Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Lung cancer chemoprevention: current status and future prospects

Nature Reviews Clinical Oncology volume 10, pages 334–343 (2013)Cite this article

Subjects

Abstract

Lung cancer is the leading cause of cancer death worldwide, making it an attractive disease for chemoprevention. Although avoidance of tobacco use and smoking cessation will have the greatest impact on lung cancer development, chemoprevention could prove to be very effective, particularly in former smokers. Chemoprevention is the use of agents to reverse or inhibit carcinogenesis and has been successfully applied to other common malignancies. Despite prior studies in lung cancer chemoprevention failing to identify effective agents, we now have the ability to identify high-risk populations, and our understanding of lung tumour and premalignant biology continues to advance. There are distinct histological lesions that can be reproducibly graded as precursors of non-small-cell lung cancer and similar precursor lesions exist for adenocarcinoma. These premalignant lesions are being targeted by chemopreventive agents in current trials and will continue to be studied in the future. In addition, biomarkers that predict risk and response to targeted agents are being investigated and validated. In this Review, we discuss the principles of chemoprevention, data from preclinical models, completed clinical trials and observational studies, and describe new treatments for novel targeted pathways and future chemopreventive efforts.

Key Points

  • The annual risk for lung cancer in patient populations readily identifiable using simple clinical and demographic characteristics approaches 2%; therefore, the potential for chemoprevention in this common cancer is high

  • No chemopreventive agents have been shown to be efficacious for lung cancer, despite numerous leads from observational studies

  • Smoking cessation remains the only intervention proven to reduce lung cancer risk

  • Lung cancer is a heterogeneous malignancy from a mutational standpoint; focusing on frequently altered pathways may be a promising strategy because molecular targeting of chemoprevention to specific mutations is challenging

  • Chemoprevention targeted to phenotypes expressing specific carcinogenic influences, including inflammation, angiogenesis, hypoxia and epithelial differentiation, appears most likely to succeed phenotypes

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Potential tobacco smoke induced carcinogenic processes for chemopreventive intervention.
Figure 2: Schematic pathway of the cyclooxygenase pathway showing conversion of arachidonic acid to prostanoids.

Similar content being viewed by others

References

  1. Sporn, M. B. Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res. 36, 2699–2702 (1976).

    CAS  PubMed  Google Scholar 

  2. Spitz, M. R. et al. A risk model for prediction of lung cancer. J. Natl Cancer Inst. 99, 715–726 (2007).

    Article  PubMed  Google Scholar 

  3. Bach, P. B. et al. Variations in lung cancer risk among smokers. J. Natl Cancer Inst. 95, 470–478 (2003).

    Article  PubMed  Google Scholar 

  4. Anthonisen, N. R. et al. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann. Intern. Med. 142, 233–239 (2005).

    Article  PubMed  Google Scholar 

  5. Jemal, A. et al. Global cancer statistics. CA Cancer J. Clin. 61, 69–90 (2011).

    Article  PubMed  Google Scholar 

  6. Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2012. CA Cancer J. Clin. 62, 10–29 (2012).

    Article  PubMed  Google Scholar 

  7. National Lung Screening Trial Research Team et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med. 365, 395–409 (2011).

  8. Johnson, B. E. Second lung cancers in patients after treatment for an initial lung cancer. J. Natl Cancer Inst. 90, 1335–1345 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Spitz, M. R. et al. An expanded risk prediction model for lung cancer. Cancer Prev. Res. (Phila.) 1, 250–254 (2008).

    Article  Google Scholar 

  10. The Health Consequences of Smoking: A Report of the Surgeon General. Office of the Surgeon General (US); Office on Smoking and Health (US). Atlanta (GA): Centers for Disease Control and Prevention (US) [online], (2004).

  11. Jha, P. et al. 21st-century hazards of smoking and benefits of cessation in the United States. N. Engl. J. Med. 368, 341–350 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Pirie, K. et al. The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in the UK. Lancet 381, 133–141 (2012).

