Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement

被引:135
作者
Kim, Hye Ryun [2 ]
Shim, Hyo Sup [3 ]
Chung, Jin-Haeng [4 ]
Lee, Young Joo [5 ]
Hong, Yun Kyoung [6 ]
Rha, Sun Young [2 ]
Kim, Se Hoon [7 ]
Ha, Sang-Jun [8 ]
Kim, Se Kyu [2 ]
Chung, Kyung Young [9 ]
Soo, Ross [10 ]
Kim, Joo Hang [2 ]
Cho, Byoung Chul [1 ,2 ]
机构
[1] Yonsei Univ, Coll Med, Div Med Oncol, Yonsei Canc Ctr, Seoul 120752, South Korea
[2] Yonsei Univ, Coll Med, Dept Internal Med, Seoul 120752, South Korea
[3] Ewha Womans Univ, Sch Med, Dept Pathol, Seoul, South Korea
[4] Seoul Natl Univ, Coll Med, Bundang Hosp, Dept Pathol, Seoul, South Korea
[5] Natl Canc Ctr, Dept Med Oncol, Goyang, South Korea
[6] JE UK Inst Canc Res, Gumi, Kyungbuk, South Korea
[7] Yonsei Univ, Coll Med, Dept Pathol, Seoul 120752, South Korea
[8] Yonsei Univ, Coll Life Sci & Biotechnol, Dept Biochem, Seoul 120752, South Korea
[9] Yonsei Univ, Coll Med, Dept Thorac & Cardiovasc Surg, Seoul 120752, South Korea
[10] Natl Univ Hlth Syst, Natl Univ Canc Inst, Dept Hematol Oncol, Singapore, Singapore
关键词
EGFR; KRAS; ALK; never-smoker; nonsmall cell lung carcinoma; FACTOR-RECEPTOR GENE; EML4-ALK FUSION GENE; SOMATIC MUTATIONS; IMPACT; GEFITINIB; SMOKING; ADENOCARCINOMA; TARGET; RATES; RISK;
D O I
10.1002/cncr.26311
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BACKGROUND: The objectives of this study were to determine the proportions of major oncogenic alterations and to examine survival in genotype-specific subsets of never-smokers with nonsmall cell lung cancer (NSCLC). METHODS: The authors concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes and investigated anaplastic lymphoma kinase (ALK) gene rearrangements in samples from 229 never-smokers with NSCLC. ALK rearrangements were identified by fluorescent in situ hybridization and were confirmed by immunohistochemistry. Mutations in EGFR (exons 18 to 21) and KRAS (codons 12 and 13) were determined by direct sequencing. RESULTS: Of 229 tumors, the frequency of EGFR mutations, ALK rearrangements, KRAS mutations, and no mutations (wild type [ WT]) in any of the 3 genes (WT/WT/WT) was 48%, 8.3%, 3.5%, and 40.2%, respectively. All genetic alterations were mutually exclusive. The median progression-free survival after treatment with EGFR tyrosine kinase inhibitors (TKIs) was 12.8 months, 6.3 months, 2.1 months, and 1.6 months in patients with EGFR mutations, the WT/WT/WT genotype, KRAS mutations, and ALK rearrangements, respectively. In a Cox regression model, the adjusted hazard ratio for the risk of disease progression after treatment with EGFR TKIs was 0.59 (95% confidence interval [ CI], 0.40-0.87; P.008) for patients with EGFR mutations, 4.58 (95% CI, 2.07-10.15; P <.001) for patients with ALK rearrangements, and 4.23 (95% CI, 1.65-10.8; P.003) for patients with KRAS mutations. Overall survival also differed significantly among genotypes. CONCLUSIONS: To the authors' knowledge, this was the largest comprehensive and concurrent analysis to date of 3 major oncogenic alterations in a cohort of East Asian never-smokers with NSCLC. Because survival outcomes differed among genotypes, and drugs that target specific alterations currently are available, genetic profiling to identify genotype-specific subsets can lead to successful treatment with appropriate kinase inhibitors. Cancer 2012; 118: 729-39. (C) 2011 American Cancer Society.
引用
收藏
页码:729 / 739
页数:11
相关论文
共 50 条
[1]   The 2004 World Health Organization classification of lung tumors [J].
Beasley, MB ;
Brambilla, E ;
Travis, WD .
SEMINARS IN ROENTGENOLOGY, 2005, 40 (02) :90-97
[2]   Incidence of lung cancer in a large cohort of non-smoking men from Sweden [J].
Boffetta, P ;
Järvholm, B ;
Brennan, P ;
Nyrén, O .
