INTRODUCTION — The epidemic of lung cancer in females is reviewed here, focusing on epidemiologic issues, risk factors, outcome, and prevention. General issues related to lung cancer risk and its clinical presentation are discussed separately. (See "Cigarette smoking and other possible risk factors for lung cancer" and "Clinical manifestations of lung cancer".)
EPIDEMIOLOGY — Worldwide, lung cancer is among the most common cancers and cancer death in females. In the United States, lung cancer is the leading cancer killer of females, having surpassed breast cancer in 1987 (table 1). Approximately 40 percent more females in the United States are expected to die annually from lung cancer compared with breast cancer [1].
The age-adjusted lung cancer death rate has risen in parallel to the smoking rate among females, with the increase in lung cancer deaths following the increase in smoking incidence by approximately 20 years. This separation reflects the latency period between smoking and death from lung cancer. Specifically, the smoking rate for females rose dramatically in the United States from 1930 to 1960, and this was followed by a rapidly increasing lung cancer death rate that began in 1960 (figure 1) [1-6]. The lung cancer death rate in females reached a plateau and has now started to decline, with a reported decrease of 1.1 percent per year since 2006 to 2007 [1,6]. The same trend has been documented in many European countries [7].
Comparison of males and females — Lung cancer mortality has been and continues to be more common in males than females [8]. However, the magnitude of this difference continues to decline [9,10].
The age-adjusted lung cancer incidence has historically been higher in males than females. However, the magnitude of this difference has decreased [1,2,4,10,11]. Moreover, given that the incidence of lung cancer has declined more steeply in young males than in young females over the past two decades, the incidence of lung cancer in non-Hispanic White individuals in the 30 to 49 year old age group is higher in females than in males, according to cancer registry data from 1995 through 2014 [12]. This reversal in trends is not accounted for by sex difference in smoking behaviors.
Among nonsmokers, the age-adjusted incidence rate of lung cancer is higher for females (14.4 to 20.8 per 100,000 person-years) than males (4.8 to 13.7 per 100,000 person-years) according to a pooled analysis of six prospective cohort studies [13]. Furthermore, in the United States, approximately 19 percent of lung cancer in females arise in never smokers compared with only 9 percent for males. However, there is no clear evidence that lung cancer in never smoking young females is increasing [14]. (See "Lung cancer in never smokers".)
RISK FACTORS — Given that smoking is the most important risk factor for the development of lung cancer in both females and males, the question arises whether there is a sex-related difference in the magnitude of the relationship between smoking and lung cancer. An additional question is whether endocrine factors affect the risk of lung cancer.
Tobacco exposure — Cigarette smoking is the main culprit for the lung cancer epidemic in females, with estimates suggesting up to 80 percent of lung cancer cases in females are related to smoking [15,16]. Females started smoking in significant numbers during and following World War II. Although smoking rates have declined since their peak in the 1960s, the current prevalence of smoking among females in the United States is still too high with an estimated 16.5 percent of females smoking in 2011 (figure 2) [17]. (See "Cigarette smoking and other possible risk factors for lung cancer".)
Reported relative risks (RR) for the development of lung cancer in female smokers compared with female nonsmokers vary greatly. RRs from reports range from 7.8 to 37.5 [18-23]. Furthermore, the magnitude of the risk increases with the duration of smoking and with the total exposure to cigarettes [16,22,24]. The risk in females who are former smokers remains significantly elevated compared with never smokers [23].
Passive smoking may also be associated with increased risk of lung cancer in never smokers, although the increased risk appears to be predominantly in females with prolonged exposure as an adult [23]. (See "Lung cancer in never smokers", section on 'Secondhand smoke' and "Secondhand smoke exposure: Effects in adults", section on 'Lung cancer'.)
Evidence is mixed but suggests that female smokers may have a higher RR of developing lung cancer than male smokers [25-29]. For example, in a large cohort study of almost 600,000 participants, approximately 6500 of whom developed lung cancer over the course of follow-up, female current smokers experienced a statistically significant increase in lung cancer risk compared with male smokers (hazard ratios [HRs] relative to nonsmokers were 1.64 for female smokers and 1.43 for male smokers) [29].
Lung cancer is not the only smoking-related tragedy in females. The World Health Organization (WHO) showed that at least 25 percent of female smokers die from a smoking-related disease [30]. In absolute numbers, approximately 300,000 females in developed countries died of smoking-related diseases in 1985. The most important smoking-related causes of death were cardiovascular disease (41 percent), lung cancer (21 percent), and chronic obstructive pulmonary disease (18 percent) [30]. Other causes include cancers of the esophagus, head and neck, and other sites as well as other respiratory diseases.
A subsequent report estimated that in 2000 there were 4.83 million deaths in the world due to smoking with an even split between industrialized and nonindustrialized. About one million of these deaths were in females, and the principal causes of death remained cardiovascular disease, lung cancer, and chronic obstructive pulmonary disease [31]. (See "Cardiovascular risk of smoking and benefits of smoking cessation" and "Chronic obstructive pulmonary disease: Risk factors and risk reduction".)
