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Lung cancer in never smokers

Heather Wakelee, MD
Section Editors
James R Jett, MD
Rogerio C Lilenbaum, MD, FACP
Deputy Editor
Sadhna R Vora, MD


Lung cancer is the leading cause of cancer death worldwide, causing about 1.6 million deaths per year [1]. Exposure to tobacco smoke is the primary etiologic factor responsible for lung cancer, and its importance is illustrated by the decline in lung cancer incidence and mortality in the United States that has accompanied the decline in smoking [2,3]. (See "Cigarette smoking and other possible risk factors for lung cancer".)

Despite the predominance of tobacco smoking as its presumed etiology, lung cancer is also a significant health problem in those with no history of smoking [4,5]. Emerging information supports the notion that lung cancer in never-smokers is distinct enough from an epidemiologic and biologic standpoint to be considered a separate entity [6-9]. Furthermore, as the numbers of never-smokers in the United States and other countries rise, the issue of lung cancer in this group becomes even more critical.

The epidemiology, risk factors, biologic differences, and potential implications for treatment of lung cancer in never-smokers are reviewed here. General aspects of lung cancer biology and management are discussed elsewhere. (See "Overview of the risk factors, pathology, and clinical manifestations of lung cancer" and "Overview of the initial evaluation, treatment and prognosis of lung cancer" and "Overview of the treatment of advanced non-small cell lung cancer".)


In general, the term “never-smoker” refers to individuals who have smoked fewer than 100 cigarettes in their lifetime. Firm data on the incidence of lung cancer in never-smokers is difficult to ascertain, because most population-based cancer registries, including the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database, do not collect patient smoking information. SEER data have been linked with population-based tobacco use information [10,11], but this only allows for estimates of lung cancer in never-smokers within broad geographic areas.

Incidence — Worldwide, lung cancer in never-smokers comprises an estimated 15 to 20 percent of cases in men and over 50 percent in women [12]. There are major geographic differences, particularly in Asia, where 60 to 80 percent of women with the disease are never-smokers [4]. The incidence of small cell lung cancer in never-smokers is exceedingly small [13], and this discussion will therefore focus on non-small cell lung cancer (NSCLC).


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  1. Brambilla E, Travis WD. Lung cancer. In: World Cancer Report, Stewart BW, Wild CP (Eds), World Health Organization, Lyon 2014.
  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66:7.
  3. Giovino GA. Epidemiology of tobacco use in the United States. Oncogene 2002; 21:7326.
  4. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers--a different disease. Nat Rev Cancer 2007; 7:778.
  5. Subramanian J, Govindan R. Lung cancer in never smokers: a review. J Clin Oncol 2007; 25:561.
  6. Yano T, Miura N, Takenaka T, et al. Never-smoking nonsmall cell lung cancer as a separate entity: clinicopathologic features and survival. Cancer 2008; 113:1012.
  7. Subramanian J, Govindan R. Molecular genetics of lung cancer in people who have never smoked. Lancet Oncol 2008; 9:676.
  8. Subramanian J, Govindan R. Lung cancer in 'Never-smokers': a unique entity. Oncology (Williston Park) 2010; 24:29.
  9. Rudin CM, Avila-Tang E, Harris CC, et al. Lung cancer in never smokers: molecular profiles and therapeutic implications. Clin Cancer Res 2009; 15:5646.
  10. Wingo PA, Ries LA, Giovino GA, et al. Annual report to the nation on the status of cancer, 1973-1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst 1999; 91:675.
  11. Jemal A, Thun MJ, Ries LA, et al. Annual report to the nation on the status of cancer, 1975-2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 2008; 100:1672.
  12. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55:74.
  13. Kurahara Y, Kawaguchi T, Tachibana K, et al. Small-cell lung cancer in never-smokers: a case series with information on family history of cancer and environmental tobacco smoke. Clin Lung Cancer 2012; 13:75.
  14. Wakelee HA, Chang ET, Gomez SL, et al. Lung cancer incidence in never smokers. J Clin Oncol 2007; 25:472.
  15. Bain C, Feskanich D, Speizer FE, et al. Lung cancer rates in men and women with comparable histories of smoking. J Natl Cancer Inst 2004; 96:826.
  16. Colditz GA, Manson JE, Hankinson SE. The Nurses' Health Study: 20-year contribution to the understanding of health among women. J Womens Health 1997; 6:49.
