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Abstract

Lung cancer is now the leading cancer killer of women, having surpassed breast cancer in 1987. Over 30,000 more US women are expected to die from lung cancer than from breast cancer annually. The vast majority of lung cancer cases are attributable to smoking, and smoking prevalence rates remain unacceptably high in US women. Mounting evidence suggests that there are significant differences in lung cancer between the sexes. Although the magnitude of the effect of smoking on the development of lung cancer may not be different, smoking appears to have an impact on the histology of lung cancer. Hormonal and biologic effects may play a role in lung cancer carcinogenesis, and may impact treatment response. A more thorough understanding of the biologically different aspects of lung cancer across different populations may lead to innovations in prevention and treatment.

Keywords

lung cancer sex differences tobacco women's cancers

Women's cancers such as breast cancer and gynecologic malignancies have received substantial attention and research funding in the recent past. However, lung cancer is now the leading cause of cancer death in women, having surpassed breast cancer in 1987. Almost twice as many women in the USA are expected to die from lung cancer than from breast cancer in 2009 (70,490 vs 40,170) [1]. There has been a significant increase in the lung cancer incidence in women over the last half century, and it is estimated that this rise will not plateau until well after 2010.

The rise in lung cancer mortality in the USA among women accompanied by decreased lung cancer death rates among males has significantly altered the patient demographics in this disease. While much of the changing epidemiology is attributable to tobacco use, it is becoming increasingly apparent that the relative risks of a particular histologic type of lung cancer, the relationship between tobacco use and lung cancer and even the response to therapy may not be the same for both sexes. Recent work suggests that genetic, molecular and hormonal differences exist between men and women with lung cancer.

Epidemiology

The age-adjusted lung cancer death rate has risen in parallel to the smoking rate among women, with the curves separated by approximately 30 years. This separation reflects the latency period between smoking and death from lung cancer. Specifically, the smoking rate of women rose in the USA from 1930 to 1960, which was followed by a rapidly increasing lung cancer death rate that began in 1960. The lung cancer death rate in women is now beginning to plateau with a reported increase of only 0.5% per year from 2001 to 2005 [2]. Although lung cancer death rates have essentially stabilized over recent years, that stabilization may be misleading because birth cohorts of women characterized by the highest smoking prevalence have yet to reach the ages of highest lung cancer risk. In fact, it is projected that deaths attributable to lung cancer will continue to increase as the at-risk population increases. Historically, lung cancer has been more common in men than in women; however, the male:female incidence ratio has narrowed dramatically, from 3.65 in 1975 to 1.65 in 1999, as the incidence rate in men declined while the rate in women continued to rise slowly [2,3].

A notable exception to these trends exists among never-smokers. In this population, the age-adjusted incidence rate of lung cancer is higher for women (14.4 to 20.8 per 100,000 persons/year) than for men (4.8 to 13.7 per 100,000 person/year) according to a pooled analysis of six large prospective cohort studies [4]. Similarly, in the NIH–AARP cohort (postal questionnaire administered from 1995 to 1996), the incidence was higher in women (25.3 per 100,000 persons/year) than in men (20.3 per 100,000 person/year) who have never smoked [5]. Recently, Thun et al. pooled information on lung cancer incidence among self-reported never-smokers from 13 large cohort studies, representing over 630,0 and 1.8 million persons for incidence and mortality, respectively. Interestingly, they found that although lung cancer death rates are higher in men than in women, younger women had higher lung cancer incidence rates than men among never-smokers of European descent, and that African-American and Asian women had higher age-standardized lung cancer incidence rates than men, even though the differences were not statistically significant [6]. In the USA, an estimated 19% of lung cancers in women occur in never-smokers, compared to approximately 9% in men [4].