INTERNATIONAL JOURNAL OF CANCER, 2001, 94 (04) :591-593
[3]   Anaplastic Lymphoma Kinase Gene Rearrangements in Non-small Cell Lung Cancer are Associated with Prolonged Progression-Free Survival on Pemetrexed [J].
Camidge, D. Ross ;
Kono, Scott A. ;
Lu, Xian ;
Okuyama, Sonia ;
Baron, Anna E. ;
Oton, Ana B. ;
Davies, Angela M. ;
Varella-Garcia, Marileila ;
Franklin, Wilbur ;
Doebele, Robert C. .
JOURNAL OF THORACIC ONCOLOGY, 2011, 6 (04) :774-780
[4]   An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors [J].
Chitale, D. ;
Gong, Y. ;
Taylor, B. S. ;
Broderick, S. ;
Brennan, C. ;
Somwar, R. ;
Golas, B. ;
Wang, L. ;
Motoi, N. ;
Szoke, J. ;
Reinersman, J. M. ;
Major, J. ;
Sander, C. ;
Seshan, V. E. ;
Zakowski, M. F. ;
Rusch, V. ;
Pao, W. ;
Gerald, W. ;
Ladanyi, M. .
ONCOGENE, 2009, 28 (31) :2773-2783
[5]   Somatic mutations affect key pathways in lung adenocarcinoma [J].
Ding, Li ;
Getz, Gad ;
Wheeler, David A. ;
Mardis, Elaine R. ;
McLellan, Michael D. ;
Cibulskis, Kristian ;
Sougnez, Carrie ;
Greulich, Heidi ;
Muzny, Donna M. ;
Morgan, Margaret B. ;
Fulton, Lucinda ;
Fulton, Robert S. ;
Zhang, Qunyuan ;
Wendl, Michael C. ;
Lawrence, Michael S. ;
Larson, David E. ;
Chen, Ken ;
Dooling, David J. ;
Sabo, Aniko ;
Hawes, Alicia C. ;
Shen, Hua ;
Jhangiani, Shalini N. ;
Lewis, Lora R. ;
Hall, Otis ;
Zhu, Yiming ;
Mathew, Tittu ;
Ren, Yanru ;
Yao, Jiqiang ;
Scherer, Steven E. ;
Clerc, Kerstin ;
Metcalf, Ginger A. ;
Ng, Brian ;
Milosavljevic, Aleksandar ;
Gonzalez-Garay, Manuel L. ;
Osborne, John R. ;
Meyer, Rick ;
Shi, Xiaoqi ;
Tang, Yuzhu ;
Koboldt, Daniel C. ;
Lin, Ling ;
Abbott, Rachel ;
Miner, Tracie L. ;
Pohl, Craig ;
Fewell, Ginger ;
Haipek, Carrie ;
Schmidt, Heather ;
Dunford-Shore, Brian H. ;
Kraja, Aldi ;
Crosby, Seth D. ;
Sawyer, Christopher S. .
NATURE, 2008, 455 (7216) :1069-1075
[6]   Mutations and addiction to EGFR:: the Achilles 'heal' of lung cancers? [J].
Gazdar, AF ;
Shigematsu, H ;
Herz, J ;
Minna, JD .
TRENDS IN MOLECULAR MEDICINE, 2004, 10 (10) :481-486
[7]  
Gealy R, 1999, CANCER EPIDEM BIOMAR, V8, P297
[8]   Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib [J].
Han, SW ;
Kim, TY ;
Hwang, PG ;
Jeong, S ;
Kim, J ;
Choi, IS ;
Oh, DY ;
Kim, LH ;
Kim, DW ;
Chung, DH ;
Im, SA ;
Kim, YT ;
Lee, JS ;
Heo, DS ;
Bang, YJ ;
Kim, NK .
JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (11) :2493-2501
[9]   EML4-ALK: Honing In on a New Target in Non-Small-Cell Lung Cancer [J].
Horn, Leora ;
Pao, William .
JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (26) :4232-4235
[10]   EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers [J].
Inamura, Kentaro ;
Takeuchi, Kengo ;
Togashi, Yuki ;
Nomura, Kimie ;
Ninomiya, Hironori ;
Okui, Michiyo ;
Satoh, Yukitoshi ;
Okumura, Sakae ;
Nakagawa, Ken ;
Soda, Manabu ;
Choi, Young Lim ;
Niki, Toshiro ;
Mano, Hiroyuki ;
Ishikawa, Yuichi .
JOURNAL OF THORACIC ONCOLOGY, 2008, 3 (01) :13-17