Air pollution — There is a relatively high burden of lung cancer in females in China and certain other countries in Asia and Africa, which is thought to be due to burning coal and wood for cooking in unventilated stoves [32]. (See "Cigarette smoking and other possible risk factors for lung cancer", section on 'Air pollution and diesel exhaust'.)
Radiation therapy — Exposure to radiation is a known risk factor for subsequent development of lung cancer as well as other cancers. This was initially demonstrated in atomic bomb survivors who had an increased lung cancer incidence years following radiation exposure [33]. (See "Cigarette smoking and other possible risk factors for lung cancer", section on 'Radiation therapy'.)
Several reports have shown that survivors of Hodgkin lymphoma who have received radiation therapy (RT) to the chest have a higher risk of developing a lung cancer compared with those who did not receive RT; this risk is further increased among smokers [34-36]. (See "Second malignancies after treatment of classic Hodgkin lymphoma", section on 'Lung cancer'.)
Similar findings have been reported in females who have received RT for breast cancer. The incidence of lung cancer is markedly increased in females who have smoked and have received RT following mastectomy for breast cancer compared with those who never smoked and did not receive postmastectomy RT [37]. (See "Cigarette smoking and other possible risk factors for lung cancer", section on 'Radiation therapy'.)
It is unclear whether the use of modern RT techniques such as intensity modulated radiation therapy (IMRT) and/or proton therapy will affect the incidence of radiation-associated lung cancer and other radiation-associated cancers. On the one hand, the incidence may be reduced given that smaller volumes of normal tissue receive high doses with these modern conformal techniques. On the other hand, the risk of second cancers could be increased with the use of IMRT and protons due to the fact that larger volumes of normal tissue receive very low doses with such techniques [38,39].
Endocrine factors — Large randomized studies suggest that estrogen plus progestin therapy is associated with an increased risk of lung cancer [40-42]. (See "Menopausal hormone therapy: Benefits and risks".)
The most extensive data come from three prospective studies:
●In the Women's Health Initiative trial, 16,608 females were randomly assigned to estrogen-progestin therapy or placebo. There was a statistically nonsignificant trend toward an increased incidence of non-small cell lung cancer in females taking estrogen-progestin therapy when compared with placebo (0.14 versus 0.11 percent; HR 1.28, 95% CI 0.94-1.73) and an increased number of deaths from lung cancer (0.11 versus 0.06 percent; HR 1.71, 95% CI 1.16-2.52) [40,41].
●In another component of the Women's Health Initiative trial, 10,739 females who had previously undergone a hysterectomy were randomly assigned to estrogen alone or placebo [43]. In a post-hoc analysis, there was no statistically significant increase in the incidence of lung cancer after a mean follow-up of eight years (HR for incidence 1.17, 95% CI 0.81-1.69) nor was there an increase in deaths from lung cancer (HR for death 1.07, 95% CI 0.66-1.72).
●The prospective Vitamins and Lifestyle (VITAL) study followed a cohort of over 36,000 peri- and postmenopausal females during six years of follow-up [42]. After adjusting for smoking and other confounding factors, the risk of incident lung cancer was increased for those who used an estrogen plus progestin. The risk was proportional to duration of hormone exposure (HR 1.48, 95% CI 1.03-2.12 for those with ≥10 years exposure to an estrogen plus progestin).
Endocrine factors also may have an impact on the natural history of disease if lung cancer does develop [44]. (See 'Outcome' below.)
Other risk factors — Risk factors other than smoking that have been established for the development of lung cancer in males have also been confirmed for females. (See "Cigarette smoking and other possible risk factors for lung cancer".) These include:
●A family history of lung cancer, which is both a risk factor on its own and has a significant interaction with smoking [45,46].
●A history of prior lung disease, which is a known risk factor in males and has been shown to be a risk factor in two case-control studies limited to females [47,48].
●An unresolved issue for both males and females is the relation between diet and vitamins and the development of lung cancer [49-53].
HISTOLOGY — There is a consistent difference in the distribution of histologic types of lung cancer between males and females. Adenocarcinoma has replaced squamous cell carcinoma as the most common histologic type for both males and females, but proportionally more females than males are diagnosed with adenocarcinoma, and more males than females are diagnosed with squamous cell carcinoma [11,21,22,54].
A contemporary population-based case-control study of 4220 people in Italy demonstrated that among females diagnosed with lung cancer, the histologic sub-types were adenocarcinoma for 54 percent and squamous cell carcinoma for 11 percent compared with 38 and 30 percent, respectively, for males diagnosed with lung cancer [22]. Similar results were reported based on the United States National Surveillance, Epidemiology, and End Results (SEER) database. Histologic sub-types of lung cancer for 228,572 people diagnosed between 1975 and 1999 showed rates of adenocarcinoma and squamous cell carcinoma of 45 and 21 percent for females, compared with 33 and 36 percent for males [11].