  17. Bernstein L, Allen M, Anton-Culver H, et al. High breast cancer incidence rates among California teachers: results from the California Teachers Study (United States). Cancer Causes Control 2002; 13:625.
  18. Kolonel LN, Henderson BE, Hankin JH, et al. A multiethnic cohort in Hawaii and Los Angeles: baseline characteristics. Am J Epidemiol 2000; 151:346.
  19. Haiman CA, Stram DO, Wilkens LR, et al. Ethnic and racial differences in the smoking-related risk of lung cancer. N Engl J Med 2006; 354:333.
  20. Yong LC, Brown CC, Schatzkin A, et al. Intake of vitamins E, C, and A and risk of lung cancer. The NHANES I epidemiologic followup study. First National Health and Nutrition Examination Survey. Am J Epidemiol 1997; 146:231.
  21. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) Seer*Stat Database: Incidence - SEER 13 Regs Public-Use, Nov 2004 Sub for Expanded Races (1992-2002). National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch. Released April 2005, based on the November 2004 submission. 2005.
  22. Ou SH, Ziogas A, Zell JA. Epidemiology study of never-smokers with non-small cell lung cancer (NSCLC): High percentages of Asian and Hispanic female never-smokers and the significance of Asian ethnicity (abstract 8004). J Clin Oncol 2008; 26:15s.
  23. Ou SH, Ziogas A, Zell JA. Asian ethnicity is a favorable prognostic factor for overall survival in non-small cell lung cancer (NSCLC) and is independent of smoking status. J Thorac Oncol 2009; 4:1083.
  24. Thun MJ, Hannan LM, Adams-Campbell LL, et al. Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies. PLoS Med 2008; 5:e185.
  25. Boffetta P, Järvholm B, Brennan P, Nyrén O. Incidence of lung cancer in a large cohort of non-smoking men from Sweden. Int J Cancer 2001; 94:591.
  26. Thun MJ, Henley SJ, Burns D, et al. Lung cancer death rates in lifelong nonsmokers. J Natl Cancer Inst 2006; 98:691.
  27. Zell JA, Ou SH, Ziogas A, Anton-Culver H. Epidemiology of bronchioloalveolar carcinoma: improvement in survival after release of the 1999 WHO classification of lung tumors. J Clin Oncol 2005; 23:8396.
  28. Kawaguchi T, Matsumura A, Fukai S, et al. Japanese ethnicity compared with Caucasian ethnicity and never-smoking status are independent favorable prognostic factors for overall survival in non-small cell lung cancer: a collaborative epidemiologic study of the National Hospital Organization Study Group for Lung Cancer (NHSGLC) in Japan and a Southern California Regional Cancer Registry databases. J Thorac Oncol 2010; 5:1001.
  29. Peto R, Darby S, Deo H, et al. Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies. BMJ 2000; 321:323.
  30. Nyberg F, Agudo A, Boffetta P, et al. A European validation study of smoking and environmental tobacco smoke exposure in nonsmoking lung cancer cases and controls. Cancer Causes Control 1998; 9:173.
  31. Wells AJ, English PB, Posner SF, et al. Misclassification rates for current smokers misclassified as nonsmokers. Am J Public Health 1998; 88:1503.
  32. Brenner DR, Hung RJ, Tsao MS, et al. Lung cancer risk in never-smokers: a population-based case-control study of epidemiologic risk factors. BMC Cancer 2010; 10:285.
  33. Donington JS, Le QT, Wakelee HA. Lung cancer in women: exploring sex differences in susceptibility, biology, and therapeutic response. Clin Lung Cancer 2006; 8:22.
  34. Wakai K, Ando M, Ozasa K, et al. Updated information on risk factors for lung cancer: findings from the JACC Study. J Epidemiol 2005; 15 Suppl 2:S134.
  35. Kawaguchi T, Takada M, Kubo A, et al. Gender, histology, and time of diagnosis are important factors for prognosis: analysis of 1499 never-smokers with advanced non-small cell lung cancer in Japan. J Thorac Oncol 2010; 5:1011.
  36. Gomez SL, Chang ET, Shema SJ, et al. Survival following non-small cell lung cancer among Asian/Pacific Islander, Latina, and Non-Hispanic white women who have never smoked. Cancer Epidemiol Biomarkers Prev 2011; 20:545.
  37. Liu NS, Spitz MR, Kemp BL, et al. Adenocarcinoma of the lung in young patients: the M. D. Anderson experience. Cancer 2000; 88:1837.
