Chapter 23

the Gender-Specific aspects of Lung Cancer

Rebecca L. ToonkeL1, and chaRLes a. PoweLL2

1Postdoctoral Research Fellow, Columbia University, Division of Pulmonary, Allergy, and Critical Care Medicine, New York, NY, USA2Associate Professor of Medicine, Columbia University, Division of Pulmonary, Allergy, and Critical Care Medicine, New York, NY, USA

Copyright 2010, Elsevier Inc. All rights reserved.260 2010

Principles of Gender-Specific Medicine

IntroductIon

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

While lung cancer continues to be the leading cause of cancer death in men and women, lung cancer mortality 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 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

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 General’s 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

hand, the frequency of women smoking decreased 47% to the current level of 17%.9

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.

Are lung cAncers In smokers And nonsmokers dIfferent?

Worldwide, about 53% of women and 25% of men with lung cancer are never-smokers.11 Thus, among those with lung cancer, women are significantly more likely to be life-time never-smokers than men.12–16 It is clear that different histologic subtypes of lung cancer predominate in smok-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%.

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 l the Gender-Specific aspects of Lung Cancer 261

to 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,17–19 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

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:C–T:A transversions predominating as opposed to the G:C–A: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.

Mutations of the epithelial growth factor receptor (EGFR) are more common among tumors from nonsmokers,28–31 while Kras mutations predominate in tumors from smokers and G:C-T:A transversions are found exclusively in smok-ers.32–36 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.29,37–41 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.

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.

Are lung cAncers In men And women dIfferent?

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.12,13,15,45–47 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 age12–14,16,47–49 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.

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.

Are women more susceptIble to lung cAncer?

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?

Most studies suggest that women are more susceptible to the carcinogenic effects of cigarette smoke.14,50,52–54 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 1.5–2.5) 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

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study of 1889 never-smokers and current smokers, Zang and Wynder reported odds ratios for lung cancer were 1.2–1.7-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

A few studies suggest that women do not have an increased susceptibility to the carcinogenic effects of cigarette smoke.56–59 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.

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 40–79 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 40–59, a similar incidence among those aged 60–79, 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.

potentIAl mechAnIsms for A gender effect on lung cAncer

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 exposures

While 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: 1.32–2.18) for nonsmoking women as opposed to 1.64 (95% CI: 1.29–2.07) 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

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.63,65–70 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,63,66,71,73–75 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.

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 papilloma virus serotypes 16 and 18 (HPV 16/18). Cheng et al. found that among female nonsmokers with lung cancer, the odds ratio for infection, as detected by PCR, was significantly higher in women than men.84 If validated, this intriguing finding may provide insights into the role of infection in lung carcinogenesis.

Overall, current evidence suggests that second-hand smoke and cooking oil vapor exposures are important contributors to lung cancer risk in never-smoking women. Minimization of these exposures is a logical strategy to lower the incidence of lung cancer in never smoking women.

Chapter 23 l the Gender-Specific aspects of Lung Cancer 263

molecular epidemiology

In cigarette smokers, lung cancer arises as the consequence of cumulative genetic and epigenetic alterations to the bronchial epithelium that culminates in carcinoma in sus-ceptible individuals. Within cigarette smoke are thousands of particulate compounds, of which at least 60 have been determined by the International Agency for Research on Cancer (IARC) to be carcinogenic in humans or laboratory animals.85 These carcinogens include polycyclic aromatic hydrocarbons (PAH) such as Benzo-[a]-pyrene (BaP), and nicotine derived nitrosamines such as NNK. The response to carcinogen exposure is mediated by enzyme systems that metabolize endogenous chemicals and xenobiot-ics. Although initially thought to be restricted to the liver, it is clear these enzymes are expressed and active in other organs, including the lung. The metabolism of environmen-tal pollutants and drugs is divided into two reaction classes, phase I (functionalization) and phase II (conjugation).

Inter-individual phenotypic heterogeneity is associated with allelic variants that exist within each gene family. PAH are metabolized by CYP1A1 and by CYP1B1. There are at least 12 variant alleles of CYP1A1, some of which are asso-ciated with increased enzyme inducibility and have been examined in lung cancer case-control studies. CYP1A1 induces the conversion of BaP to its toxic metabolite BaP-diol epoxide, which binds covalently to DNA to form DNA adducts, a validated biomarker of DNA damage and lung cancer risk. Polymorphisms in exon 7 of CYP1A1 have been associated with an increased risk for lung cancer86 and CYP1A1 expression has been shown to be higher in females and to be associated with increased DNA adduct levels.87 Other recent studies suggest that induction of CYP1A1 may be mediated by crosstalk between the estro-gen and aryl hydroxylase receptors.88

