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Journal of Clinical Oncology, Vol 25, No 5 (February 10), 2007: pp. 469-471 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.4623
Lung Cancer, Smoke Exposure, and SexUniversity of Texas Southwestern Medical Center, Dallas, TX; and the American Cancer Society, Atlanta, GA Lung cancer is the most preventable of all of the major forms of cancer because 85% to 90% of deaths from lung cancer are a result of active cigarette smoking.1 However, even in people who have never smoked, lung cancer accounts for approximately 15,000 deaths annually,2 similar to the number of deaths projected for ovarian cancer in 2006 and more than the number of deaths projected for brain cancer, bladder cancer, or multiple myeloma.3 Two important articles4,5 in this issue provide insights about sex differences in the epidemiology and molecular characteristics of lung cancer in lifelong nonsmokers. Nearly a decade ago, one of us (A.F.G.) postulated that differences in the histologic distribution of lung cancer between men and women signaled important differences in disease pathogenesis in response to tobacco smoke.6 Today, the evidence is substantially stronger, yet the issue seems more complex than ever. The report by Wakelee et al4 provides the first direct evidence that lung cancer incidence is higher among women than men who have never smoked based on five prospective cohort studies in the United States and one in Sweden. These data are particularly interesting because previous studies of lung cancer in lifelong nonsmokers have examined death rates but not incidence. Two massive American Cancer Society cohorts,2 together with other studies that are smaller or have shorter follow-up,8-16 collectively demonstrate that the death rate from lung cancer is approximately 25% higher in men than in women who have never smoked. It is important that other large cohorts attempt to replicate the observation by Wakelee et al4 that the opposite seems to be true for lung cancer incidence in never smokers age 40 to 79 years. Furthermore, replication would support the hypothesis by Henschke et al17 that women may be more susceptible to develop lung cancer than men but are less likely to die from the disease. Studies are also needed to determine whether the survival difference between male and female never smokers is large enough to account for the lower lung cancer death rates in women despite their higher incidence. Wakelee et al4 also note that the proportion of lung cancers that are adenocarcinoma is highest among male and female lifelong nonsmokers, intermediate in former smokers, and lowest in current smokers. It is well known that adenocarcinoma is the predominant cell type of lung cancer in women and in lifelong nonsmokers. What is less well known is that comparisons of proportions do not provide a direct comparison of risk. For example, although adenocarcinoma makes up a larger proportion of lung cancers in women than in men age 50 years and older, the incidence rate of adenocarcinoma is actually higher in men than women in the same age groups based on population-based cancer incidence registries in the United States. The reason why adenocarcinoma predominates in women is not that the risk of developing adenocarcinoma is higher in women than in men, but rather that the risk of developing other cell types of lung cancer, particularly squamous cell and small-cell cancers, is much lower. As Wakelee et al indicate,4 their study has certain limitations; it cannot assess whether the incidence of lung cancer among lifelong nonsmokers has changed over time or whether the pattern differs in geographic regions other than North America and northern Europe. Several prior studies have indicated that the proportion of never smokers in females with lung cancers is much higher than their male counterparts in certain parts of China and other Asian countries where women are exposed to indoor air pollution from unventilated fumes from cooking and heating at much higher concentrations than in the West. Here, too, comparisons of proportions are less informative than are comparisons based on incidence rates. In Asia, even more than in the United States,2 women comprise the majority of lifelong nonsmokers over age 60 years. The larger denominator, rather than any inherent sex difference in susceptibility, may explain why women outnumber men among never smokers with lung cancer. Subramanian and Govindan5 provide a comprehensive review of the current state of our knowledge about lung cancers in never smokers. Although they do not specifically point out the relationship between tobacco exposure and sex, many of the features of this disease, as discussed in their review, indicate a close interaction (Table 1). The higher incidence rate in women who have never smoked has already been discussed. Peripherally arising adenocarcinomas account for the majority of lung cancers occurring both in never smokers and in women. For practical purposes, centrally located small-cell carcinomas virtually never occur in never smokers, and squamous cell carcinomas are relatively rare.