  38. Toh CK, Gao F, Lim WT, et al. Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity. J Clin Oncol 2006; 24:2245.
  39. Brennan P, Buffler PA, Reynolds P, et al. Secondhand smoke exposure in adulthood and risk of lung cancer among never smokers: a pooled analysis of two large studies. Int J Cancer 2004; 109:125.
  40. Gorlova OY, Zhang Y, Schabath MB, et al. Never smokers and lung cancer risk: a case-control study of epidemiological factors. Int J Cancer 2006; 118:1798.
  41. Vineis P, Airoldi L, Veglia F, et al. Environmental tobacco smoke and risk of respiratory cancer and chronic obstructive pulmonary disease in former smokers and never smokers in the EPIC prospective study. BMJ 2005; 330:277.
  42. Wu A. Carcinogenic effects. In: Health Effects of Exposure to Environmental Tobacco Smoke, Shopland DR, Zeise L, Dunn A (Eds), National Cancer Institute, Bethesda, MD 1999.
  43. Vineis P, Alavanja M, Buffler P, et al. Tobacco and cancer: recent epidemiological evidence. J Natl Cancer Inst 2004; 96:99.
  44. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum 2004; 83:1.
  45. Vineis P, Hoek G, Krzyzanowski M, et al. Lung cancers attributable to environmental tobacco smoke and air pollution in non-smokers in different European countries: a prospective study. Environ Health 2007; 6:7.
  46. Clément-Duchêne C, Vignaud JM, Stoufflet A, et al. Characteristics of never smoker lung cancer including environmental and occupational risk factors. Lung Cancer 2010; 67:144.
  47. Asomaning K, Miller DP, Liu G, et al. Second hand smoke, age of exposure and lung cancer risk. Lung Cancer 2008; 61:13.
  48. Kurahashi N, Inoue M, Liu Y, et al. Passive smoking and lung cancer in Japanese non-smoking women: a prospective study. Int J Cancer 2008; 122:653.
  49. Olivo-Marston SE, Yang P, Mechanic LE, et al. Childhood exposure to secondhand smoke and functional mannose binding lectin polymorphisms are associated with increased lung cancer risk. Cancer Epidemiol Biomarkers Prev 2009; 18:3375.
  50. Taylor R, Najafi F, Dobson A. Meta-analysis of studies of passive smoking and lung cancer: effects of study type and continent. Int J Epidemiol 2007; 36:1048.
  51. Veglia F, Vineis P, Overvad K, et al. Occupational exposures, environmental tobacco smoke, and lung cancer. Epidemiology 2007; 18:769.
  52. Wang A, Kubo J, Luo J, et al. Active and passive smoking in relation to lung cancer incidence in the Women's Health Initiative Observational Study prospective cohort. Ann Oncol 2015; 26:221.
  53. Krishnan VG, Ebert PJ, Ting JC, et al. Whole-genome sequencing of asian lung cancers: second-hand smoke unlikely to be responsible for higher incidence of lung cancer among Asian never-smokers. Cancer Res 2014; 74:6071.
  54. Leuraud K, Schnelzer M, Tomasek L, et al. Radon, smoking and lung cancer risk: results of a joint analysis of three European case-control studies among uranium miners. Radiat Res 2011; 176:375.
  55. Samet JM. Radon and lung cancer. J Natl Cancer Inst 1989; 81:745.
  56. Krewski D, Lubin JH, Zielinski JM, et al. A combined analysis of North American case-control studies of residential radon and lung cancer. J Toxicol Environ Health A 2006; 69:533.
  57. Darby S, Hill D, Auvinen A, et al. Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies. BMJ 2005; 330:223.
  58. Sandler DP, Weinberg CR, Shore DL, et al. Indoor radon and lung cancer risk in connecticut and utah. J Toxicol Environ Health A 2006; 69:633.
  59. Alberg AJ, Brock MV, Samet JM. Epidemiology of lung cancer: looking to the future. J Clin Oncol 2005; 23:3175.
  60. Gottschall EB. Occupational and environmental thoracic malignancies. J Thorac Imaging 2002; 17:189.
  61. Neuberger JS, Field RW. Occupation and lung cancer in nonsmokers. Rev Environ Health 2003; 18:251.
  62. van Loon AJ, Kant IJ, Swaen GM, et al. Occupational exposure to carcinogens and risk of lung cancer: results from The Netherlands cohort study. Occup Environ Med 1997; 54:817.
