INTRODUCTION — The epidemic of lung cancer in women 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 the third most common cancer in women, behind breast and colorectal cancers, and the second leading cause of female cancer death [1]. In the United States, lung cancer is the leading cancer killer of women, having surpassed breast cancer in 1987 (table 1). More than 50 percent more women in the United States are expected to die annually from lung cancer compared with breast cancer [2].
The age-adjusted lung cancer death rate has risen in parallel to the smoking rate among women, 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 women 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) [3-7]. The lung cancer death rate in women has reached a plateau and has now started to decline with a reported decrease of 1.1 percent per year from 2003 to 2009 [7]. The same trend has been documented in many European countries [8].
Comparison of men and women — Lung cancer mortality has been and continues to be more common in men than women [1]. However, the magnitude of this difference continues to decline due to increases in the female lung cancer mortality rate while the mortality rate in males has decreased [9,10].
The age-adjusted lung cancer incidence has historically been higher in men than women. However, the magnitude of this difference has decreased, which reflects the fact that the female incidence rate is stabilizing while the male incidence rate continues to decrease [5,10,11]. Moreover, given that the incidence of lung cancer has declined more steeply in young men than in young women over the past two decades, the incidence of lung cancer in non-Hispanic whites in the 30 to 49 year old age group is now higher in women than in men, according to cancer registry data from 1995 through 2014 [12]. This reversal in trends is not accounted for by gender difference in smoking behaviors.
Among nonsmokers, the age-adjusted incidence rate of lung cancer is higher for women (14.4 to 20.8 per 100,000 person-years) than men (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 women arises in never smokers compared with only 9 percent for men. However, there is no clear evidence that lung cancer in never smoking young women 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 women and men, the question arises whether there is a gender-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 women, with estimates suggesting up to 80 percent of lung cancer cases in women are related to smoking [15,16]. Women 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 women in the United States is still too high with an estimated 16.5 percent of women 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 women smokers compared with women 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 women 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 women 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 women smokers may have a higher RR of developing lung cancer than men 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, women current smokers experienced a statistically significant increase in lung cancer risk compared with men smokers (hazard ratios [HRs] relative to nonsmokers were 1.64 for women smokers and 1.43 for men smokers) [29].
Lung cancer is not the only smoking-related tragedy in women. The World Health Organization (WHO) showed that at least 25 percent of women smokers die from a smoking-related disease [30]. In absolute numbers, approximately 300,000 women 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 countries. About one million of these deaths were in women, 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 women 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 women who have received RT for breast cancer. The incidence of lung cancer is markedly increased in women 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. 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 women 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 women 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 women 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 women 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 men have also been confirmed for women. (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 men and has been shown to be a risk factor in two case-control studies limited to women [47,48].
●An unresolved issue for both men and women 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 men and women. Adenocarcinoma has replaced squamous cell carcinoma as the most common histologic type for both men and women, but proportionally more women than men are diagnosed with adenocarcinoma, and more men than women 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 women 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 men 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 women, compared with 33 and 36 percent for men [11]. Furthermore, rates of all lung cancer types in women and adenocarcinoma in men continue to rise [55].
Part of the explanation for differing distributions of lung cancer histology as well as different lung cancer biologies for men and women could be due to gender-related different susceptibilities to various molecular aberrations caused by smoking or other potential carcinogens [21,56]. There may also be differences in somatic gene mutations between the genders. For example, epidermal growth factor receptor (EGFR) mutations are more prevalent in women and nonsmokers [57,58]. There do not appear to be differences in the prevalence of KRAS or EML4-ALK mutations between women and men [56]. 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 intergender differences in these characteristics [58].
OUTCOME — Contemporary studies indicate that the prognosis of lung cancer in women is better than in men, at least for patients with adenocarcinoma [59-62]:
●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) [59]. Multivariate 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 [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 women (46 versus 38 percent in men).
●A meta-analysis that included 2349 patients from five randomized trials evaluating contemporary, platinum-based chemotherapy regimens found that women had a longer overall survival than men (median 9.6 versus 8.6 months, HR 0.86, 95% CI 0.78-0.95) [62]. 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 women versus men of 0.79 in studies using univariate analyses and 0.78 (p<0.0001) in studies using multivariate analyses [63].
Endocrine factors may also affect the natural history of disease in women who develop NSCLC [41,44]. In the Women's Health Initiative trial, women 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 women diagnosed with lung cancer [64].
Gender-related differences in lung cancer gene mutations (eg, EGFR mutations) may also explain some of the treatment outcome disparities between women and men [56]. Female gender is a significant clinical prognostic factor for patients treated with epidermal growth factor receptor tyrosine kinase inhibitors.
TREATMENT — Solving the problem of lung cancer in women 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 [65]. Smoking prevalence rates for men and women in the United States have decreased since their peaks in the 1960s. Smoking rates for United States women were 34 percent in 1965 and 21 percent in 2000 [66]. 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 women with less than a high school education were three times higher than for women with a college education [67,68].
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 gender should be addressed as a specific research variable. Women should be actively recruited for enrollment in lung cancer clinical trials [15,49,69].
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
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 — Lung cancer has reached epidemic proportions in women, and it is now the leading cancer killer in women as well as men. The vast majority of lung cancer cases are attributable to smoking, and smoking prevalence rates in women are still unacceptably high.
It is unresolved whether etiologic factors contributing to lung cancer differ in women and men, 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 genders, 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 women diagnosed with lung cancer.