    Article  PubMed  Google Scholar 

  13. Tong, L., Spitz, M. R., Fueger, J. J. & Amos, C. A. Lung carcinoma in former smokers. Cancer 78, 1004–1010 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Halpern, M. T., Gillespie, B. W. & Warner, K. E. Patterns of absolute risk of lung cancer mortality in former smokers. J. Natl Cancer Inst. 85, 457–464 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Hennekens, C. H. et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N. Engl. J. Med. 334, 1145–1149 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Omenn, G. S. et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J. Natl Cancer Inst. 88, 1550–1559 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Lockwood, W. W. et al. Divergent genomic and epigenomic landscapes of lung cancer subtypes underscore the selection of different oncogenic pathways during tumor development. PLoS ONE 7, e37775 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nicholson, A. G. et al. Reproducibility of the WHO/IASLC grading system for pre-invasive squamous lesions of the bronchus: a study of inter-observer and intra-observer variation. Histopathology 38, 202–208 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Jonsson, S. et al. Chromosomal aneusomy in bronchial high-grade lesions is associated with invasive lung cancer. Am. J. Respir. Crit. Care Med. 177, 342–347 (2008).

    Article  PubMed  Google Scholar 

  20. Salaun, M. et al. Molecular predictive factors for progression of high-grade preinvasive bronchial lesions. Am. J. Respir. Crit. Care Med. 177, 880–886 (2008).

    Article  PubMed  Google Scholar 

  21. van Boerdonk, R. A. et al. DNA copy number alterations in endobronchial squamous metaplastic lesions predict lung cancer. Am. J. Respir. Crit. Care Med. 184, 948–956 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Franklin, W. A. et al. Widely dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis. J. Clin. Invest. 100, 2133–2137 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wistuba, I. I. et al. Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma. Oncogene 18, 643–650 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. McCaughan, F. et al. Progressive 3q amplification consistently targets SOX2 in preinvasive squamous lung cancer. Am. J. Respir. Crit. Care Med. 182, 83–91 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Travis, W. D. et al. Bronchioloalveolar carcinoma and lung adenocarcinoma: the clinical importance and research relevance of the 2004 World Health Organization pathologic criteria. J. Thorac. Oncol. 1, S13–S19 (2006).

    Article  PubMed  Google Scholar 

  26. Tang, X. et al. EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients. Cancer Res. 65, 7568–7572 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Meert, A. P. et al. Epidermal growth factor receptor expression in pre-invasive and early invasive bronchial lesions. Eur. Respir. J. 21, 611–615 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Soh, J. et al. Sequential molecular changes during multistage pathogenesis of small peripheral adenocarcinomas of the lung. J. Thorac. Oncol. 3, 340–347 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Slaughter, D. P., Southwick, H. W. & Smejkal, W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 6, 963–968 (1953).

    Article  CAS  PubMed  Google Scholar 

  30. Rusch, V., Klimstra, D., Linkov, I. & Dmitrovsky, E. Aberrant expression of p53 or the epidermal growth factor receptor is frequent in early bronchial neoplasia and coexpression precedes squamous cell carcinoma development. Cancer Res. 55, 1365–1372 (1995).

    CAS  PubMed  Google Scholar 

  31. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012).

  33. Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Veronesi, G. et al. Randomized phase II trial of inhaled budesonide versus placebo in high-risk individuals with CT screen-detected lung nodules. Cancer Prev. Res. (Phila.) 4, 34–42 (2011).

    Article  CAS  Google Scholar 

  35. Lam, S. et al. A randomized phase IIb trial of pulmicort turbuhaler (budesonide) in people with dysplasia of the bronchial epithelium. Clin. Cancer Res. 10, 6502–6511 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. van den Berg, R. M. et al. CT detected indeterminate pulmonary nodules in a chemoprevention trial of fluticasone. Lung Cancer 60, 57–61 (2008).

    Article  PubMed  Google Scholar 

  37. Final report on the aspirin component of the ongoing Physicians' Health Study. Steering Committee of the Physicians' Health Study Research Group. N. Engl. J. Med. 32, 129–135 (1989).