  63. Peters S, Kromhout H, Olsson AC, et al. Occupational exposure to organic dust increases lung cancer risk in the general population. Thorax 2012; 67:111.
  64. Guha N, Merletti F, Steenland NK, et al. Lung cancer risk in painters: a meta-analysis. Environ Health Perspect 2010; 118:303.
  65. Chen CL, Hsu LI, Chiou HY, et al. Ingested arsenic, cigarette smoking, and lung cancer risk: a follow-up study in arseniasis-endemic areas in Taiwan. JAMA 2004; 292:2984.
  66. Ferreccio C, González C, Milosavjlevic V, et al. Lung cancer and arsenic concentrations in drinking water in Chile. Epidemiology 2000; 11:673.
  67. Martinez VD, Thu KL, Vucic EA, et al. Whole-genome sequencing analysis identifies a distinctive mutational spectrum in an arsenic-related lung tumor. J Thorac Oncol 2013; 8:1451.
  68. Feskanich D, Ziegler RG, Michaud DS, et al. Prospective study of fruit and vegetable consumption and risk of lung cancer among men and women. J Natl Cancer Inst 2000; 92:1812.
  69. Galeone C, Negri E, Pelucchi C, et al. Dietary intake of fruit and vegetable and lung cancer risk: a case-control study in Harbin, northeast China. Ann Oncol 2007; 18:388.
  70. Lam TK, Cross AJ, Consonni D, et al. Intakes of red meat, processed meat, and meat mutagens increase lung cancer risk. Cancer Res 2009; 69:932.
  71. Lim WY, Chuah KL, Eng P, et al. Meat consumption and risk of lung cancer among never-smoking women. Nutr Cancer 2011; 63:850.
  72. Gorlova OY, Weng SF, Hernandez L, et al. Dietary patterns affect lung cancer risk in never smokers. Nutr Cancer 2011; 63:842.
  73. Boffetta P, Nyberg F. Contribution of environmental factors to cancer risk. Br Med Bull 2003; 68:71.
  74. Yu IT, Chiu YL, Au JS, et al. Dose-response relationship between cooking fumes exposures and lung cancer among Chinese nonsmoking women. Cancer Res 2006; 66:4961.
  75. Ko YC, Cheng LS, Lee CH, et al. Chinese food cooking and lung cancer in women nonsmokers. Am J Epidemiol 2000; 151:140.
  76. Kleinerman RA, Wang Z, Wang L, et al. Lung cancer and indoor exposure to coal and biomass in rural China. J Occup Environ Med 2002; 44:338.
  77. Gao YT, Blot WJ, Zheng W, et al. Lung cancer among Chinese women. Int J Cancer 1987; 40:604.
  78. Wang TJ, Zhou BS, Shi JP. Lung cancer in nonsmoking Chinese women: a case-control study. Lung Cancer 1996; 14 Suppl 1:S93.
  79. Shen XB, Wang GX, Huang YZ, et al. Analysis and estimates of attributable risk factors for lung cancer in Nanjing, China. Lung Cancer 1996; 14 Suppl 1:S107.
  80. Turner MC, Krewski D, Pope CA 3rd, et al. Long-term ambient fine particulate matter air pollution and lung cancer in a large cohort of never-smokers. Am J Respir Crit Care Med 2011; 184:1374.
  81. Hamra GB, Guha N, Cohen A, et al. Outdoor particulate matter exposure and lung cancer: a systematic review and meta-analysis. Environ Health Perspect 2014; 122:906.
  82. Olsson AC, Gustavsson P, Kromhout H, et al. Exposure to diesel motor exhaust and lung cancer risk in a pooled analysis from case-control studies in Europe and Canada. Am J Respir Crit Care Med 2011; 183:941.
  83. Yorifuji T, Kashima S, Tsuda T, et al. Long-term exposure to traffic-related air pollution and the risk of death from hemorrhagic stroke and lung cancer in Shizuoka, Japan. Sci Total Environ 2013; 443:397.
  84. Travis LB, Gospodarowicz M, Curtis RE, et al. Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. J Natl Cancer Inst 2002; 94:182.
  85. Littman AJ, Thornquist MD, White E, et al. Prior lung disease and risk of lung cancer in a large prospective study. Cancer Causes Control 2004; 15:819.