Risk factors

Smoking

Although many people who have never smoked develop lung cancer, smoking is the overwhelming cause of lung cancer. Of patients with lung cancer, 85–90% are former or current tobacco users. When examining smoking trends in women, causality from the rise in lung cancer over the past century is clearly evident. Prevalence of smoking was 18% in 1935 with a peak of 33% in 1965. There has been a slow decline in cigarette use by women over the past decades; however, almost a fifth of US women continue to smoke despite all that is known about the devastating effects of tobacco consumption. Following the increase in smoking prevalence in women form 1930, mortality from lung cancer in women increased by 600% from 1930 to 1997 [7].

There remains some controversy over whether women who smoke are at increased risk for developing lung cancer than male smokers. Several reports of case-control studies have argued that women are more vulnerable to tobacco carcinogens than men [8,9]. Other cohort studies have demonstrated similar odds ratios (ORs) for lung cancer among men and women [5,10 –12]. Although these differences in risk have been widely touted, the weight of the evidence suggests that there is truly little difference in relative risk among men and women smokers, and in fact, current efforts should focus upon the growing body of evidence that suggests that the biology of the disease differs between the sexes.

Other risk factors

Certainly, hormonal-based influences in the development of lung cancer have been studied. Taioli and Wynder presented evidence that exogenous and endogenous estrogens may play a role in the development of lung adenocarcinoma in women [13]. Using case–control data, they showed the following: early age at menopause (40 years or younger) is associated with a reduced risk of adenocarcinoma of the lung (OR = 0.3); the use of estrogen-replacement therapy is associated with a higher risk of adenocarcinoma of the lung (OR = 1.7); and there is a positive interaction between estrogen replacement, smoking and the development of adenocarcinoma of the lung (OR = 32.4). Blackman et al. investigated the use of estrogen-replacement therapy and lung cancer in another case-control trial [14]. The OR for lung cancer among women who used estrogen-replacement therapy for over 3 months was 1.0, independently of duration or type of estrogen. In this study, estrogen use alone appeared not to be an independent risk factor for lung cancer. Schabath and colleagues, again using a case-control design, evaluated the association between hormone-replacement therapy and lung cancer risk in 499 women with lung cancer and 519 age-matched control subjects [15]. In this study, hormone-replacement therapy was associated with a 34% overall reduction in lung cancer risk after controlling for age, ethnicity, tobacco exposure, body mass index and menopausal status. However, because the hypothesis of the study was to identify molecular markers for lung cancer, the authors urged caution in interpretation as the dose and duration of hormone use was not rigorously obtained. Recently, in a yet unpublished report from the Women's Health Initiative in which postmenopausal women were randomized to either estrogen plus progestin or placebo, it was noted that although the incidence of lung cancer was not increased with hormone-replacement therapy, there was a significant increase in mortality from non-small-cell lung cancer (NSCLC) [16]. Additional prospective studies are needed to gain a better understanding of the relationship among cigarette smoke, estrogen use and lung cancer.

Human papilloma virus (HPV) infection is a well-recognized event in the pathogenesis of cervical cancer. Utilizing polymerase chain reaction (PCR) and in situ hybridization, HPV was detected in the tumors of 49% of women with lung cancer who also had a history of high-grade cervical intraepithelial neoplasia (grade III) [17]. A Taiwanese study revealed the presence of HPV DNA (types 16 and 18) in the cancer cells of never-smoking women with lung cancer. Interestingly, these cases included squamous cell cancer, which is not commonly associated with never smoking [18]. Recently, in an analysis of 53 publications with over 4500 cases, Klein et al. found that the mean incidence of HPV in lung cancer was 24.5%. While in Europe and North America, the average reported frequencies were 17 and 15%, respectively, the mean number of HPV cases in Asian samples was 35.7% [19]. They also found that HPV was detectable in all histologic types and had considerable heterogeneity of expression by region with areas such as Taiwan having rates in excess of 80%. The authors also noted that if HPV was causally related to lung cancer, then HPV could be the second most important risk factor for acquiring lung cancer after cigarette smoking. They also concluded that this view was supported by the epidemiologic observation in never-smoking Taiwanese females who have very high HPV detection rates as well as unusually high mortality from lung cancer. However, there remain many important questions, and additional research is certainly needed to understand the role of HPV in lung cancer.