  38. Cook, N. R. et al. Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial. JAMA 294, 47–55 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Peto, R. et al. Randomised trial of prophylactic daily aspirin in British male doctors. Br. Med. J. (Clin. Res. Ed.) 296, 313–316 (1988).

    Article  CAS  Google Scholar 

  40. van Zandwijk, N., Dalesio, O., Pastorino, U., de Vries, N. & van Tinteren, H. EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the European Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J. Natl Cancer Inst. 92, 977–986 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Lippman, S. M. et al. Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J. Natl Cancer Inst. 93, 605–618 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Blumberg, J. & Block, G. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study in Finland. Nutr. Rev. 52, 242–245 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. Slatore, C. G., Littman, A. J., Au, D. H., Satia, J. A. & White, E. Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer. Am. J. Respir. Crit. Care Med. 177, 524–530 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Karp, D. D. et al. A phase III, intergroup, randomized, double-blind, chemoprevention trial of selenium (Se) supplementation in resected stage I non-small cell lung cancer (NSCLC) [abstract]. J. Clin. Oncol. 18 (Suppl.), CRA7004 (2010).

    Article  Google Scholar 

  45. Kelly, R. J., Lopez-Chavez, A. & Szabo, E. Criteria of evidence to move potential chemopreventive agents into late phase clinical trials. Curr. Drug Targets 12, 1983–1988 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Keith, R. L. & Miller, Y. E. Lung cancer: genetics of risk and advances in chemoprevention. Curr. Opin. Pulm. Med. 11, 265–271 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Prentice, R. L. Surrogate endpoints in clinical trials: definition and operational criteria. Stat. Med. 8, 431–440 (1989).

    Article  CAS  PubMed  Google Scholar 

  48. Miller, Y. E. et al. Bronchial epithelial Ki-67 index is related to histology, smoking, and gender, but not lung cancer or chronic obstructive pulmonary disease. Cancer Epidemiol. Biomarkers Prev. 16, 2425–2431 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Spira, A. et al. Effects of cigarette smoke on the human airway epithelial cell transcriptome. Proc. Natl Acad. Sci. USA 101, 10143–10148 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Spira, A. et al. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat. Med. 13, 361–366 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Rahman, S. M. et al. Lung cancer diagnosis from proteomic analysis of preinvasive lesions. Cancer Res. 71, 3009–3017 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ostroff, R. M. et al. Unlocking biomarker discovery: large scale application of aptamer proteomic technology for early detection of lung cancer. PLoS ONE 5, e15003 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Peled, N. et al. Non-invasive breath analysis of pulmonary nodules. J. Thorac. Oncol. 7, 1528–1533 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Kelly, K. et al. A randomized phase II chemoprevention trial of 13-CIS retinoic acid with or without alpha tocopherol or observation in subjects at high risk for lung cancer. Cancer Prev. Res. (Phila.) 2, 440–449 (2009).

    Article  CAS  Google Scholar 

  55. Lee, J. S. et al. Randomized placebo-controlled trial of isotretinoin in chemoprevention of bronchial squamous metaplasia. J. Clin. Oncol. 12, 937–945 (1994).

    Article  CAS  PubMed  Google Scholar 

  56. Keith, R. L. et al. Oral iloprost improves endobronchial dysplasia in former smokers. Cancer Prev. Res. (Phila.) 4, 793–802 (2011).

    Article  CAS  Google Scholar 

  57. Kim, E. S. et al. Biological activity of celecoxib in the bronchial epithelium of current and former smokers. Cancer Prev. Res. (Phila.) 3, 148–159 (2010).

    Article  CAS  Google Scholar 

  58. Mao, J. T. et al. Lung cancer chemoprevention with celecoxib in former smokers. Cancer Prev. Res. (Phila.) 4, 984–993 (2011).

    Article  CAS  Google Scholar 

  59. Chang, B. et al. Natural history of pure ground-glass opacity lung nodules detected by low-dose CT scan. Chest 143, 172–178 (2013).