  86. Mayne ST, Buenconsejo J, Janerich DT. Previous lung disease and risk of lung cancer among men and women nonsmokers. Am J Epidemiol 1999; 149:13.
  87. Wu AH, Fontham ET, Reynolds P, et al. Previous lung disease and risk of lung cancer among lifetime nonsmoking women in the United States. Am J Epidemiol 1995; 141:1023.
  88. Hubbard R, Venn A, Lewis S, Britton J. Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study. Am J Respir Crit Care Med 2000; 161:5.
  89. Wells C, Mannino DM. Pulmonary fibrosis and lung cancer in the United States: analysis of the multiple cause of death mortality data, 1979 through 1991. South Med J 1996; 89:505.
  90. Ciotti M, Giuliani L, Ambrogi V, et al. Detection and expression of human papillomavirus oncogenes in non-small cell lung cancer. Oncol Rep 2006; 16:183.
  91. Chen YC, Chen JH, Richard K, et al. Lung adenocarcinoma and human papillomavirus infection. Cancer 2004; 101:1428.
  92. Cheng YW, Chiou HL, Sheu GT, et al. The association of human papillomavirus 16/18 infection with lung cancer among nonsmoking Taiwanese women. Cancer Res 2001; 61:2799.
  93. Bohlmeyer T, Le TN, Shroyer AL, et al. Detection of human papillomavirus in squamous cell carcinomas of the lung by polymerase chain reaction. Am J Respir Cell Mol Biol 1998; 18:265.
  94. Hasegawa Y, Ando M, Kubo A, et al. Human papilloma virus in non-small cell lung cancer in never smokers: a systematic review of the literature. Lung Cancer 2014; 83:8.
  95. Anantharaman D, Gheit T, Waterboer T, et al. No causal association identified for human papillomavirus infections in lung cancer. Cancer Res 2014; 74:3525.
  96. Wu AH, Fontham ET, Reynolds P, et al. Family history of cancer and risk of lung cancer among lifetime nonsmoking women in the United States. Am J Epidemiol 1996; 143:535.
  97. Brownson RC, Alavanja MC, Caporaso N, et al. Family history of cancer and risk of lung cancer in lifetime non-smokers and long-term ex-smokers. Int J Epidemiol 1997; 26:256.
  98. Wu PF, Lee CH, Wang MJ, et al. Cancer aggregation and complex segregation analysis of families with female non-smoking lung cancer probands in Taiwan. Eur J Cancer 2004; 40:260.
  99. Schwartz AG, Yang P, Swanson GM. Familial risk of lung cancer among nonsmokers and their relatives. Am J Epidemiol 1996; 144:554.
  100. Gorlova OY, Weng SF, Zhang Y, et al. Aggregation of cancer among relatives of never-smoking lung cancer patients. Int J Cancer 2007; 121:111.
  101. Gao Y, Goldstein AM, Consonni D, et al. Family history of cancer and nonmalignant lung diseases as risk factors for lung cancer. Int J Cancer 2009; 125:146.
  102. Tse LA, Yu IT, Rothman N, et al. Joint effects of environmental exposures and familial susceptibility to lung cancer in Chinese never smoking men and women. J Thorac Oncol 2014; 9:1066.
  103. Gorlova OY, Weng SF, Zhang Y, et al. DNA repair capacity and lung cancer risk in never smokers. Cancer Epidemiol Biomarkers Prev 2008; 17:1322.
  104. Amos CI, Pinney SM, Li Y, et al. A susceptibility locus on chromosome 6q greatly increases lung cancer risk among light and never smokers. Cancer Res 2010; 70:2359.
  105. Wang Y, Broderick P, Webb E, et al. Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat Genet 2008; 40:1407.
  106. Wang Y, Broderick P, Matakidou A, et al. Role of 5p15.33 (TERT-CLPTM1L), 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) variation and lung cancer risk in never-smokers. Carcinogenesis 2010; 31:234.
  107. Hsiung CA, Lan Q, Hong YC, et al. The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia. PLoS Genet 2010; 6.
  108. Li Y, Sheu CC, Ye Y, et al. Genetic variants and risk of lung cancer in never smokers: a genome-wide association study. Lancet Oncol 2010; 11:321.
  109. Truong T, Hung RJ, Amos CI, et al. Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J Natl Cancer Inst 2010; 102:959.
