Data from Frequency of Driver Mutations in Lung Adenocarcinoma from Female Never-Smokers Varies with Histologic Subtypes and Age at Diagnosis

Abstract

<div>Abstract<p><b>Purpose:</b> 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 <i>EGFR</i>, <i>ALK</i>, <i>HER2</i>, and <i>KRAS</i>. Here, we examined the status of known driver mutations specifically in female never-smokers with lung adenocarcinoma.</p><p><b>Experimental Design:</b> Tumors were genotyped for mutations in <i>EGFR</i>, <i>KRAS</i>, <i>ALK</i>, <i>HER2</i>, and <i>BRAF</i>. 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.</p><p><b>Results:</b> Two hundred and sixty-six (76.2%) tumors harbored <i>EGFR</i> mutations, 16 (4.6%) <i>HER2</i> mutations, 15 (4.3%) <i>EML4-ALK</i> fusions, seven (2.0%) <i>KRAS</i> mutations, and two (0.6%) <i>BRAF</i> mutations. In univariate analysis, patients harboring <i>EGFR</i> mutations were significantly older (<i>P</i> < 0.001), whereas patients harboring <i>HER2</i> mutations were significantly younger (<i>P</i> = 0.036). Higher prevalence of <i>KRAS</i> (<i>P</i> = 0.028) and <i>HER2</i> (<i>P</i> = 0.021) mutations was found in invasive mucinous adenocarcinoma (IMA). The frequency of <i>EGFR</i> mutations was positively correlated with acinar predominant tumors (<i>P</i> = 0.002). Multivariate analysis revealed that older age at diagnosis (<i>P</i> = 0.013) and acinar predominant subtype (<i>P</i> = 0.005) were independent predictors of <i>EGFR</i> mutations. Independent predictors of <i>HER2</i> mutations included younger age (<i>P</i> = 0.030) and IMA (<i>P</i> = 0.017). IMA (<i>P</i> = 0.006) and poor differentiation (<i>P</i> = 0.028) were independently associated with <i>KRAS</i> mutations.</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 18(7); 1947–53. ©2012 AACR</i>.</p></div>