung cancer patients with primary and acquired EGFR T790M mutation

“…However, several studies have recently indicated that primary T790M mutation was present in a minor subgroup of patients prior to the TKIs treatment . The prevalence of primary T790M mutation varied by different detection methods, ranging from 0.5%–79% . However, this variation might be due to the false‐positive rate caused by highly sensitive methods used in clinical molecular testing .…”

“…With the emergence of osimertinib and high sensitivity detection method, primary T790M mutation attracted more attention . In the past, several specialists regarded primary T790M mutant as a poor prognostic factor due to its extremely poor response to first TKIs . Although primary T790M mutant patients showed better response to osimertinib, the median OS for primary T790M mutation patients was worse compared to that of acquired T790M mutation patients (29.9 months vs .…”

“…Previous studies have suggested that EGFR T790M mutant is a major cause of acquired resistance to EGFR TKIs. 10,14,[22][23][24] However, several studies have recently indicated that primary T790M mutation was present in a minor subgroup of patients prior to the TKIs treatment. 25 The prevalence of primary T790M mutation varied by different detection methods, ranging from 0.5%-79%.…”

“…However, with the development of highly sensitive methods, primary EGFR T790M mutation could be occasionally identified by routine molecular testing in TKI‐naive nonsmall cell lung cancer (NSCLC) patients . Previous studies have indicated that patients with primary T790M mutations had a poor response to first generation TKIs …”

“…13 Previous studies have indicated that patients with primary T790M mutations had a poor response to first generation TKIs. 14 Osimertinib (AZD9291) is an oral FDA-approved irreversible pyrimidine-based EGFR TKI agent that could form an irreversible covalent bond with EGFR T790M or EGFR mutation via the cysteine-797 residue. 15 The clinical efficacy of osimertinib had been proven by AURA studies.…”