  110. Ahn MJ, Won HH, Lee J, et al. The 18p11.22 locus is associated with never smoker non-small cell lung cancer susceptibility in Korean populations. Hum Genet 2012; 131:365.
  111. Yang P, Li Y, Jiang R, et al. A rigorous and comprehensive validation: common genetic variations and lung cancer. Cancer Epidemiol Biomarkers Prev 2010; 19:240.
  112. Lan Q, Hsiung CA, Matsuo K, et al. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat Genet 2012; 44:1330.
  113. Raimondi S, Boffetta P, Anttila S, et al. Metabolic gene polymorphisms and lung cancer risk in non-smokers. An update of the GSEC study. Mutat Res 2005; 592:45.
  114. Wenzlaff AS, Cote ML, Bock CH, et al. CYP1A1 and CYP1B1 polymorphisms and risk of lung cancer among never smokers: a population-based study. Carcinogenesis 2005; 26:2207.
  115. Taioli E, Gaspari L, Benhamou S, et al. Polymorphisms in CYP1A1, GSTM1, GSTT1 and lung cancer below the age of 45 years. Int J Epidemiol 2003; 32:60.
  116. Jung CY, Choi JE, Park JM, et al. Polymorphisms in the hMSH2 gene and the risk of primary lung cancer. Cancer Epidemiol Biomarkers Prev 2006; 15:762.
  117. Lo YL, Hsiao CF, Jou YS, et al. Polymorphisms of MLH1 and MSH2 genes and the risk of lung cancer among never smokers. Lung Cancer 2011; 72:280.
  118. Schwartz AG, Prysak GM, Bock CH, Cote ML. The molecular epidemiology of lung cancer. Carcinogenesis 2007; 28:507.
  119. Bonner MR, Bennett WP, Xiong W, et al. Radon, secondhand smoke, glutathione-S-transferase M1 and lung cancer among women. Int J Cancer 2006; 119:1462.
  120. Wenzlaff AS, Cote ML, Bock CH, et al. GSTM1, GSTT1 and GSTP1 polymorphisms, environmental tobacco smoke exposure and risk of lung cancer among never smokers: a population-based study. Carcinogenesis 2005; 26:395.
  121. Wu X, Wang L, Ye Y, et al. Genome-wide association study of genetic predictors of overall survival for non-small cell lung cancer in never smokers. Cancer Res 2013; 73:4028.
  122. Kang HG, Lee SY, Jeon HS, et al. A functional polymorphism in CSF1R gene is a novel susceptibility marker for lung cancer among never-smoking females. J Thorac Oncol 2014; 9:1647.
  123. Bell DW, Gore I, Okimoto RA, et al. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat Genet 2005; 37:1315.
  124. Ikeda K, Nomori H, Mori T, et al. Novel germline mutation: EGFR V843I in patient with multiple lung adenocarcinomas and family members with lung cancer. Ann Thorac Surg 2008; 85:1430.
  125. Ohtsuka K, Ohnishi H, Kurai D, et al. Familial lung adenocarcinoma caused by the EGFR V843I germ-line mutation. J Clin Oncol 2011; 29:e191.
  126. van Noesel J, van der Ven WH, van Os TA, et al. Activating germline R776H mutation in the epidermal growth factor receptor associated with lung cancer with squamous differentiation. J Clin Oncol 2013; 31:e161.
  127. Yamamoto H, Higasa K, Sakaguchi M, et al. Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas. J Natl Cancer Inst 2014; 106:djt338.
  128. Mosselman S, Polman J, Dijkema R. ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett 1996; 392:49.
  129. Stabile LP, Davis AL, Gubish CT, et al. Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res 2002; 62:2141.
  130. Mollerup S, Jørgensen K, Berge G, Haugen A. Expression of estrogen receptors alpha and beta in human lung tissue and cell lines. Lung Cancer 2002; 37:153.
  131. Wu CT, Chang YL, Shih JY, Lee YC. The significance of estrogen receptor beta in 301 surgically treated non-small cell lung cancers. J Thorac Cardiovasc Surg 2005; 130:979.
  132. Taioli E, Wynder EL. Re: Endocrine factors and adenocarcinoma of the lung in women. J Natl Cancer Inst 1994; 86:869.
  133. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321.
  134. Schwartz AG, Wenzlaff AS, Prysak GM, et al. Reproductive factors, hormone use, estrogen receptor expression and risk of non small-cell lung cancer in women. J Clin Oncol 2007; 25:5785.
