Principles of Gender-Specific Medicine || The Gender-Specific Aspects of Lung Cancer

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<ul><li><p>rates have been declining in men since 1990, but have only recently plateaued in women. With 71 030 female deaths predicted in 2008, lung cancer will account for the death of more women than breast and all gynecological cancers </p><p>lung cancer are never-smokers. Thus, among those with lung cancer, women are significantly more likely to be life-time never-smokers than men.1216 It is clear that different histologic subtypes of lung cancer predominate in smok-</p><p>e</p><p>R</p><p>ity</p><p>erCopyright 2010, Elsevier Inc. All rights reserved.260Principles of Gender-Specific Medicine 2010</p><p>combined.3,4 Because the current death rate for nonsmoking US women is similar to historical values from the 1930s,5 the more than 500% increase in female deaths since that time is likely largely directly attributable to an increase in the prevalence of smoking among women.6</p><p>Smoking accounts for approximately 90% of lung cancer deaths.7 The prevalence of cigarette smoking among both US men and women peaked in 1964 (50% in men and 32% in women) prior to the publication of the Surgeon Generals Report on smoking and health.8 Subsequently, smoking prevalence rates have steadily declined in both sexes, but to a greater degree in men. In 2007, 22% of men were cur-rent smokers, a reduction of 56% since 1964. On the other </p><p>ers compared to nonsmokers. Compared to the histology of other common cancers of the breast, and colon, which are all adenocarcinoma, the histology of lung cancer is heterogenous. Lung cancer histology is comprised of two major classes: small cell and non-small cell lung carcinoma (NSCLC), which comprise 15% and 85% of lung cancer cases, respec-tively. Small cell carcinoma is rare in never-smokers and is associated with an overall 5-year survival of less than 10%.</p><p>Non-small cell carcinoma is comprised of squamous cell carcinoma, large cell carcinoma, and adenocarcinoma subtypes. NSCLC treatment options and prognosis are guided by stage of cancer as determined by the TNM clas-sification and 5-year survival ranges from 5% in Stage 4 Chapter 23</p><p>IntroductIon</p><p>Lung cancer is the leading cause of cancer death among women.1 In the United States, lung cancer incidence in women is second only to breast cancer, accounts for approx-imately 12% of new cancer diagnoses each year, and will affect 1 in 17 women over her lifetime.2 Reflecting shifting patterns in smoking behavior, the incidence of lung cancer in men has stabilized in recent years, but continues to rise in women. Between 1990 and 2008, lung cancer incidence in men increased 12% (from 102 000 to 114 690 cases/year), while the incidence in women increased 82% (from 55 000 to 100 330). Thus, while women accounted for 35% of those diagnosed with lung cancer in 1990, 47% of patients diagnosed with lung cancer in 2008 were women.3,4</p><p>While lung cancer continues to be the leading cause of cancer death in men and women, lung cancer mortality </p><p>the Gender-SpCancer</p><p>Rebecca L. ToonkeL1, and cha1Postdoctoral Research Fellow, Columbia UniversNew York, NY, USA2Associate Professor of Medicine, Columbia UnivNew York, NY, USAhand, the frequency of women smoking decreased 47% to the current level of 17%.9</p><p>It is not clear whether gender-related differences in lung cancer incidence and mortality are solely attributable to trends in cigarette smoking prevalence. Epidemiological and molecular studies suggest that gender-associated differ-ences in tumor biology and lung cancer susceptibility may contribute to lung cancer mortality and incidence, inde-pendent of cigarette smoking.10 Because cigarette smoking status is clearly associated with susceptibility, it is a com-mon source of confounding bias in these studies.</p><p>Are lung cAncers In smokers And nonsmokers dIfferent?</p><p>Worldwide, about 53% of women and 25% of men with 11</p><p>cific aspects of Lung </p><p>Les a. PoweLL2</p><p>, Division of Pulmonary, Allergy, and Critical Care Medicine, </p><p>sity, Division of Pulmonary, Allergy, and Critical Care Medicine, </p></li><li><p>Chapterto 70% in Stage 1. Prognosis is also associated with his-tology, with the prognosis for adenocarcinoma being more favorable than that for squamous and large cell carcinoma. Adenocarcinoma is the most common histologic subtype in never-smokers,1719 while small cell and squamous cell carcinoma are more common in current or former smokers. Thus smoking-associated prognosis differences may be influenced by the greater proportion of nonsmokers with adenocarcinoma12 and by the increasing frequency of the adenocarcinoma subtype bronchioloalveolar carcinoma in nonsmokers, which is associated with longer survival than other adenocarcinoma subtypes.20</p><p>The clinical differences in outcomes of smokers and non-smokers are supported by molecular studies that indicate the molecular alterations of lung tumors from smokers and nonsmokers are different. For example, chromosomal copy number aberrations and loss of heterozygosity are associ-ated with smoking status.21,22 Also, tumor cell DNA from smokers shows a global increase in promoter hypermethyl-ation and a dose-dependent specific increase in methylation of the tumor suppressor genes APC and p16.23,24 P53 muta-tions are also more common in lung tumors from smokers with G:CT:A transversions predominating as opposed to the G:CA:T transitions that are more common in tumors from nonsmokers.25 Importantly, recent studies indicate that the gene expression profiles of lung adenocarcinomas from smokers differ from those in never-smokers,26,27 sug-gesting differential pathway activation in tumors caused by cigarette smoking compared with tumors caused by other environmental exposures.