Human Cancer Biology Frequency of DriverMutations in LungAdenocarcinoma from Female Never-Smokers Varies with Histologic Subtypes and Age at Diagnosis

Purpose: Our 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 Design: Tumors were genotyped for mutations in EGFR, KRAS, ALK, HER2, and BRAF. Data on age, stage, tumor differentiation, histologic subtypes, andmolecular alterationswere recorded from 349 resected lung adenocarcinomas fromfemale never-smokers.We further compared the clinicopathologic parameters according to mutational status of these genes. Results: Two hundred and sixty-six (76.2%) tumors harbored EGFR mutations, 16 (4.6%) HER2 mutations, 15 (4.3%) EML4-ALK fusions, seven (2.0%) KRASmutations, and two (0.6%) BRAFmutations. In univariate analysis, patients harboring EGFR mutations were significantly older (P < 0.001), whereas patients harboring HER2 mutations were significantly younger (P 1⁄4 0.036). Higher prevalence of KRAS (P1⁄4 0.028) andHER2 (P1⁄4 0.021)mutations was found in invasivemucinous adenocarcinoma (IMA). The frequency of EGFR mutations was positively correlated with acinar predominant tumors (P 1⁄4 0.002). Multivariate analysis revealed that older age at diagnosis (P 1⁄4 0.013) and acinar predominant subtype (P 1⁄4 0.005) were independent predictors of EGFR mutations. Independent predictors of HER2 mutations included younger age (P 1⁄4 0.030) and IMA (P 1⁄4 0.017). IMA (P 1⁄4 0.006) and poor differentiation (P 1⁄4 0.028) were independently associated with KRAS mutations. Conclusions: The 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. Clin Cancer Res; 18(7); 1–7. 2012 AACR.