  135. Oh SW, Myung SK, Park JY, et al. Hormone therapy and risk of lung cancer: a meta-analysis. J Womens Health (Larchmt) 2010; 19:279.
  136. Kabat GC, Miller AB, Rohan TE. Reproductive and hormonal factors and risk of lung cancer in women: a prospective cohort study. Int J Cancer 2007; 120:2214.
  137. Paulus JK, Asomaning K, Kraft P, et al. Parity and risk of lung cancer in women. Am J Epidemiol 2010; 171:557.
  138. Patel JD, Gray RG, Stewart JA, et al. Tamoxifen does not reduce the risk of lung cancer in women. J CLin Oncol 2005; 23:673s (abstract).
  139. Chlebowski RT, Schwartz AG, Wakelee H, et al. Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet 2009; 374:1243.
  140. Chlebowski RT, Anderson GL, Manson JE, et al. Lung cancer among postmenopausal women treated with estrogen alone in the women's health initiative randomized trial. J Natl Cancer Inst 2010; 102:1413.
  141. Chlebowski RT, Wakelee HA, Rohan TE, et al. Smoking and estrogen plus progestin (E+P) and lung cancer incidence and mortality (abstract 1524). American Society of Clinical Oncology 2013; 31:suppl.
  142. Sonobe M, Manabe T, Wada H, Tanaka F. Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma. Br J Cancer 2005; 93:355.
  143. Kosaka T, Yatabe Y, Endoh H, et al. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 2004; 64:8919.
  144. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med 2005; 353:133.
  145. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004; 101:13306.
  146. Pham D, Kris MG, Riely GJ, et al. Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas. J Clin Oncol 2006; 24:1700.
  147. Tam IY, Chung LP, Suen WS, et al. Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res 2006; 12:1647.
  148. Toyooka S, Matsuo K, Shigematsu H, et al. The impact of sex and smoking status on the mutational spectrum of epidermal growth factor receptor gene in non small cell lung cancer. Clin Cancer Res 2007; 13:5763.
  149. Lee YJ, Shim HS, Kang YA, et al. Dose effect of cigarette smoking on frequency and spectrum of epidermal growth factor receptor gene mutations in Korean patients with non-small cell lung cancer. J Cancer Res Clin Oncol 2010; 136:1937.
  150. Dutu T, Michiels S, Fouret P, et al. Differential expression of biomarkers in lung adenocarcinoma: a comparative study between smokers and never-smokers. Ann Oncol 2005; 16:1906.
  151. Lee YJ, Cho BC, Jee SH, et al. Impact of environmental tobacco smoke on the incidence of mutations in epidermal growth factor receptor gene in never-smoker patients with non-small-cell lung cancer. J Clin Oncol 2010; 28:487.
  152. Kawaguchi T, Ando M, Kubo A, et al. Long exposure of environmental tobacco smoke associated with activating EGFR mutations in never-smokers with non-small cell lung cancer. Clin Cancer Res 2011; 17:39.
  153. Le Calvez F, Mukeria A, Hunt JD, et al. TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. Cancer Res 2005; 65:5076.
  154. Riely GJ, Kris MG, Rosenbaum D, et al. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res 2008; 14:5731.
  155. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009; 27:4247.
  156. Rodig SJ, Mino-Kenudson M, Dacic S, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 2009; 15:5216.
  157. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010; 363:1693.
  158. Zhang X, Zhang S, Yang X, et al. Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression. Mol Cancer 2010; 9:188.
  159. Toyooka S, Tsuda T, Gazdar AF. The TP53 gene, tobacco exposure, and lung cancer. Hum Mutat 2003; 21:229.
  160. Planchard D, Domont J, Taranchon E, et al. The NER proteins are differentially expressed in ever smokers and in never smokers with lung adenocarcinoma. Ann Oncol 2009; 20:1257.
  161. Mountzios G, Planchard D, Besse B, et al. Mitogen-activated protein kinase activation in lung adenocarcinoma: a comparative study between ever smokers and never smokers. Clin Cancer Res 2008; 14:4096.
  162. Lo YL, Hsiao CF, Jou YS, et al. ATM polymorphisms and risk of lung cancer among never smokers. Lung Cancer 2010; 69:148.
  163. Wong MP, Fung LF, Wang E, et al. Chromosomal aberrations of primary lung adenocarcinomas in nonsmokers. Cancer 2003; 97:1263.