The role of estrogens and their receptors is complex and multifaceted, as summarized by Subramanian and Govindan5 and in other studies,18,19 and estrogens and their receptors may play a role in the pathogenesis of cancers occurring in smokers and never smokers. By influencing expression of polymorphic genes that regulate tobacco carcinogen metabolism, estrogens may play a role in carcinogenesis both by sex bias and at an individual level. Of interest, lung cancers may, on occasion, express relatively high levels of estrogen receptors alpha and beta, but their expression does not seem to show a sex bias (J. Minna and Y. Jeong, personal communication, October 2006). Studies from Taiwan suggest that women never smokers have greater DNA adduct formation and DNA damage and a higher incidence of oncogenic strains of human papillomavirus in their lung cancers.20 Lung and other solid tumors are characterized by a large number of molecular changes. There are striking differences affecting several genes in tumors occurring in ever and never smokers, and some of these also show important sex differences. Mutations in the p53 gene are present in all lung cancers, both in smokers and never smokers, whereas mutations in the KRAS gene are predominantly present in smokers with adenocarcinoma histology. Mutations in both genes show a preponderance of G:T transversions, resulting from adduct formation by tobacco carcinogens. In contrast, mutations in the p53 gene arising in never smokers are frequently G:A transitions. An analysis of the p53 mutation databases indicated that the different spectra of p53 mutational patterns among smoker and never smoker cancers were almost entirely a result of differences between lung cancers in women, whereas male tumors did not show significant differences.21 Because KRAS mutations are rare in never smoker cancers, the mutational pattern in never and ever smoker tumors cannot be compared. Most studies have not indicated a sex bias for KRAS mutations independent of tobacco exposure. Perhaps the most intriguing recent molecular finding has been the presence of mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene in lung cancers (summarized in Shigematsu and Gazdar22). Prior clinical observations had indicated that the response of non–small-cell lung cancers to tyrosine kinase inhibitors that target EGFR was related to the following four independent factors: adenocarcinoma histology, never-smoking status, female sex, and East Asian ethnicity. Mutations in the EGFR gene target the same subpopulations and represent the first molecular change characteristic of non–small-cell lung cancers occurring in never smokers. Mutations in the HER2 gene (a member of the EGFR gene family), although much rarer, target the same subpopulations.28 Of great interest, mutations in EGFR (and HER2) are mutually exclusive of KRAS mutations in lung cancers.22 KRAS mutations lie downstream of EGFR in the signaling pathway, thus making redundant the presence of activating mutations in both genes in the same individual tumor. Inactivation of tumor suppressor genes by DNA methylation of their promoter sequences is frequent in all cancers, and each tumor type may have its characteristic spectrum of methylated genes. Of interest, the methylation patterns of tumors arising in smokers and never smokers are different and may be related to their characteristic mutational changes.23 However, sex does not seem to be related to methylation patterns. Why do lung cancers occur in never smokers? Genetic factors may play a role in cancers occurring both in smokers and never smokers. The much higher rates in East Asians also suggest a role for genetic predisposition as well as reflect the differences in indoor air pollution mentioned earlier. Recently, a major lung cancer susceptibility locus was found to map to chromosome 6q23-25.29 Even light smoke exposure greatly increased the risk in individuals with inherited susceptibility. Although a rare inherited mutation in the EGFR gene has been described,30 the vast majority of mutations are somatic in origin.22 Environmental tobacco smoke is often stated to be the major cause of lung cancer in never smokers. However, as reviewed in Subramanian and Govindan,5 several studies indicate that environmental tobacco smoke is a relatively weak carcinogen that is unlikely to account for most of the lung cancers that occur in never smokers. The major sex, clinicopathologic, therapeutic, and molecular differences in adenocarcinomas occurring in smokers and never smokers suggest that the cancers arise via very different pathways. We have suggested that tobacco carcinogens activate or mutate the RAS gene, whereas in the absence of such activation (in never smokers), the upstream pathway (EGFR or related genes) is activated by factor(s) yet to be discovered.31 However, because not all cancers have activated the KRAS or EGFR signaling pathways, alternate pathways to cancer must exist in both smokers and never smokers. Clearly, lack of an understanding of the factors responsible for lung cancers in never smokers is a major deficiency that must be addressed before we can explore preventive strategies. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author indicated no potential conflicts of interest.