    Article  PubMed  Google Scholar 

  60. Lam, S. et al. A phase I study of myo-inositol for lung cancer chemoprevention. Cancer Epidemiol. Biomarkers Prev. 15, 1526–1531 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Gustafson, A. M. et al. Airway PI3K pathway activation is an early and reversible event in lung cancer development. Sci. Transl. Med. 2, 26ra25 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Malkinson, A. M., Koski, K. M., Evans, W. A. & Festing, M. F. Butylated hydroxytoluene exposure is necessary to induce lung tumors in BALB mice treated with 3-methylcholanthrene. Cancer Res. 57, 2832–2824 (1997).

    CAS  PubMed  Google Scholar 

  63. Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Regales, L. et al. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors. PLoS ONE 2, e810 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Fisher, G. H. et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev. 15, 3249–3262 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mirvish, S. S. The carcinogenic action and metabolism of urethan and N-hydroxyurethan. Adv. Cancer Res. 1, 1–42 (1968).

    Google Scholar 

  68. Witschi, H. Tobacco smoke as a mouse lung carcinogen. Exp. Lung Res. 24, 385–394 (1998).

    Article  CAS  PubMed  Google Scholar 

  69. Wang, Y. et al. A chemically induced model for squamous cell carcinoma of the lung in mice: histopathology and strain susceptibility. Cancer Res. 64, 1647–1654 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Hudish, T. M. et al. N-nitroso-tris-chloroethylurea induces premalignant squamous dysplasia in mice. Cancer Prev. Res. (Phila.) 5, 283–289 (2012).

    Article  CAS  Google Scholar 

  71. Stearman, R. S. et al. Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model. Am. J. Pathol. 167, 1763–1775 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wang, D. & DuBois, R. N. Eicosanoids and cancer. Nat. Rev. Cancer 10, 181–193 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Vane, J. R. Prostacyclin: a hormone with a therapeutic potential. The Sir Henry Dale Lecture for 1981. J. Endocrinol. 95, 3P–43P (1982).

    CAS  PubMed  Google Scholar 

  74. Nemenoff, R. et al. Prostacyclin prevents murine lung cancer independent of the membrane receptor by activation of peroxisomal proliferator--activated receptor gamma. Cancer Prev. Res. (Phila.) 1, 349–356 (2008).

    Article  CAS  Google Scholar 

  75. Chang, T. H. & Szabo, E. Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor gamma in non-small cell lung cancer. Cancer Res. 60, 1129–1138 (2000).

    CAS  PubMed  Google Scholar 

  76. Keshamouni, V. G. et al. Peroxisome proliferator-activated receptor-gamma activation inhibits tumor progression in non-small-cell lung cancer. Oncogene 23, 100–108 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Lyon, C. M. et al. Rosiglitazone prevents the progression of preinvasive lung cancer in a murine model. Carcinogenesis 30, 2095–2099 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wang, Y. et al. Chemopreventive effects of pioglitazone on chemically induced lung carcinogenesis in mice. Mol. Cancer Ther. 9, 3074–3082 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Fu, H. et al. Chemoprevention of lung carcinogenesis by the combination of aerosolized budesonide and oral pioglitazone in A/J mice. Mol. Carcinog. 50, 913–921 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wattenberg, L. W. et al. Chemoprevention of pulmonary carcinogenesis by brief exposures to aerosolized budesonide or beclomethasone dipropionate and by the combination of aerosolized budesonide and dietary myo-inositol. Carcinogenesis 21, 179–182 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Keith, R. L. et al. Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer. Cancer Res. 62, 734–740 (2002).

    CAS  PubMed  Google Scholar 

  82. Karoor, V., Le, M., Merrick, D., Dempsey, E. C. & Miller, Y. E. Vascular endothelial growth factor receptor 2-targeted chemoprevention of murine lung tumors. Cancer Prev. Res. (Phila.) 3, 1141–1147 (2010).

    Article  CAS  Google Scholar 

  83. Stabile, L. P. et al. Prevention of tobacco carcinogen-induced lung cancer in female mice using antiestrogens. Carcinogenesis 33, 2181–2189 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Moody, T. W. et al. Indomethacin reduces lung adenoma number in A/J mice. Anticancer Res. 21, 1749–1755 (2001).