  164. Sanchez-Cespedes M, Ahrendt SA, Piantadosi S, et al. Chromosomal alterations in lung adenocarcinoma from smokers and nonsmokers. Cancer Res 2001; 61:1309.
  165. Divine KK, Pulling LC, Marron-Terada PG, et al. Multiplicity of abnormal promoter methylation in lung adenocarcinomas from smokers and never smokers. Int J Cancer 2005; 114:400.
  166. Tessema M, Yu YY, Stidley CA, et al. Concomitant promoter methylation of multiple genes in lung adenocarcinomas from current, former and never smokers. Carcinogenesis 2009; 30:1132.
  167. Seike M, Goto A, Okano T, et al. MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers. Proc Natl Acad Sci U S A 2009; 106:12085.
  168. Dasgupta S, Soudry E, Mukhopadhyay N, et al. Mitochondrial DNA mutations in respiratory complex-I in never-smoker lung cancer patients contribute to lung cancer progression and associated with EGFR gene mutation. J Cell Physiol 2012; 227:2451.
  169. Govindan R, Ding L, Griffith M, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 2012; 150:1121.
  170. Kim SC, Jung Y, Park J, et al. A high-dimensional, deep-sequencing study of lung adenocarcinoma in female never-smokers. PLoS One 2013; 8:e55596.
  171. Johnson B, et al. A multicenter effort to identify driver mutations and employ targeted therapy in patients with lung adenocarcinomas: The Lung Cancer Mutation Consortium (abstract 8019). American Society of Clinical Oncology 2013 meeting.
  172. Cancer Genome Atlas Research Network, Weinstein JN, Collisson EA, et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet 2013; 45:1113.
  173. Pao W, Hutchinson KE. Chipping away at the lung cancer genome. Nat Med 2012; 18:349.
  174. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012; 18:378.
  175. Kim HR, Shim HS, Chung JH, et al. Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement. Cancer 2012; 118:729.
  176. Zhang Y, Sun Y, Pan Y, et al. Frequency of driver mutations in lung adenocarcinoma from female never-smokers varies with histologic subtypes and age at diagnosis. Clin Cancer Res 2012; 18:1947.
  177. Hosgood HD 3rd, Pao W, Rothman N, et al. Driver mutations among never smoking female lung cancer tissues in China identify unique EGFR and KRAS mutation pattern associated with household coal burning. Respir Med 2013; 107:1755.
  178. Varghese AM, Sima CS, Chaft JE, et al. Lungs don't forget: Comparison of the KRAS and EGFR mutation profile and survival of collegiate smokers and never smokers with advanced lung cancers. J Thorac Oncol 2013; 8:123.
  179. Nordquist LT, Simon GR, Cantor A, et al. Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung. Chest 2004; 126:347.
  180. Sardari Nia P, Weyler J, Colpaert C, et al. Prognostic value of smoking status in operated non-small cell lung cancer. Lung Cancer 2005; 47:351.
  181. Bryant A, Cerfolio RJ. Differences in epidemiology, histology, and survival between cigarette smokers and never-smokers who develop non-small cell lung cancer. Chest 2007; 132:185.
  182. Tsao AS, Liu D, Lee JJ, et al. Smoking affects treatment outcome in patients with advanced nonsmall cell lung cancer. Cancer 2006; 106:2428.
  183. Yano T, Miura N, Takenaka T, et al. Surgical results of non-small cell lung cancer in never-smokers as a separate entity (abstract). J Clin Oncol 2008; 26:398s. (Abstract available online at www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD, accessed on June 4, 2008).
  184. Subramanian J, Velcheti V, Gao F, Govindan R. Presentation and stage-specific outcomes of lifelong never-smokers with non-small cell lung cancer (NSCLC). J Thorac Oncol 2007; 2:827.
  185. Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005; 23:5892.
  186. Meguid RA, Hooker CM, Harris J, et al. Long-term survival outcomes by smoking status in surgical and nonsurgical patients with non-small cell lung cancer: comparing never smokers and current smokers. Chest 2010; 138:500.
  187. Kawaguchi T, Takada M, Kubo A, et al. Performance status and smoking status are independent favorable prognostic factors for survival in non-small cell lung cancer: a comprehensive analysis of 26,957 patients with NSCLC. J Thorac Oncol 2010; 5:620.
  188. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366:1527.
  189. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353:123.
  190. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361:947.
  191. Han JY, Park K, Kim SW, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 2012; 30:1122.