</p><p>Mutations of the epithelial growth factor receptor (EGFR) are more common among tumors from nonsmokers,2831 while Kras mutations predominate in tumors from smokers and G:C-T:A transversions are found exclusively in smok-ers.3236 Because EGFR mutations occur more frequently in tumors from nonsmokers, these patients also have higher rates of response to targeted therapy with tyrosine kinase inhibitors such as gefitinib and erlotinib.29,3741 While it is not clear that nonsmokers also have an improved response to standard adjuvant chemotherapy,42 studies have found a sur-vival advantage for nonsmokers compared with smokers. In an analysis of 654 patients with adenocarcinoma, Nordquist et al. found a 5-year survival of 23% for never-smokers vs. 16% for current smokers (p 0.004).43 Another group examined data on 1405 patients with lung cancer and found smoking status to be an independent predictor of cancer-specific survival in multivariate analysis.44 Equally impor-tant, the survival of smokers with lung cancer may also be affected by poorer underlying lung function and a higher fre-quency of comorbidities such as cardiovascular disease.</p><p>Taken together, these studies indicate that smoking status is associated with clinically important differences in tumor molecular features and with survival and suggest this may be an important bias in studies that examine gender related differences. 23 l the Gender-Specific aspects of Lung Cancer 261</p><p>Are lung cAncers In men And women dIfferent?</p><p>A number of important differences between lung cancers in men and women have been identified. While adenocarcinoma is the most frequent diagnosis in women, men are more likely to develop squamous or small cell carcinoma.12,13,15,4547 Notably, bronchioloalveolar carcinoma also occurs more commonly in women.10,13,15,46 As noted above, these dif-ferences may be attributable in part to differences in smok-ing status.19 Women tend to be diagnosed with lung cancer at a younger age1214,16,4749 and at an earlier stage than men.12,13,47,49,50 However, men and women with adenocarci-noma present younger than those with squamous cell carci-noma, suggesting that diagnosis at a younger age in women may simply reflect the greater proportion of women with adenocarcinoma (and in turn, perhaps just a greater propor-tion of nonsmokers).14,16,48,51 Likewise, the increased fre-quency of bronchioloalveolar carcinoma, a slower growing and less aggressive subtype, may also contribute to diagnosis at an earlier stage in women.</p><p>Alternatively, it is possible that women are diagnosed at younger ages and earlier stages because of differences at presentation. Men are more likely to complain of hemop-tysis, weight loss, and chest pain, while women are more likely to be asymptomatic.15 Although this difference in presentation may be partially attributable to the increased frequency of centrally located squamous cell carcinomas in men vs. peripherally located adenocarcinoma in women, it is also possible that it is due to gender differences in report-ing of symptoms and health care utilization.</p><p>Are women more susceptIble to lung cAncer?</p><p>Lung cancer arises as the result of a complex interplay of envi-ronmental exposures (such as tobacco smoke, diet, cooking fumes, and occupational exposures) and individual suscep-tibilities (such as genetic, epigenetic, and hormonal factors). What is the evidence that there is an increased female suscep-tibility to lung cancer? Are female smokers more susceptible to lung cancer than male smokers, after controlling for the exposure (i.e., are women more susceptible to the same dose of tobacco carcinogens)? Are nonsmoking women more sus-ceptible to lung cancer than nonsmoking men?