Spectrum Of Targeted-therapy Related Oncogenic Driver Mutations In Lung Adenocarcinoma Of Smokers

[BACKGROUND]Lung cancer is the most frequently diagnosed cancers in men and the leading cause of cancer-related death in both developed and developing countries. Despite the therapeutic progress, the overall5-year survival remains low. In the last decade, target therapy had developed rapidly, especially the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib. Wealth of data from genomic, expression, mutational, and proteomic profiling studies, as well as various mouse lung tumor models, has led to the identification of additional molecular driver mutations in lung cancer. Based on these results, one promising treatment strategy involves the further subdivision of NSCLC into clinically relevant molecular subsets, according to a classification schema based on specific so-called driver mutations, such as EGFR, KRAS, HER2, BRAF, PIK3CA and EML4-ALK.[OBJECTIVE]We performed this analysis to reveal the association between6well-identified oncogenic driver mutations and clinical and pathological features in lung adenocarcinomas from smokers in East Asia. It may have the potentiality to optimize existing treatment strategies and clinical trial design.[METHODS]In this series,230resected lung adenocarcinomas from smoker (>100cigarettes in lifetime) at single center (Shanghai Cancer Center, Shanghai, China) were tested for mutation in EGFR, KRAS, BRAF, HER2, EML4-ALK and PIK3CA. Further we compared the mutation frequency with sex, age at diagnosis, stage, differentiation, smoking dose, and histological subtype. [RESULTS]Among230smokers, we detected100(43.5%) EGFR mutations,38(16.5%) KRAS mutations,8(3.5%) PIK3CA mutations,7(3.0%) BRAF mutations and7(3.0%) EML4-ALK fusions. No HER2mutation was found. EGFR mutations occurred at a significantly higher frequency in patients with smoking dose≤20pack-years (p<0.001) or age≥60years old at diagnosis (p=0.018). Smoking dose>20pack-years and age<60years old at diagnosis were associated with the presence of KRAS mutation. With regard to association between histological subtypes and driver mutation frequency, EGFR mutation had positive correlation with histological subtype micropapillary (p=0.003), lepidic (p=0.011), as well as papillary (p=0.05) predominant adenocarcinoma. Negative correlation was found between EGFR mutation and solid predominant (p<0.001), as well as invasive mucinous adenocarcinoma (IMA)(p=0.006). Besides, KRAS mutation had positive correlation with IMA (p=0.043). The frequency of EGFR mutation decreased with increasing tobacco dose. In contrast, higher frequency of KRAS mutations was observed with increasing tobacco dose. Generally, the frequency of these driver mutations tested in our study decreased with increasing smoking dose.[CONCLUSIONS]This study represents the first comprehensive and concurrent analysis of these six well-identified driver mutations in a large cohort of lung adenocarcinoma from East-Asian smokers. Our molecular data in conjunction with the clinical and pathological features indicated that prospective genotyping of lung adenocarcinomas from smokers for these genetic alterations could lead to rationally chosen targeted therapy in the overwhelming majority of cases.