Concurrent gene alterations with EGFR mutation and treatment efficacy of EGFR-TKIs in Chinese patients with non-small cell lung cancer

Abstract

PurposeWe investigated the frequency of concurrent genes in EGFR-mutant non-small cell lung cancer patients and determined its value in predicting the efficacy of EGFR-TKIs treatment.MethodsThree hundred and twenty patients, who harbored EGFR activating mutations and received EGFR-TKIs treatment, were examined for another eight genes including KRAS, NRAS, PIK3CA, BRAF, and HER2 mutations and ALK, ROS1, and RET fusion genes based on reverse transcription PCR. Progression-free survival and overall survival with EGFR-TKIs treatment were evaluated using Kaplan-Meier methods and compared between different patients using log-rank tests.RESULTSTwenty-one (6.6%) of 320 EGFR mutant samples with additional gene alterations were identified. The most common concurrent gene was PIK3CA mutation (n = 9), followed by EML4-ALK rearrangement (n = 6), HER2 mutation (n = 3), RET rearrangement (n = 1), ROS1 rearrangement (n = 1) and KRAS mutation (n = 1). Patients with single EGFR mutation had a significantly longer progression-free survival than those with concurrent genes (10.9 vs. 6.0 months, P = 0.002). Among the 21 cases, patients with PIK3CA mutation had the longest median progression-free survival (7.6 months), followed by ALK rearrangement (5.0 months) and other gene types (1.2 months). No overall survival difference was found between patients with single EGFR mutation and concurrent gene alterations (21.0 vs.17.6 months, P = 0.17).ConclusionWe demonstrated that concurrent gene alterations occurred in some patients with EGFR mutations. Concurrent gene alterations decreased the efficacy of EGFR-TKIs.

Clinical features and therapeutic options in non‐small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF

“…Rare mutations, such as the HER2 mutation and MET exon 14 skipping, can co‐occur with EGFR mutations, and patients with these types of coalteration have been reported to respond well to EGFR‐TKI or combined therapy . In our center, patients first diagnosed with NSCLC were routinely screened for EGFR , ALK , ROS1 , KRAS , and BRAF alterations.…”

“…Concomitant driver gene mutations in EGFR and ALK have been detected in 1.3%‐15.4% of the patients with non‐small cell lung cancer (NSCLC), depending on the method used . Among the patients harboring EGFR / ALK coalterations, some responded to treatment with an EGFR‐TKI (ie, gefitinib, erlotinib, icotinib, or afatinib), while others responded to treatment with an ALK‐TKI (crizotinib) or both . To the best of our knowledge, there is currently no consensus for the optimal management for these patients.…”

“…Rare driver gene mutations, such as the erb‐b2 receptor tyrosine kinase 2 ( HER2 ) mutation or MET proto‐oncogene ( MET ) exon 14 skipping, have also been found to co‐occur with other oncogenic driver mutations and were reported to respond well to TKI therapy . Meanwhile, other concomitant mutations, such as TP53 or PIK3CA mutations combined with EGFR mutations or ALK rearrangements, have been found to influence the treatment effect of TKI therapy .…”

Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line

“…In NSCLC, oncogenic driver mutations are typically mutually exclusive, although cases of mutations in multiple driver genes are increasingly reported [5,[7][8][9][10][11][12][13][14]. EGFR/KRAS co-mutation is likely to represent a certain proportion of cases of multiple mutations in NSCLC [12].…”

“…In NSCLC prior to treatment, the majority of oncogenic driver mutations are mutually exclusive with other mutations [5,6]. However, recent studies have shown that additional driver mutations such as KRAS, ALK, and PI3K mutations co-exist with EGFR-mutations in a certain percentage of lung cancers [5,[7][8][9][10][11][12][13][14]. Of note, these driver mutations have been found not only in different cell populations in tumors, but also within the same cell population [15,16].…”