Histology

Lung cancer histologies include squamous cell carcinoma, adenocarcinoma, small-cell carcinoma and large-cell carcinoma. NSCLC accounts for more than 85% of all lung cancers, and includes the histologic subtypes squamous cell carcinoma and large-cell carcinoma, which arise from the epithelial cells lining the bronchi, and adenocarcinoma, which develops from the glandular tissue in the peripheral regions of the lung. There is a consistent difference in the distribution of histologic types of lung cancer between men and women. Adenocarcinoma is currently the most common histologic subtype in both men and women, and women have proportionally more adenocarcinoma and less squamous cell carcinoma compared to men. Part of the explanation for differing distributions of lung cancer histology between men and women could be related to differences in smoking patterns. However, this explanation cannot account for all of the differences in the observed differences. For example, male smokers have a similar OR for the development of squamous cell and small-cell carcinomas, whereas women smokers appear to have a much higher OR for the development of small-cell compared with squamous cell carcinoma [20,21].

Sex-based differences in lung cancer biology

Genetic differences

Genetic variation between men and women is present in some genes that encode carcinogen-metabolizing enzymes. The CYP1A1 gene codes for an enzyme that is central to the metabolism of carcinogenic polycyclic aromatic hydrocarbons [22]. Activation of polycyclic aromatic hydrocarbons by the CYP1A1 gene product leads to highly reactive substances that bind to DNA, forming adducts [23]. Increased expression of the CYP1A1 gene in the lung has been demonstrated in female smokers compared with male smokers [24]. Increased CYP1A1 enzymes expression may be the result of induction by hormones, notably estrogen.

Although the CYP1A1 gene codes for Phase I enzymes that metabolically activate carcinogens, Phase II enzymes compete with Phase I carcinogen-activating enzymes to inhibit the formation of free radicals and also to catalyze the conversion of reactive intermediates to inactive conjugates that are more water soluble and more readily excreted [25]. The most common polymorphism in the Phase II detoxification enzymes is the glutathione S-transferase M1 (GSTM1)- null genotype, which is present in 40–60% of the general population owing to a gene deletion [26]. Expression of the null phenotype may be a marker of susceptibility, and the effects of GSTM1 gene deletion may be heightened among female smokers [27]. The effect of polymorphisms in both the CYP1A1 and GSTM1 genes could contribute to differences in the etiology of lung cancer in women.

Other lines of evidence for sex-related differences in lung cancer come from studies on the gastrin-releasing peptide receptor (GRPR). A number of studies have shown that gastrin-releasing peptide (GRP), a bombesin-like peptide, plays a role in neoplasia by stimulating cell proliferation [28]. In normal tissues, this peptide stimulates the growth of bronchial epithelial cells and has been implicated as regulator of human lung development. The effect of these peptides is mediated mainly through an interaction with the GRPR. The gene for GRPR is X-linked, located on chromosome Xp22, near a cluster of genes that escape X-inactivation. Women, therefore, can have two actively transcribed alleles of the GRPR gene, compared with only one in men. It has been reported that GRPR mRNA expression was noted in 55% of female ‘nonsmokers’ but only 0% of male ‘nonsmokers’, and that 75% of women who were short-term smokers (1-25 pack years) had GRPR mRNA expression compared with 20% of male short-term smokers.

The reason that the heterogeneity between men and women with lung cancer first became apparent was that there were stark clinical differences in response to the drug gefitinib, a tyrosine kinase inhibitor of the EGF receptor (EGFR). Significant responses to both gefitinib and erlotinib were found to correspond to mutations in the tyrosine kinase domain of EGFR that resulted in constitutively activated downstream signaling. In lung cancer, these activating mutations are more common in women and never-smokers [29 –32].

