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) h1 l2 t, `$ y* rClinical Cancer Researchclincancerres.aacrjournals.org
# p! k: x8 Y% \ v1 FPublished OnlineFirst February 8, 2012; doi: 10.1158/1078-0432.CCR-11-2511 % K6 G: a2 e8 X3 J4 N
Clin Cancer Res April 1, 2012 18; 1947
; X! ~( A3 ~: W1 d; \Frequency of Driver Mutations in Lung Adenocarcinoma from Female Never-Smokers Varies with Histologic Subtypes and Age at Diagnosis + ^$ ]) c' B: f! O7 g. [; M" a# g7 h
Yang Zhang1,3, Yihua Sun1,3, Yunjian Pan1,3, Chenguang Li1,3, Lei Shen2,3, Yuan Li2,3, Xiaoyang Luo1,3, Ting Ye1,3, Rui Wang1,3, Haichuan Hu1,3, Hang Li1,3, Lei Wang1,3, William Pao4, and Haiquan Chen1,3 0 w' q3 M' x0 G" t
+ Author Affiliations: x% g. C& b( o8 i+ C' z X
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Authors' Affiliations: Departments of 1Thoracic Surgery and 2Pathology, Fudan University Shanghai Cancer Center; 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; and 4Vanderbilt-Ingram Cancer Center, Nashville, Tennessee / X$ o4 M: R. g
Corresponding Author:. t% X& H; f9 `" H J. e- G
Haiquan Chen, Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai 200032, China. Phone: 86-21-6417-5590; Fax: 86-21-6268-6511; E-mail: hqchen1@yahoo.com; and William Pao, Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232. Phone: 615-936-3524; Fax: 615-343-7602; E-mail: william.pao@vanderbilt.edu
. K. ? D) z# p- NY. Zhang, Y. Sun, and Y. Pan contributed equally to this work and should be considered co-first authors.
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/ r- L" i% P2 D$ Y6 X" @ jAbstract
1 u1 x7 B8 S$ M% gPurpose: 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. / Z* @3 b7 A" A$ }
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Experimental Design: Tumors 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. $ J! d& a$ ]8 O6 E2 h- u- c
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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%) 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. 3 q% L2 y e+ v7 f6 P4 a0 e
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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); 1947–53. ©2012 AACR.
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