Research On Oncogenic Driver Mutations In Lung Adenocarcinoma

Part I Frequency of driver mutations in lung adenocarcinoma from female never-smokers varies with histologic subtypes and age at diagnosisOur previous study revealed that90%(47of52;95%CI:0.79-0.96) of Chinese never-smokers with lung adenocarcinoma harbor known oncogenic driver mutations in just four genes:EGFR, ALK, HER2, and KRAS. Here, we examined the status of known driver mutations specifically in female never-smokers with lung adenocarcinoma.Tumors were genotyped for mutations in EGFR, KRAS, ALK, HER2, and BRAE. Data on age, stage, tumor differentiation, histological subtypes, and molecular alterations were recorded from349resected lung adenocarcinomas from female never-smokers. We further compared the clinicopathological parameters according to mutational status of these genes.Two hundred and sixty-six (76.2%) tumors harbored EGFR mutations,16(4.6%) NER2mutations,15(4.3%) EML4-ALK fusions, seven (2.0%) KRAS mutations, and two (0.6%) BRAFmutations. In univariate analysis, patients harboring EGFR mutations were significantly older (P<0.001), whereas patients harboring HER2mutations were significantly younger (P=0.036). Higher prevalence of KRAS (P=0.028) and HER2(P=0.021) mutations was found in invasive mucinous adenocarcinoma (IMA). The frequency of EGFR mutations was positively correlated with acinar predominant tumors (P=0.002). Multivariate analysis revealed that older age at diagnosis (P=0.013) and acinar predominant subtype (P=0.005) were independent predictors of EGFR mutations. Independent predictors of HER2mutations included younger age (P=0.030) and IMA (P=0.017). IMA (P=0.006) and poor differentiation (P=0.028) were independently associated with KRAS mutations.The frequency of driver mutations in never-smoking female lung adenocarcinoma varies with histological subtypes and age at diagnosis. These data have implications for both clinical trial design and therapeutic strategies. Part II Prevalence, clinicopathologic characteristics and molecular associations of EGFR exon20insertion mutations in East Asian patients with lung adenocarcinoma.Compared to lung adenocarcinomas with classic activating EGFR mutations (EGFR exon19deletions and L858R), those harboring exon20insertion mutations usually show de-novo resistance to EGFR tyrosine kinase inhibitors (TKIs), and were rarely studied. We aimed to define the prevalence, clinicopathologic characteristics and molecular associations of EGFR exon20insertion mutations in East Asian lung adenocarcinoma patients.One thousand and eighty-six lung adenocarcinomas were sequenced for EGFR mutations. Data on age, sex, smoking history, tumor differentiation, pathologic TNM stage, adenocarcinoma histologic subtypes, recurrence-free and overall survival were collected. EGFR copy number variations and protein expression in lung adenocarcinomas with EGFR exon20insertion mutations were investigated.EGFR exon20insertion mutations were present in2.9%of lung adenocarcinomas from East Asian patients and4.7%of all the EGFR mutations. Compared to those with classic activating EGFR mutations, lung adenocarcinomas with exon20insertion mutations were characterized by significantly younger age at diagnosis (P=0.032for exon20insertions vs. L858R), shorter relapse-free survival (P=0.045for exon20insertions vs. exon19deletions), and higher percentage of EGFR gene copy number gains (P=0.028for exon20insertions vs. exon19deletions).Lung adenocarcinomas with EGFR exon20insertion mutations were present in a substantial proportion. This subset showed distinct clinicopathologic and molecular features compared to those with classic EGFR activating mutations. Our results have implications for the development of therapeutic strategies targeting this significant cohort of lung cancer patients.