ACKNOWLEDGMENTS Supported by the University of Texas Specialized Program for Research Excellence in Lung Cancer, National Cancer Institute, Bethesda, MD. We thank John Minna and Joan Schiller for their helpful comments and support. REFERENCES 1. US Department of Health and Human Services: The Health Consequences of Smoking: A Report of the Surgeon General. Rockville, MD, US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2004, p 941 2. Thun MJ, Henley SJ, Burns D, et al: Lung cancer death rates in lifelong nonsmokers. J Natl Cancer Inst 98:691-699, 2006 3. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2006. CA Cancer J Clin 56:106-130, 2006 4. Wakelee HA, Chang ET, Gomez SL, et al: Lung cancer incidence in never smokers. J Clin Oncol 25:472-478, 2007 5. Subramanian J, Govindan R: Lung cancer in never smokers: A review. 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Kahn H: The Dorn study of smoking and mortality among U.S. veterans: Report on eight and one-half years of observation, in Haenszel W (ed): Epidemiological Study of Cancer and Other Chronic Diseases. Bethesda, MD, US Department of Health, Education, and Welfare, Public Health Service, National Cancer Institute, 1966, pp 1-126 12. Doll R, Gray R, Hafner B, et al: Mortality in relation to smoking: 22 years' observations on female British doctors. Br Med J 280:967-971, 1980[Medline] 13. Doll R, Peto R: Mortality in relation to smoking: 20 years' observations on male British doctors. Br Med J 2:1525-1536, 1976[Medline] 14. Cederlof R, Friberg L, Hrubec Z, et al: The Relationship of Smoking and Some Social Covariables to Mortality and Cancer Morbidity. Stockholm, Sweden, Department of Environmental Hygiene, The Karolinska Institute, 1975 15. Friedman G, Tekawa I, Sadler M, et al: Smoking and mortality: The Kaiser Permanente experience, in Burns D, Garfinkel L, Samet J (eds): Changes in Cigarette-Related Disease Risks and Their Implication for Prevention and Control. Bethesda, MD, National Institutes of Health, National Cancer Institute, 1997, pp 477-497 16. Best E: A Canadian Study of Smoking and Health. Ottawa, Ontario, Canada, Department of National Health and Welfare, 1966, p 137 17. Henschke CI, Yip R, Miettinen OS: Women's susceptibility to tobacco carcinogens and survival after diagnosis of lung cancer. JAMA 296:180-184, 2006 18. Gasperino J, Rom WN: Gender and lung cancer. Clin Lung Cancer 5:353-359, 2004[Medline] 19. Siegfried JM: Women and lung cancer: Does oestrogen play a role? Lancet Oncol 2:506-513, 2001[CrossRef][Medline] 20. 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 61:2799-2803, 2001 21. Toyooka S, Tsuda T, Gazdar AF: The TP53 gene, tobacco exposure, and lung cancer. Hum Mutat 21:229-239, 2003[CrossRef][Medline] 22. Shigematsu H, Gazdar AF: Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 118:257-262, 2006[CrossRef][Medline] 23. Toyooka S, Tokumo M, Shigematsu H, et al: Mutational and epigenetic evidence for independent pathways for lung adenocarcinomas arising in smokers and never smokers. Cancer Res 66:1371-1375, 2006 24. Subbaramaiah K, Telang N, Ramonetti JT, et al: Transcription of cyclooxygenase-2 is enhanced in transformed mammary epithelial cells. Cancer Res 56:4424-4429, 1996 25. Cheng YW, Hsieh LL, Lin PP, et al: Gender difference in DNA adduct levels among nonsmoking lung cancer patients. Environ Mol Mutagen 37:304-310, 2001[CrossRef][Medline] 26. Ahrendt SA, Decker PA, Alawi EA, et al: Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer 92:1525-1530, 2001[CrossRef][Medline] 27. Toyooka S, Maruyama R, Toyooka KO, et al: Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer. Int J Cancer 103:153-160, 2003[CrossRef][Medline] 28. Shigematsu S, Takahashi T, Nomura M, et al: Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 65:1642-1646, 2005 29. Bailey-Wilson JE, Amos CI, Pinney SM, et al: A major lung cancer susceptibility locus maps to chromosome 6q23-25. Am J Hum Genet 75:460-474, 2004[CrossRef][Medline] 30. 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 37:1315-1316, 2005[CrossRef][Medline] 31. Gazdar AF, Shigematsu H, Herz J, et al: Mutations and addiction to EGFR: The Achilles ‘heal’ of lung cancers? Trends Mol Med 10:481-486, 2004[CrossRef][Medline] This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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