Molecular differences

Carcinogens such as polycyclic aromatic hydrocarbons (PAH) and nitrosamines are present in tobacco smoke and exert their biologic effects after transformation through the formation of DNA adducts in target tissues and mutations in transforming genes [33]. The extent of DNA adduct formation depends on the balance between rates of oxidation or the compounds and the rates of detoxification of the reactive products by way of conjugation and DNA repair capacity. Although there is considerable variation between tobacco exposure and adduct level [34], high levels of stable adducts in lung tissue are believed to play a role in the initiation of carcinogenesis [35]. Higher smoking-related DNA adduct levels in female patients with lung cancer, when adjusted for smoking dose, have been reported in tumors and adjacent lung tissue [23]. Reduced DNA repair capacity is associated with an increased risk of lung cancer, and women are reported to have lower DNA repair capacity than men [34].

Multiple studies suggest that women may be more predisposed than men to molecular aberrations that result from the carcinogenic effects of tobacco smoke. p53 is a tumor-suppressor gene that is often mutated in lung cancer (ranging from 70% in small-cell lung cancer to 33% in lung adenocarcinoma) [36]. There is a higher frequency of the G:C to T:A transversion in the p53 tumor-suppressor gene in women who smoked compared to women who never smoked, whereas there is less variation among male smokers and never-smokers [37]. Lung cancers in women smokers demonstrate significantly more tobacco-related mutations than women who had never smoked and male smokers.

The K-ras oncogene encodes a protein that is oncogenic when mutated or overexpressed in lung tumors. One study attempted to define the patient characteristics that are associated with K-ras gene mutation and to determine whether mutation of the gene correlated with patient prognosis [38]. Mutations in codon 12 of the K-ras oncogene occurred predominantly in adenocarcinomas, were found only in patients who had a history of smoking, and were more common in women than men (26 and 17%, respectively). The investigators concluded that cigarette smoking induces K-ras mutations and the resultant clones could be further expanded by a second event that may be specific for adenocarcinoma histology. Given the sex difference in the mutation patterns, this event could involve the growth-promoting effects of hormones such as estrogen.

Hormonal differences

There are significant sex differences in lung cancer at the genetic and biochemical levels. It is therefore reasonable to postulate that these effects are mediated in some way by circulating estrogen. The classical estrogen receptor (ER)-α is a ligand-activated transcription factor that is associated with the development of estrogen-dependent cancers such as breast and endometrial carcinoma. A second ER, ER-β, was identified in 1996 and localized to chromosome 14 [39]. ER-β has biologic roles that are distinct from those of ER-α. Whereas ER-α is required for ovulation, ER-β is required for the differentiation of estrogen-sensitive tissues. Relative quantities of ER-β mRNA are highest in human granulosa cells, endothelial cells, the ovary and the lung. In tissues that express both ER-α and ER-β, there is potentially very complex gene regulation via formation of ER-α and ER-β heterodimers.

Although several investigators have reported the presence of ER-α in human lung cancer, the results are inconsistent, of uncertain clinical significance, and expression by immunohistochemistry ranges from 7 to 97% [40,41]. β-estradiol can cause proliferation in NSCLC cells and antiestrogens can block this effect [42]. ER-β can play a role in regulation of lung development, in particular alveolar formation and surfactant homeostasis, in mouse models [43].

In addition to the classic estrogenic effects in the nucleus, it is increasingly clear that estrogen signaling effects may take place via ERs in the plasma membrane, causing interactions between ERs and growth factors [44]. Growth factors such as EGF and IGF-1 stimulate the transcriptional activity of ERs in an estrogen-independent manner. Some studies suggest the existence of a non-nuclear ER that can activate pI3 kinase and the EGF family of receptors. In cells that express EGFR and ER, estrogen may stimulate cellular proliferation and survival through these alternate pathways.

