Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: a comprehensive mutation profiling from 5125 Chinese cohorts

Abstract

Background:Determining the somatic mutations of epidermal growth factor receptor (EGFR)-pathway networks is the key to effective treatment for non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors (TKIs).The somatic mutation frequencies and their association with gender, smoking history and histology was analysed and reported in this study.Methods:Five thousand one hundred and twenty-five NSCLC patients' pathology samples were collected, and EGFR, KRAS, BRAF and PIK3CA mutations were detected by multiplex testing. The mutation status of EGFR, KRAS, BRAF and PIK3CA and their association with gender, age, smoking history and histological type were evaluated by appropriate statistical analysis.Results:EGFR, KRAS, BRAF and PIK3CA mutation rates revealed 36.2%, 8.4%, 0.5% and 3.3%, respectively, across the 5125 pathology samples. For the first time, evidence of KRAS mutations were detected in two female, non-smoking patients, age 5 and 14, with NSCLC. Furthermore, we identified 153 double and coexisting mutations and 7 triple mutations. Interestingly, the second drug-resistant mutations, T790M or E545K, were found in 44 samples from patients who had never received TKI treatments.Conclusions:EGFR exons 19, 20 and 21, and BRAF mutations tend to happen in females and non-smokers, whereas KRAS mutations were more inclined to males and smokers. Activating and resistant mutations to EGFR-TKI drugs can coexist and ‘second drug-resistant mutations', T790M or E545K, may be primary mutations in some patients. These results will help oncologists to decide candidates for mutation testing and EGFR-TKI treatment.

Mutation and prognostic analyses of PIK3CA in patients with completely resected lung adenocarcinoma

“…The incidence of PIK3CA mutation was around 3% in lung adenocarcinoma and 5–10% in squamous cell carcinoma 12, 13, 14, 15. In this study, the frequency of PIK3CA mutation at 2.8% was consistent with that of previous studies.…”

“…Mutation in PIK3CA signaling pathways may induce resistance to EGFR‐TKIs of lung cancer patients. Although reported in previous studies, treatment and efficacy data of patients harboring PIK3CA mutations were not available 12, 13. The results of a meta‐analysis showed that PIK3CA mutation adversely affected the clinical efficacy and OS of NSCLC patients on EGFR‐TKIs 14.…”

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

“…BRAF p.V600E mutation is more frequent in females 52,54 and never smokers 54 in some studies, but several studies failed to show these associations. 49,50,53,58 One distinction between BRAF mutations and other Figure 1 Forest plot of sensitivity and specificity for immunohistochemistry (IHC)-based determination of ROS1 rearrangement positivity compared with fluorescence in situ hybridization.…”

“…FN, false-negative; FP, false-positive; TN, true-negative; TP, true-positive. jmd.amjpathol.org -The Journal of Molecular Diagnostics targetable oncogenes is that non-p.V600E BRAF mutations (particularly the exon 11 mutations) may coexist with mutations in KRAS, 49,52,53,59 whereas the p.V600E mutations are mutually exclusive of KRAS, EGFR, or ALK alterations.…”

“…95 Five studies attempted to identify associations between patient or tumor characteristics and KRAS mutational status. 49,52,92,93,95 Two MAs 93,94 reported on overall survival and EGFR-TKI response rates when KRAS mutationepositive patients were treated with standard care. All included studies were assessed for quality and none were found to have methodologic flaws that would raise concerns about the studies' findings (SDC Table 16).…”