</p><p>Most studies suggest that women are more susceptible to the carcinogenic effects of cigarette smoke.14,50,5254 In a study of 17 425 current and former smokers undergoing CT screening for lung cancer, Henschke and colleagues reported an odds ratio for lung cancer of 1.9 (95% CI 1.52.5) in women compared with men when controlled for both age and pack-years. Women were diagnosed with lung cancer at a median of 47 pack-years, while men were diagnosed at a median of 64 pack-years.46 In a well-designed, case control </p></li><li><p>SeCt ion 4 l Pulmonology262study of 1889 never-smokers and current smokers, Zang and Wynder reported odds ratios for lung cancer were 1.21.7-fold higher for women than men both for never-smokers and for smokers. The odds ratios increased with increasing levels of exposure, again suggesting an increased susceptibility to the carcinogenic effects of smoke in women.10 Support for this hypothesis also comes from evidence that women may be more susceptible to the health effects of cigarette smoke generally. For example, a meta-analysis of studies on smok-ing induced morbidity and mortality showed a higher over-all disease effect in women.55</p><p>A few studies suggest that women do not have an increased susceptibility to the carcinogenic effects of cigarette smoke.5659 This is expected given the complexities in controlling for gender- related differences in cigarette smoke exposure levels. In order to address susceptibility while controlling for gender differ-ences in the exposure to cigarette smoke and its effect on lung cancer risk, investigators have compared incidence rates of lung cancer in nonsmoking men and women.</p><p>Female nonsmokers appear to have an increased risk for lung cancer compared with nonsmoking males. Wakelee and colleagues examined lung cancer incidence in never-smoking men and women aged 4079 in six large prospec-tive cohorts and found that while the age-adjusted incidence rates for women in each cohort ranged from 14.4 to 20.8 per 100 000 person-years, rates for men were significantly lower at 4.8 to 13.7 per 100 000 person-years.60 Thun et al. however pooled data on never-smokers from 13 large cohort studies and detected no difference in incidence and death rates between males and females of European descent aged 40 and above.5 The pooled age-standardized incidence rates were 14.0 per 100 000 and 13.8 per 100 00 for men and women, respectively. Women may also have a higher incidence among those aged 4059, a similar incidence among those aged 6079, and a lower incidence among those older than 80 years (p 0.06). While both of these studies included three of the same cohorts, their differ-ent approaches (i.e. incidence vs. death rates, pooled vs. non-pooled data, and age-adjusted vs. age-standardized rates) may account for their disparate outcomes. Thus, further study will be needed to definitively answer the question of whether female nonsmokers are at an increased risk for lung cancer.</p><p>potentIAl mechAnIsms for A gender effect on lung cAncer</p><p>Epidemiologic studies show clear trends of increasing rates of lung cancer deaths in women and in the proportion of lung cancer cases occurring in never-smokers. Environmental exposures, molecular epidemiology, and hormonal influ-ences may also contribute to gender differences in lung cancer.environmental exposuresWhile some studies have estimated that environmental tobacco smoke, or second-hand smoke exposure results in an excess risk of 20% for lung cancer in never-smokers,61 others have found a more modest increase in lung cancer risk.62 While few have studied the differential exposure and effect of second-hand smoke on men and women, a pooled analysis of 14 studies in China detected an odds ratio for sec-ond-hand smoke-related lung cancer of 1.70 (95% CI: 1.322.18) for nonsmoking women as opposed to 1.64 (95% CI: 1.292.07) for the population at large.63 Another study found an increased risk for lung cancer among Japanese women liv-ing with a smoking spouse, however no study has compared a similar incidence to the incidence of lung cancer in non-smoking men living with a smoking spouse.64</p><p>In addition to environmental tobacco smoke, women worldwide are also exposed to higher levels of several envi-ronmental pollutants associated with lung cancer, such as cooking oil vapor and coal dust. Several studies have identi-fied volatilization of cooking oil fumes from open woks and poorly ventilated kitchens as a risk factor for lung cancer in nonsmoking women in the developing world.63,6570 In a case-control study of 672 Chinese women and 735 controls, cooking with rapeseed oil and stir-frying more than thirty dishes per week were identified as risk factors for lung can-cer.71 In vitro studies have also shown mutagenic effects of heated rapeseed and soybean oils.72 While most studies suggest that environmental exposure to coal dust and lung cancer are linked,63,66,71,7375 not all studies agree.76 If coal dust exposure is associated with lung cancer, then, as with cooking oil vapors, women in developing countries may be at a greater risk than men because of poorly ventilated indoor coal stoves.</p><p>While women may have an increased risk of lung can-cer related to exposures in the home, they have a decreased risk for lung cancer associated with occupational exposures such as asbestos, chromium, and arsenic.77,78 Other envi-ronmental exposures such as domestic radon,79,80 arsenic contamination of drinking water,81,82 and dietary factors83 have been implicated in lung cancer risk, but no clear gen-der associations have been identified. A novel exposure recently linked with lung cancer risk in women is infec-tion with human...</p></li></ul>