Estrogens may be involved in lung tumorigenesis at many different levels. They may act as ER ligands, activating cellular proliferation pathways. Alternatively, they may undergo metabolic activation to reactive intermediates that can produce DNA adducts or cause oxidative damage. This potential role of estrogens in lung cancer is understudied and only more research can yield new insights into the mechanisms underlying its effects.

Therapeutic implications

Although the toll of lung cancer on women is enormous, women have superior responses to therapy for lung cancer. This appears to be true regardless of stage, therapeutic modality, or histology. For example, an analysis from the Surveillance, Epidemiology and End Results (SEER) and Medicare databases for 1991 to 1999 studied the outcomes in almost 19,0 patients over 65 years of age with stage I or II NSCLC [45]. Multivariable analysis revealed that both lung cancer-specific survival and overall survival were significantly better in women in all treatment groups (surgery with or without additional postoperative treatment, radiation therapy or chemotherapy without surgery, or untreated), with hazard ratios of 0.72 to 0.78. This translated to higher 5-year survival rates in women, 46 versus 38%.

Certainly, sex-related differences in lung cancer gene mutations (EGFR mutations) may be responsible for some of the treatment outcome disparities between men and women as patients with some EGFR tyrosine kinase mutations not only prognostically have improved survival, but also are more responsive to drugs such as gefitinib and erlotinib. However, it may be that hormonal influences, although protective for most of one's life, can then either accelerate the transition of a preneoplastic lesion to an overt malignancy or promote growth once malignancy is evident.

Future perspective

Lung cancer deaths would be minimized significantly if fewer people smoked since almost 90% of lung cancer cases are attributable to smoking. Smoking rates remain unacceptably high despite all that is known about the negative health effects of tobacco smoke. Estimates of smoking prevalence in 2006 remained over 20% [2]. The prevalence of smoking is highest among young girls and the less educated. Currently, more young women than young men smoke. Tobacco marketing has been directed to young women with themes such as independence, and they include models that are generally athletic, thin and beautiful. Some tobacco companies, even today, continue to design cigarette lines especially for women.

Lung cancer has reached epidemic proportions in women, and it is now the leading cause of cancer death in women as well as men. In 2009, almost 71,000 women will die from lung cancer as opposed to over 40,000 from breast cancer. The vast majority of lung cancers are directly attributable to smoking and almost 20% of women continue to smoke. Although is appears unlikely that women have a greater risk for developing lung cancer than men, it is clear that the histologic spectrum varies between the sexes and that molecular differences do exist.

Areas for significant study include not only understanding of the epidemiology of lung cancer and smoking trends among women, but also a more thorough study of the complex interplay between carcinogens, susceptibility and sex-specific influences that have led to the epidemic of lung cancer in women. It is incumbent upon us to promote research and study of these differences as a better understanding of lung cancer will lead to improvements in therapy for both men and women.

Executive summary

Lung cancer is the leading cause of cancer death among women.

It is projected that deaths attributable to lung cancer will continue to increase as the at-risk population increases.

Cigarette smoking is the main cause of the high rates of lung cancer in women, and it is unlikely that women are more susceptible to the carcinogenic effects of tobacco than are men.

There is a consistent difference in the distribution of histologic types of lung cancer between men and women, and this may be influenced by hormonal factors.

Genetic differences in carcinogen-metabolizing genes such as CYP1A1 and GSTM1 and oncogenes such as the EGFR and K-ras may contribute to observed differences in behavior.

Women may also have a reduced DNA-repair capacity compared with men.

Estrogens may be involved in lung tumorigenesis at many different levels, from signaling to growth promotion.

Women have superior survival when treated with surgery, radiation or chemotherapy compared to men.

A more thorough understanding of the complex interplay between carcinogens, susceptibility and sex-specific influences is desperately needed.

Footnotes

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Lung Cancer: A Biologically Different Disease in Women?