• Yang Zhang, Yihua Sun, Yunjian Pan, Chenguang Li, Lei Shen, Yuan Li, Xiaoyang Luo, Ting Ye, Rui Wang, Haichuan Hu, Hang Li, Lei Wang, William Pao, and Haiquan Chen.
• Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai 200032, China.
• Clin Cancer Res. 2012 Apr 1; 18 (7): 1947-53.

PurposeOur previous study revealed that 90% [47 of 52; 95% confidence interval (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.Experimental DesignTumors were genotyped for mutations in EGFR, KRAS, ALK, HER2, and BRAF. Data on age, stage, tumor differentiation, histologic subtypes, and molecular alterations were recorded from 349 resected lung adenocarcinomas from female never-smokers. We further compared the clinicopathologic parameters according to mutational status of these genes.ResultsTwo hundred and sixty-six (76.2%) tumors harbored EGFR mutations, 16 (4.6%) HER2 mutations, 15 (4.3%) EML4-ALK fusions, seven (2.0%) KRAS mutations, and two (0.6%) BRAF mutations. In univariate analysis, patients harboring EGFR mutations were significantly older (P < 0.001), whereas patients harboring HER2 mutations 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 HER2 mutations 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.ConclusionsThe frequency of driver mutations in never-smoking female lung adenocarcinoma varies with histologic subtypes and age at diagnosis. These data have implications for both clinical trial design and therapeutic strategies.©2012 AACR.

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