Phase II enzyme detoxification conjugations occur with moieties such as glucoronide, mercapturic acid, acetate, methyl, sulphate, glycine, glutamine, thiocyanate, and gluco-side, resulting in a hydrophilic product that is readily excret-able.89 Phase II enzymes include glutathione S-transferases (GSTs), uridine diphosphate glucuronosyltransferases, sul-photransferases, epoxidases, acyltransferases, acetyltrans-ferases, methyltransferases, and transaminases. The most frequently studied Phase II enzymes are the GSTs, which function to conjugate electrophilic compounds, such as BaP with glutathione. The GSTM1 class occurs in null form in 50% of the white population. Two studies have linked deletions of GSTM1 with lung cancer risk in nonsmoking women, especially those exposed to high levels of environmental tobacco smoke.90,91 In addition, the UDP-glucuronyltransferase enzymes (UDPs) have been implicated in lung cancer risk in women. Recent studies suggest that UDPs expression may be regulated by estro-gen and that deletion polymorphisms in the UGT2B17 gene (the most potent hepatic enzyme against the tobacco

carcinogen NNK) may be associated with lung cancer risk in women but not men.92,93

The role of susceptibility factors in lung carcinogenesis traditionally has been examined in case-control studies. However, data obtained from the case-control study design may be confounded by recall bias and by information bias due to the presence of lung cancer. The results may be obscured by the long time interval between exposure to mutagens and the development of lung cancer. To address these concerns, researchers have recently directed efforts to developing intermediate biomarkers of lung cancer for the determination of lung cancer susceptibility factors. These intermediate biomarkers include well-characterized molecular dosimeters of cigarette carcinogen exposure, such as PAH-DNA adducts. Studies have shown that ele-vated adduct levels and impaired DNA repair capacity are associated with an increased risk for lung cancer94 and gender differences in metabolism and DNA repair have been observed.95 In a study of 62 nonsmoking lung cancer patients and 20 controls, DNA adduct levels were found to be significantly higher in lung tissue from women than men.96 Similarly, lung DNA adduct levels per pack-year of smoke exposure are significantly higher in non-smoking women than men.87,97

Other genes potentially involved in lung cancer risk include the nicotinic acetylcholine receptor (nAchR) and the gastrin-releasing peptide receptor (GRPR). Recent results from three genome wide association studies of lung cancer risk identified common variants in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 that were associated with nicotine dependence and/or lung cancer risk.98–100 Although there was a slight increased risk for women compared with men (p 0.06) in the IARC Central European cohort, there was no increased risk for women in the Iceland cohort. The gene encoding gastrin-releasing peptide receptor (GRPR), which is important in mediating signaling pathways important for lung cell growth, is located on the X-chromosome and is known to escape X-chromosome inactivation in females. Expression of GRPR is higher in women than in men and is upregu-lated in response to tobacco smoke, thus suggesting a role for gender associated gene expression differences that may be important in lung carcinogenesis.101

Tumor genetics may also play a role in female lung cancer susceptibility and prognosis. For example, loss of heterozygosity at chromosome 11p15 was found to occur more commonly in men and among smokers, and was associated with a poorer overall survival. However, because smoking exposure was not controlled for in this study, it is unclear if the observed effect of gender simply reflects a smaller number of female smokers.102 Alterations in tumor cell p53 expression and activity have also been linked to gender. Guinee et al. identified a higher frequency of p53 transversion mutations in lung cancer cells from female smokers103 and Mukhopadhyay and colleagues observed

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that estradiol promotes apoptosis in lung cancer lines via activation of p53.104 In conclusion, several lines of evi-dence suggest that the molecular epidemiology of lung cancer may be different in men and women and may help to explain the observed differences in lung cancer suscepti-bility and prognosis.

hormones

There is increasing evidence that estrogens play a criti-cal role in lung cancer susceptibility and prognosis. Later menarche and shorter cycle lengths have been associated with an increased incidence of lung cancer65 while early menopause has been shown to be protective.105 Notably, in a study of 766 patients with small cell lung cancer, female gender was identified as an independent predictor of response and survival, but only for women under the age of 60, supporting a putative tumor suppressive effect of estro-gen manifested as a shift towards increased lung cancer mortality among postmenopausal women.106

Estrogens bind two receptor subtypes with high affin-ity, ER and ER. Both receptors have been identified in normal lung tissue107–109 as well as resected lung tumor specimens.110–113 In vitro studies have demonstrated estro-gen receptor expression and response by NSCLC cell lines as well as normal lung fibroblasts and bronchial epithe-lium.111,114 Estrogen metabolites have also been shown to have antiangiogenic and pro-apoptotic effects.104,115 The role of estrogen in lung cancer is complicated by the fact that its effect may be receptor-dependent, with ER pro-moting and ER inhibiting gene transcription.116

The effects of estradiol on lung cancer may not be lim-ited to cells expressing the estrogen receptor. A second receptor, the type II estrogen binding site, binds to both estrogen and tamoxifen and inhibits cell growth in a dose-dependent manner.117 Also, estrogens have been shown to mediate effects on the EGFR pathway. Stabile et al. showed that EGFR expression is downregulated in response to estrogen and is upregulated in response to the estrogen receptor antagonist fulvestrant. Using a murine xenograft model, treatment with combination gefitinib and fulvestrant suppressed tumor growth 60% as opposed to 49% and 32% for gefitinib or fulvestrant alone.118