Part of the explanation for differing distributions of lung cancer histology as well as different lung cancer biologies for males and females could be due to sex-related different susceptibilities to various molecular aberrations caused by smoking or other potential carcinogens [21,55]. There may also be differences in somatic gene mutations between the sexes. For example, epidermal growth factor receptor (EGFR) mutations are more prevalent in females and nonsmokers [56,57]. There do not appear to be differences in the prevalence of KRAS or EML4-ALK mutations between females and males [55]. It has been suggested, although not definitively demonstrated, that estrogen may influence histologic and molecular features of lung cancer and may explain some of the observed intersex differences in these characteristics [57].
OUTCOME — Contemporary studies indicate that the prognosis of lung cancer in females is better than in males, at least for patients with adenocarcinoma [58-61]:
●An analysis from the United States Surveillance, Epidemiology, and End Results (SEER) and Medicare databases for 1991 to 1999 studied the outcomes in almost 19,000 patients over 65 years of age with stage I or II non-small cell lung cancer (NSCLC) [58]. Multivariate analysis revealed that both lung cancer-specific survival and overall survival were significantly better in females in all treatment groups (surgery with or without additional postoperative treatment, radiation therapy [RT] or chemotherapy without surgery, or untreated), with hazard ratios (HRs) of 0.72 to 0.78. Overall, these differences were reflected in a higher five-year survival rate in females (46 versus 38 percent in males).
●A meta-analysis that included 2349 patients from five randomized trials evaluating contemporary, platinum-based chemotherapy regimens found that females had a longer overall survival than males (median 9.6 versus 8.6 months; HR 0.86, 95% CI 0.78-0.95) [61]. A significant difference was limited to patients with adenocarcinoma (median 10.9 versus 8.4 months; HR 0.70, 95% CI 0.59-0.83); the difference was not significant in patients with nonadenocarcinoma (survival 8.8 versus 8.5 months; HR 0.97, 95% CI 0.85-1.10).
●A second meta-analysis that included 39 articles and 86,800 patients showed statistically significant improvement in overall survival with HRs for females versus males of 0.79 in studies using univariate analyses and 0.78 (p<0.0001) in studies using multivariate analyses [62].
Endocrine factors may also affect the natural history of disease in females who develop NSCLC [41,44]. In the Women's Health Initiative trial, females on combined estrogen-progestin therapy had a significantly shorter survival compared with those given placebo (median survival 9.4 versus 16.1 months, HR 1.59) [40,41]. These findings are consistent with the hypothesis that endocrine factors either accelerate the transition of a preneoplastic lesion to an overt malignancy or promote tumor growth once a malignancy is evident.
Although these data require confirmation, discontinuation of postmenopausal hormone therapy should be considered in females diagnosed with lung cancer [63].
Sex-related differences in lung cancer gene mutations (eg, EGFR mutations) may also explain some of the treatment outcome disparities between females and males [55]. Female sex is a significant clinical prognostic factor for patients treated with EGFR tyrosine kinase inhibitors.
TREATMENT — Solving the problem of lung cancer in females has three major components: prevention, early detection, and improved methods of treatment.
Prevention — The most effective intervention will be to stop people from smoking altogether, since approximately 85 to 90 percent of lung cancer cases are attributable to smoking [64]. Smoking prevalence rates for males and females in the United States have decreased since their peaks in the 1960s. Smoking rates for United States females were 34 percent in 1965 and 21 percent in 2000 [65]. Smoking prevalence in the United States in 2011 was about 19 percent [17]. Convincing individuals to stop smoking, however, is not an easy task. Smoking rates remain unacceptably high despite the overwhelming evidence that smoking causes lung cancer as well as other fatal health problems. (See "Overview of smoking cessation management in adults".)
The prevalence of smoking is disproportionately high among young girls and the less educated. In 2000, 30 percent of high school girls were smokers, and a report from 2001 described that smoking rates for females with less than a high school education were three times higher than for females with a college education [66,67].
The study of other methods of lung cancer prevention, including the role of diet and vitamins, should also be pursued. (See "Chemoprevention of lung cancer".)
Early detection — The data from clinical trials examining screening and the delineation of specific populations for whom this approach is beneficial are discussed separately. (See "Screening for lung cancer".)
Improvements in treatment — Substantial gains are being made in the treatment of lung cancer, particularly with respect to understanding the underlying pathogenesis and personalizing cancer care on that basis. (See "Overview of the initial treatment of advanced non-small cell lung cancer" and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)
Preclinical and clinical trials should continue to be supported, and sex should be addressed as a specific research variable. Females should be actively recruited for enrollment in lung cancer clinical trials [15,49,68].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)
SUMMARY
●Epidemiology – Although the incidence of lung cancer in females (and males) continues to decrease, it remains the leading cancer killer in females as well as males. The vast majority of lung cancer cases are attributable to smoking, and smoking prevalence rates in females are still unacceptably high. (See 'Epidemiology' above.)
●Risk factors – It is unresolved whether etiologic factors contributing to lung cancer differ in females and males, but there do appear to be some distinctions. The magnitude of the effect of smoking on the risk of developing the disease may not be different across the sexes, but smoking appears to have an impact on the histology of lung cancer.
Finally, although the evidence is not entirely clear, endocrine factors may influence both the development of lung cancer and its subsequent natural history. Consideration should be given to discontinuing postmenopausal hormone therapy in females diagnosed with lung cancer.
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