    CAS  PubMed  Google Scholar 

  85. Kisley, L. R. et al. Celecoxib reduces pulmonary inflammation but not lung tumorigenesis in mice. Carcinogenesis 23, 1653–1660 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Liby, K. T. & Sporn, M. B. Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol. Rev. 64, 972–1003 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Liby, K. et al. The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis. Mol. Cancer Ther. 7, 1251–1257 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Liby, K. et al. The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice. Cancer Res. 67, 2414–2419 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Algra, A. M. & Rothwell, P. M. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol. 13, 518–527 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. Oh, S. W. et al. Aspirin use and risk for lung cancer: a meta-analysis. Ann. Oncol. 22, 2456–2465 (2011).

    Article  PubMed  Google Scholar 

  91. Rothwell, P. M. et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377, 31–41 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Parimon, T. et al. Inhaled corticosteroids and risk of lung cancer among patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 175, 712–719 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Govindarajan, R. et al. Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J. Clin. Oncol. 25, 1476–1481 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Mazzone, P. J. et al. The effect of metformin and thiazolidinedione use on lung cancer in diabetics. BMC Cancer 12, 410 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ferrara, A. et al. Cohort study of pioglitazone and cancer incidence in patients with diabetes. Diabetes Care 34, 923–929 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Smiechowski, B. B., Azoulay, L., Yin, H., Pollak, M. N. & Suissa, S. The use of metformin and the incidence of lung cancer in patients with type 2 diabetes. Diabetes Care 36, 124–129 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Bodmer, M., Becker, C., Jick, S. S. & Meier, C. R. Metformin does not alter the risk of lung cancer: a case-control analysis. Lung Cancer 78, 133–137 (2012).

    Article  PubMed  Google Scholar 

  98. Lai, S. W. et al. Antidiabetes drugs correlate with decreased risk of lung cancer: a population-based observation in Taiwan. Clin. Lung Cancer 13, 143–148 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Noto, H., Goto, A., Tsujimoto, T. & Noda, M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS ONE 7, e33411 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Soranna, D. et al. Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis. Oncologist 17, 813–822 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Memmott, R. M. et al. Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev. Res. (Phila.) 3, 1066–1076 (2010).

    Article  CAS  Google Scholar 

  102. Engelman, J. A. & Cantley, L. C. Chemoprevention meets glucose control. Cancer Prev. Res. (Phila.) 3, 1049–1052 (2010).

    Article  CAS  Google Scholar 

  103. Siegfried, J. M., Hershberger, P. A. & Stabile, L. P. Estrogen receptor signaling in lung cancer. Semin. Oncol. 36, 524–531 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ganti, A. K., Sahmoun, A. E., Panwalkar, A. W., Tendulkar, K. K. & Potti, A. Hormone replacement therapy is associated with decreased survival in women with lung cancer. J. Clin. Oncol. 24, 59–63 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Chlebowski, R. T. et al. Lung cancer among postmenopausal women treated with estrogen alone in the women's health initiative randomized trial. J. Natl Cancer Inst. 102, 1413–1421 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Clague, J. et al. Menopausal hormone therapy does not influence lung cancer risk: results from the California Teachers Study. Cancer Epidemiol. Biomarkers Prev. 20, 560–564 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Brinton, L. A. et al. Unopposed estrogen and estrogen plus progestin menopausal hormone therapy and lung cancer risk in the NIH-AARP Diet and Health Study Cohort. Cancer Causes Control 23, 487–496 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Coombes, R. C. et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N. Engl. J. Med. 350, 1081–1092 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Goss, P. E. et al. Exemestane for breast-cancer prevention in postmenopausal women. N. Engl. J. Med. 364, 2381–2391 (2011).