Estrogen and progesterone receptors have also been iden-tified in some resected human lung cancer specimens.110,119 While Canver et al. found positive immunostaining for estrogen receptors in 62 of 64 NSCLC specimens, another study found detectable staining in only 2 of 32 speci-mens.114,120 Positive tumor immunostaining for ER has been associated with improved survival in men.121 Recently, Niikawa et al. examined 59 frozen NSCLC specimens and found that 73% had higher intratumoral estradiol concen-trations than surrounding non-neoplastic lung tissue. They also found that intratumoral estradiol concentration was positively correlated with tumor size.122 Another group

identified gender dependent expression patterns of intratu-moral estrogen receptors by using RT-PCR to show estrogen receptor gene expression in 85% of specimens from women but only 15% of specimens from men.123

The role of HRT and effects on estrogen signaling may alter lung cancer risk. Adami et al. found a relative risk for lung cancer of 1.3 (95%CI: 0.9–1.7) for women receiving HRT.124 Taioli et al. also found an increased risk of adeno-carcinoma in women receiving hormone replacement ther-apy (HRT), however, subgroup analyses revealed that this effect was limited only to smokers.105 Not all studies have identified an increased risk for lung cancer associated with HRT,125 and several demonstrate a protective effect.126–130 In a case-control study of 499 women with lung cancer and 519 controls, Schabath et al. found a 34% reduction in the overall risk of lung cancer associated with the use of HRT after controlling for age and smoking status.126 Similarly, Schwartz et al. found the duration of HRT use in postmeno-pausal women to be associated with a reduction in lung can-cer risk (OR 0.88, 95% CI 0.78–1.00).127 Prospective trials will be needed to definitively address this issue.

do women wIth lung cAncer hAve A better prognosIs thAn men?

It has been suggested that while women may be more sus-ceptible to lung cancer than men, they may also have a bet-ter prognosis. While men certainly have a higher death rate from lung cancer than women, it is unclear if this is due to inherent biologic differences between men and women or is simply a result of multiple potential confounders such as smoking prevalence, histology, stage at diagnosis, co-morbid disease, and underlying lung function. For exam-ple, while many studies do show a survival advantage for women with lung cancer, they also show that women are more often never-smokers, present at an earlier stage, have better underlying lung function and fewer co-morbidities, and are less likely to require extensive surgical operations such as pneumonectomy.12,13,15

Despite these potential confounders, several studies suggest that women may have a better response to treat-ment and a better survival after surgical resection for NSCLC.12,13,15,47,49,131–133 A study of 2531 patients in the SWOG database treated for advanced NSCLC between 1974 and 1988 identified female gender as an independent predic-tor of survival134 and these results have been confirmed by others.16,135,136 While some have found female gender to be predictive of improved survival at all stages,47,51,137 others have found the effect to be limited.13,15,132 However, because women nonsmokers outnumber men and most studies do not control for smoking history, it is difficult to determine if the survival advantage is due to gender differences or smoking status.

Chapter 23 l the Gender-Specific aspects of Lung Cancer 265

Therefore, studies that adjust for total tobacco expo-sure are of particular interest. Henschke et al. found that female smokers with NSCLC identified by CT screening had a hazard ratio for death of 0.48 (95% CI: 0.25–0.89) compared with males after controlling for stage and pack-years.46 Similarly, in a prospective study of 4618 patients treated for NSCLC at the Mayo Clinic, men were found to have a relative risk of death from lung cancer of 1.20 (95% CI: 1.11–1.30) after adjusting for age, stage, and pack-years smoked.138

A survival advantage for women has also been observed in SCLC. An analysis of 1745 patients with SCLC in the CALGB database identified female gender in multivari-ate analysis to be an independent predictor of treatment response and survival for both limited and extensive dis-ease.139 Similar results were seen in a pooled analysis of three German multicenter trials where women were found to have a higher rate of complete remission (35% vs. 25%) and an improved two year survival (19% vs. 8%).106 Other studies also found that female gender predicted improved survival, but did not control for extent of disease.140,141 In summary, the data do seem to support a survival advantage for women with both SCLC and NSCLC.

conclusIons

Cigarette smoking remains the leading cause of lung cancer death and of cancer death in women of the world. While it is not yet clear if women are more susceptible to lung can-cer, current evidence does suggest that women with lung cancer have an improved prognosis compared to men with similar cigarette smoke exposure. Potential explanations for observed gender disparities in lung cancer include environ-mental exposures, molecular genetic factors, and hormonal differences. The gap between male and female smoking prevalence is narrowing and we are likely to see the inci-dence and death rates from lung cancer in women begin to approach those in men. As research continues to be directed towards understanding gender-specific aspects of lung can-cer susceptibility and prognosis, advocacy for public policy initiatives will help prevent and reduce smoking prevalence in girls and women. Exposure to environmental pollutants can be remediated, which is a strategy that may be helpful in lowering the incidence of lung cancer in never smoking women in developing countries.

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