    Article  CAS  PubMed  Google Scholar 

  110. Key, T. J. Fruit and vegetables and cancer risk. Br. J. Cancer 104, 6–11 (2011).

    Article  CAS  PubMed  Google Scholar 

  111. Young, R. P. et al. COPD prevalence is increased in lung cancer, independent of age, sex and smoking history. Eur. Respir. J. 34, 380–386 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Burge, P. S. et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 320, 1297–1303 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N. Engl. J. Med. 343, 1902–1909 (2000).

  114. Vestbo, J. et al. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 353, 1819–1823 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  116. Gupta, R. A. et al. Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer. Proc. Natl Acad. Sci. USA 97, 13275–13280 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Alvarez-Calderon, F., Gregory, M. A. & Degregori, J. Using functional genomics to overcome therapeutic resistance in hematological malignancies. Immunol. Res. 55, 100–115 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Wang, D. L. et al. Topical delivery of 13-cis-retinoic acid by inhalation up-regulates expression of rodent lung but not liver retinoic acid receptors. Clin. Cancer Res. 6, 3636–3645 (2000).

    CAS  PubMed  Google Scholar 

  119. Mendez, L. B., Gookin, G. & Phalen, R. F. Inhaled aerosol particle dosimetry in mice: a review. Inhal. Toxicol. 22, 1032–1037 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Keith, R. L. et al. Angiogenic squamous dysplasia in bronchi of individuals at high risk for lung cancer. Clin. Cancer Res. 6, 1616–1625 (2000).

    CAS  PubMed  Google Scholar 

  121. Karoor, V. et al. Alveolar hypoxia promotes murine lung tumor growth through a VEGFR-2/EGFR-dependent mechanism. Cancer Prev. Res. (Phila.) 5, 1061–1071 (2012).

    Article  CAS  Google Scholar 

  122. Omenn, G. S. et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med. 334, 1150–1155 (1996).

    Article  CAS  PubMed  Google Scholar 

  123. Kurie, J. M. et al. N-(4-hydroxyphenyl)retinamide in the chemoprevention of squamous metaplasia and dysplasia of the bronchial epithelium. Clin. Cancer Res. 6, 2973–2979 (2000).

    CAS  PubMed  Google Scholar 

  124. Arnold, A. M. et al. The effect of the synthetic retinoid etretinate on sputum cytology: results from a randomised trial. Br. J. Cancer 65, 737–743 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. McLarty, J. W. et al. Beta-carotene, vitamin A, and lung cancer chemoprevention: results of an intermediate endpoint study. Am. J. Clin. Nutr. 62, 1431S–1438S (1995).

    Article  CAS  PubMed  Google Scholar 

  126. Heimburger, D. C. et al. Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12. Report of a preliminary randomized, double-blind intervention trial. JAMA 259, 1525–3150 (1988).

    Article  CAS  PubMed  Google Scholar 

  127. Lam, S. et al. A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia. J. Natl Cancer Inst. 94, 1001–1009 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge support from the Department of Veterans Affairs Merit Review Program; NCI (Colorado SPORE in Lung Cancer—P50 CA58187 and R01 CA164780-02); and an Early Detection Award from the LUNGevity Foundation.

Author information

Authors and Affiliations

  1. Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, VA Eastern Colorado Healthcare System, University of Colorado Denver School of Medicine, 1055 Clermont Street, Box 151, Denver, 80220, CO, USA

    Robert L. Keith & York E. Miller

Authors
  1. Robert L. Keith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. York E. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors researched data for the article, made a substantial contribution to the discussion of the content, wrote the article and edited it prior to submission.

Corresponding author

Correspondence to Robert L. Keith.

Ethics declarations

Competing interests

R. L. Keith is on the speaker's bureau for Boehringer-Ingelheim and Pfizer. R. L. Keith and Y. E. Miller have submitted a patent application for the use of prostacyclin agonists (iloprost clathrate) for Bayer-Schering for the chemoprevention of lung cancer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Keith, R., Miller, Y. Lung cancer chemoprevention: current status and future prospects. Nat Rev Clin Oncol 10, 334–343 (2013). https://doi.org/10.1038/nrclinonc.2013.64

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2013.64

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer