Lung cancer in women is a modern epidemic and a major health crisis. Cigarette smoking remains the most important risk factor for lung cancer, and unfortunately smoking rates are either stabilized or continue to increase among women. Women may not be more susceptible to the carcinogenic effects of tobacco, but the biology of lung cancer differs between the sexes. This paper summarizes the biological sex differences in lung cancer, including molecular abnormalities, growth factor receptors, hormonal influences, DNA repair capacity, as well as differences in the histology and treatment outcomes of lung cancer in women.
Key points
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Although the incidence of lung cancer in women is declining at a slower rate than in men, in many countries the incidence rate is increasing.
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Lung cancer is the leading cause of cancer deaths in women.
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Smoking remains the most important risk factor in women, but nonsmoking women are at higher risk for lung cancer compared with nonsmoking men.
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Sex-based differences in hormonal, environmental, and molecular factors may exist.
Introduction
Lung cancer remains a significant health problem worldwide for both men and women and is the leading cause of cancer death in many countries. Age-adjusted lung cancer incidence rates have historically been higher in men than in women, but the gap has narrowed, reflecting a decrease in the incidence rate in men and an increase in women. In the last 20 years, lung cancer incidence has been declining in many parts of the world, but the decline has been more notable in men. Smoking remains the most important risk factor, and increasing tobacco use in women in many parts of the world will further exacerbate the incidence and mortality of lung cancer in women. Tobacco exposure alone does not tell the entire story; lung cancer in nonsmokers is more common in women. Data support sex-based differences in the biology of lung cancer, but research has been limited. In this article, the authors summarize sex differences in incidence and mortality; tobacco exposure and risk; biological mechanisms that may affect risk, and differences in histology, prognosis, and treatment of lung cancer in women.
Epidemiology of lung cancer in women
Incidence and Mortality
Although age-adjusted lung cancer incidence rates have historically been higher for men than for women in the United States, the gap has narrowed and incidence rates continue to decline more rapidly in men than in women (2.9 vs 1.5 per 100,000, respectively) ( Fig. 1 ), partially explained by historical differences in tobacco cessation and increase in smoking prevalence in women. A population-based study on incidence of lung cancer according to sex, race/ethnic group, and age group (ages 30–54 years) in the United States confirmed the trend of a more rapid decline in incidence among men, but alarmingly, female-to-male incidence rate ratios (IRR) increased from 0.82 (confidence interval [CI] 0.70–0.85) to 1.13 (CI 1.08–1.18) during 1995 to 1999 and 2010 to 2014, respectively. Crossover to higher incidence rate of lung cancer in younger women occurred in white women (0.88 [CI 0.84–0.92] to 1.17 [CI 1.11–1.23]) and more notably among Hispanic women (0.79 [CI 0.67–0.92] to 1.22 [CI 01.04–0.1.44]).
Worldwide, lung cancer remains the most common cancer with an estimated 1.2 million new cases in 2018 and is projected to be a major health problem well through the first half of this century, particularly in women and in developing countries that continue to observe increasing incidence rates. Country-specific data from GLOBOCAN 2012 on temporal trends of lung cancer incidence in 38 countries/regions, stratified by sex, revealed that incidence rates in men had increased in1, decreased in 22, and remained stable in 15 countries, whereas in women, rates had increased in 19, decreased in 1, and remained stable in 18 countries. Highest incidence rates of lung cancer in women are seen in North America, Northern and Western Europe, Australia, and New Zealand, and the epidemic is still in early stages in China, Indonesia, and several African countries ( Fig. 2 ).
Lung cancer accounts for about 1.8 million deaths worldwide and is the leading cause of cancer deaths in women in 28 countries ( Fig. 3 ). , In a recent study, age-standardized mortality rates (ASMR) for breast and lung cancer per 100,000 women were calculated from 2008 to 2014 and projected for 2015, 2020, 2025, and 2030 using a Bayesian log-linear Poisson model. Between 2015 and 2030, the median ASMR for lung cancer is projected to increase from 11.2 to 16.0 in 52 countries, whereas declines are expected for breast cancer, from 16.1 to 14.7. In half of the countries analyzed, and in nearly three-quarters of those classified as high-income countries, the ASMR for lung cancer has already surpassed or will surpass the breast cancer ASMR before 2030.
Smoking and Lung Cancer Risk
Cigarette smoking is the major cause of lung cancer among female smokers in United States and contributes to about 90% of lung cancer deaths. A study measuring temporal trends in mortality across 3 time periods (1959–1965, 1982–1988, and 2000–2010) among female smokers revealed a large increase (by a factor of 16.8) in deaths from lung cancer over the entire 50-year period, about half of which occurred during the past 20 years. Among women, whites have the highest incidence of tobacco-related lung cancer (54.3%) compared with blacks (49.2%), American Indian/Alaskan Natives (39%), and Asian/Pacific Islanders (27.9%).
Although the overall prevalence of cigarette smoking in the United States has decreased from 42% in 1964 to 15.5% in 2016 (13.5% in women vs 17.5% in men), smoking rates have remained relatively stable in recent years (2014–2017). , Using data from the National Health Interview Survey from 1970 through 2016, Jemal and colleagues calculated the prevalence of current smoking and average number of cigarettes smoked daily according to sex, age, and race/ethnic group and found that in younger cohorts, the difference in smoking prevalence between men and women became progressively smaller due to female and male smoking initiation rates converging and decreased smoking cessation rates among women. Although smoking prevalence has been decreasing worldwide, trends in smoking vary dramatically across countries and gender. Women smoke at nearly the same rate as men in high-income countries but they smoke much less than men in many low- and middle-income countries. A major global concern is that projected smoking prevalence rates in women will increase in low- and middle-income countries.
Stabilization of smoking rates in women in some countries and increase in other countries worldwide is alarming considering the 52.7% incidence of new tobacco-related lung cancer cases and indicates a critical need to address factors contributing to female smoking. ,
Lung Cancer in Nonsmokers
Worldwide, an estimated 25% of patients with lung cancer are never smokers, and lung cancer in never-smokers is the seventh most common cause of cancer deaths. , In the United States, approximately 10% to 15% of non-small cell lung cancer (NSCLC) cases occur annually in nonsmokers, more commonly in women than men (17.5% vs 6.9%, respectively; P <.001) and more commonly in black than white patients. , This is in contrast to Asia, where more than 50% of women with lung cancer are never-smokers. , Although the basis for the high rate of lung cancer in Asian never-smokers is unknown, exposure to fumes from heating cooking oils and burning coal in poorly ventilated areas have been implicated. Adenocarcinoma is the most frequent lung cancer histology in never-smokers, often with specific driver mutations.
Differences in lung cancer risk between men and women
Susceptibility to Tobacco Carcinogens
The increase in female smoking rates after 1960s followed by the dramatic increase in lung cancer incidence rates led to the hypothesis that women may be at higher risk after exposure to tobacco carcinogens. Earlier studies showed that in smokers, the odds ratio (OR) for development of small cell lung cancer was more than double in women than in men and that women had 1.5 to 2 times higher risk for developing all major histologic types of lung cancer with the same exposure to cigarette smoke. Women with lung cancer are younger, start smoking at a later age, and smoke less intensively than men. Furthermore, a higher relative risk associated with ever-smoking and level of smoking has been reported in women than men for all lung cancers (12.7 and 9.1 for ever-smoking and 27.9 vs 9.6 for level of smoking, respectively), suggesting that smoking-related morbidity and mortality may have a greater impact on women than men. ,
Increased susceptibility to tobacco carcinogens is controversial, as several studies have found the risk to be similar between men and women. A study evaluating 279,214 men and 184,623 women in the United States showed smoking was associated with similar incidence rates of all histologic subtypes of lung cancer except squamous cell, which had a higher incidence in men. A European study compared 3723 men and women with lung cancer with 4075 controls and found that risk comparing ever-smokers with never-smokers was higher among men than women (OR 16.1 versus 4.2, respectively). A case-control study collected information on lifetime smoking history and evaluated the role of smoking in lung cancer risk combined with environmental and genetic factors. The OR for lung cancer in women was 12.3 compared with 42.2 in men (for all subjects, smokers and nonsmokers), whereas the OR for lung cancer in female ever-smokers was 7.2 compared with 7.1 in male ever-smokers. When evaluated in the context of histologic subtypes, OR for pack-years among adenocarcinoma subtypes was higher in men than in women, with a negative interaction between female sex and smoking ( P = .005), leading to a conclusion that there is no support for a higher susceptibility to tobacco-related lung cancer in women. A recent study reported that although smoking prevalence was lower in women born after 1965, the incidence rate of lung cancer was significantly higher, especially in white and Hispanic women, who smoke less than young Hispanic men, leading investigators to conclude that sex differences in smoking behavior do not fully explain increased lung cancer rates in young women.
Women may not be more susceptible to the carcinogenic effects of tobacco smoke, but there is emerging data supporting sex-based differences in the biology of lung cancer. Of particular interest is the increased incidence of lung cancer in women never-smokers despite less exposure to occupational carcinogens lending weight to other mechanisms driving the increased incidence in women ( Box 1 ).
Hormonal Factors
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Estrogen receptors: overexpressed in human NSCLC cell lines; may play a role in gene regulation, modulation of gene expression in tumor cells, direct carcinogenesis via formation of DNA adducts, growth factor gene activation, stimulating angiogenesis, accelerating metabolism of smoking-related carcinogens.
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Progesterone: inhibits cell proliferation and induces apoptosis in NSCLC, inhibits cell migration
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Molecular Changes
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DNA adducts: formed by activation of polycyclic aromatic hydrocarbons (PAH) that bind to DNA; lead to mutations in tumor growth genes
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Cytochrome P450 enzymes: CYP1A1; responsible for activation of PAH
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Glutathione S-transferases: detoxify active forms of PAH
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Genetic Factors
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p53 gene: tumor suppressor gene that, when activated, minimizes damage from DNA, metabolic stressors, or oncogenes; susceptible to mutations that alter its function or cause it to undergo oncogenic activities
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Kristin rat sarcoma viral oncogene (KRAS) mutation : oncogenic when overexpressed
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DNA repair: essential to repair damage to genome from exogenous and endogenous factors; decreased DNA repair capacity is associated with increased lung cancer risk
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Growth factors: involved in signaling pathways related to initiation of the cell cycle, cell proliferation, differentiation, migration, apoptosis; alterations result in unregulated cell growth; gastrin-releasing peptide is X-linked and stimulates growth of bronchial epithelial cells and is involved in mitogenesis of small cell and non-small cell lung cancers; endothelial growth factor receptor has tyrosine kinase activity, and activation triggers a signaling cascade leading to malignant cell proliferation, decreased apoptosis, increased tumor cell motility, and angiogenesis
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Genetic predisposition : variations in 3 locations in the genome were associated with lung cancer in Asian female never-smokers
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Infections
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Human papilloma virus (HPV) : high-risk HPV causes genomic instability that can lead to malignant transformation
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Nontuberculous mycobacteria : chronic inflammatory microenvironment may predispose to development of lung cancer
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Prior History of Radiation
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Radiation therapy for breast cancer: associated with increased risk of second primary lung cancer
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Biologic factors
Hormonal Effects
Estrogen receptors (ER), specifically ERβ, are expressed in the lung and likely play a role in fetal lung development. ERβ has been demonstrated in human NSCLC cell lines; is overexpressed relative to normal lung tissue; is a functional receptor with affinity for the active form of estrogen, β-estradiol; and its activity can be blocked in vitro with the ER inhibitor fulvestrant. Exactly how estrogen is involved in lung carcinogenesis is not well known, but several possible mechanisms have been reported ( Box 2 ). ,
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Modulate expression of PH metabolizing enzymes
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Modulate gene expression and regulation
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Act as direct carcinogen via the formation of DNA adducts
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Activate several growth factors genes such a transforming growth factor (TGF) alpha and epidermal growth factor (EGF) that mediate cell division in lung cancer
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Stimulate angiogenesis
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Interact with cigarette smoking by accelerating metabolism of smoking-derived carcinogens
Progesterone has been shown to inhibit cell proliferation and induce apoptosis in NSCLC; inhibiting cell migration via progesterone receptors (PR) correlates with longer overall survival. Aromatase plays a role in the conversion of androstenedione to estrone and testosterone to B-estradiol and has been detected in lung tissue. Aromatase-positive NSCLC cells have been shown to produce B-estradiol with decrease in growth of human NSCLC in vitro when treated with aromatase inhibitors indicating potential tumor secretion of estrogens, especially within inflammatory cells responding to cancer cells within the lung. Studies have shown lower incidence of primary lung cancer in patients with breast cancer after treatment with tamoxifen and greater chance of survival in women older than 65 years who expressed lower levels of aromatase in stage I and II NSCLC. ,
A link between hormonal factors and lung cancer risk has been debated. An increased risk of lung cancer in women due to hormone replacement therapy (HRT) and interactions with smoking (OR 1.7 and 32.4 in nonsmokers and smokers, respectively) has been reported. Although a population-based study consisting of 23,244 women undergoing HRT showed an increased risk (relative risk [RR] 1.26) of lung cancer, with most of the cases occurring in women younger than 60 years, the higher prevalence of smokers in the cohort compared with the population could have explained the 26% excess of lung cancer. In contrast, 3 cohort studies suggested a protective role of endogenous estrogen with reduction in lung cancer risk with later onset of menopause. Schabath and colleagues reported a reduced risk of lung cancer (OR 0.59) in current smokers undergoing HRT, although this protective effect was not seen in former or never smokers. A meta-analysis examining the impact of estrogen therapy, combined estrogen/progestin therapy (EPT), and any HRT on lung cancer risk showed a 27% decrease in women treated with any HRT regardless of smoking history. Subset analysis of lung adenocarcinoma revealed a significant increased risk (attributable risk of 76%) in women ever treated with HRT and no change in risk among women treated with combined EPT.
Molecular Changes
DNA adducts
Bulky DNA adducts, formed by activation of polycyclic aromatic hydrocarbons (PAHs) to highly reactive compounds that bind to DNA, are higher in women with lung cancer. CYP1A1 gene, one of the cytochrome P450 enzymes, activates PAH, whereas the enzyme glutathione S-transferase (GST) detoxifies active forms of PAH; and individuals with higher inducible CYP1A1 or decreased GSTM1 phenotypes may be at higher risk of lung cancer than those without those phenotypes. In vitro studies revealed higher baseline levels of CYP1A1 in cell lines of female origin as well as higher CYP1A1 activity after exposure to cigarette smoke concentrate, indicating increased susceptibility to carcinogens in female cell lines. , A study of normal lung tissue from 159 patients with lung cancer showed that female and male smokers had higher levels of DNA adducts compared with nonsmokers, although women in the study had lower smoke exposure (22.9 vs 33 pack-years) and were younger (56.2 years vs 62.2 years). Moreover, female smokers had significantly higher levels of DNA adducts compared with male smokers (25.3 vs 12 per 10 8 DNA bases), which correlated with CYP1A1 mRNA expression, indicating sex differences in PAH-DNA adduct formation in the lung. Among nonsmoking women, CYP1A1 polymorphisms are associated with increased risk of lung cancer, thus contributing to the increased overall risk of lung cancer in women, regardless of smoking history.
Genetic mutations
Sporadic cancers occur as a result of spontaneous or DNA-damage associated mutations within somatic cells. The tumor protein 53 gene (p53) is a tumor-suppressor gene that, when activated by certain stressors, causes downstream reactions that counteract or minimize damage from DNA, metabolic stressors, or oncogenes. p53 is susceptible to numerous alterations and oncogenic activities and is a common tumor-associated mutation seen in lung cancer. , Smoking induces p53 mutations by forming DNA adducts. Kure and colleagues examined 115 surgically resected NSCLCs and demonstrated a higher frequency of p53 mutations and DNA adducts in women than in men despite lower exposure to carcinogens from cigarette smoking in female patients, suggesting that women may be at greater risk for tobacco-related NSCLC regardless of level of smoking exposure. Higher frequency of p53 mutations in female smokers compared with male smokers and female never-smokers has been reported suggesting that lung cancers in female smokers demonstrate more tobacco-related mutations than in male smokers and female nonsmokers.
Kirsten rat sarcoma viral oncogene (K-ras) mutation, within the Ras family of oncogenes, encodes a protein that is oncogenic when overexpressed. K-ras mutations are more common in smokers compared with nonsmokers (35%–43% versus 0%–6%, respectively) and in adenocarcinoma and are associated with DNA adduct formation. Among never-smokers, the most common K-ras mutation is a transversion mutation from G→A (known as G12D), whereas the most common K-ras mutation in former and current smokers is a G→T transversion mutation, known as G12C. The G12C mutation was reported to be more frequent in women than in men with lung cancer although more commonly, women had smoked less and were younger (34 pack-years vs 40 pack-years on average), suggesting that women are more susceptible to smoking-related K-ras mutant lung adenocarcinomas. Nelson and colleagues reported a statistically significant association between female sex and K-ras mutations (OR = 3.3; 95% CI: 1.9–7.9) after adjustment for carcinogen exposures and a strong association between K-ras mutation and decreased survival in stage I lung adenocarcinoma.
DNA repair capacity
DNA repair is critical to repairing damage to the genome from exogenous environmental toxins and endogenous factors. A family of proteins is involved in removing and repairing damaged DNA segments, and a correlation between carcinogenesis and DNA adducts has been reported. Female smokers are reported to have higher levels of DNA adducts than male smokers after adjusting for smoking dose (13.2–17.8 vs 9–9.7 per 10 6 , respectively). , , A case-control study of 764 patients with lung cancer and 677 controls found significantly lower DNA repair capacity in women than men (7.46% vs 8.15%), and decreased DNA repair capacity was found to be associated with increased lung cancer risk in younger patients, female patients, and those with a family history of lung cancer. ,
Growth factors
Growth factors and their signaling pathways are involved in initiation of the cell cycle, cell proliferation, differentiation, and apoptosis; and genetic aberrations in signaling pathways can lead to unregulated expression of growth and subsequent developmental abnormalities, and chronic diseases. Gastrin-releasing peptide (GRP) is a growth factor within the bombesin-like peptide family that stimulates growth of bronchial epithelial cells and helps regulate human lung development by acting as an autocrine and paracrine growth factor for fetal lung tissue. GRP is secreted by pulmonary neuroendocrine cells and is thought to play a role in mitogenesis both in small cell cancers and NSCLCs. , , The gene for the GRP receptor (GRPR) is X-linked and located near a cluster of genes that escape X inactivation, thus women can have 2 actively transcribed alleles for the GRPR gene. GRPR mRNA expression was more common in female than in male nonsmokers (55% and 0%, respectively) and in female smokers with less tobacco exposure (1–25 pack-years) compared with men with similar exposure (75% and 20%, respectively). Furthermore, women with GRPR mRNA expression developed lung cancer with significantly less tobacco exposure than men (41 and 59.9 pack-years, respectively). Activation of cells that secrete GRP results in activation of proteins involved in pathways regulating cell proliferation, survival, and migration, suggesting that GRP may play a role in metastasis as well as cell proliferation. Higher levels of GRP are expressed in adenocarcinoma, the most common histology in nonsmokers, and human airway cells exposed to estrogen show increased GRPR expression, suggesting that GRPR gene may be regulated by estrogen. ,
Endothelial growth factor receptor (EGFR/ErbB1) is a member of a family of cell membrane receptors with tyrosine kinase activity that includes HER1, HER2/neu, HER3, and HER4. Activation of EGFR triggers a signaling cascade leading to increased malignant cell proliferation, decreased malignant cell apoptosis, increased tumor cell motility, and angiogenesis. EGFR mutations are found in 10% to 15% of NSCLCs but are more frequent in adenocarcinomas (80.9%), women (69.7%), and never-smokers (66.6%). HER-2/Neu is a growth factor receptor that mediates cell proliferation and survival, and overexpression is more common in lung adenocarcinomas in women than in men (20.5% vs 3.2%, respectively).
Additional risk factors
Genetic Factors
Although environmental factors such as exhaust from indoor cooking and second-hand tobacco smoke account for some cases of lung cancer in Asian women who have never smoked, they do not account for all cases of lung cancer in this population. Genome-wide association studies (GWAS) compare DNA markers across the genome between people with a disease and people without a disease. One of the largest GWAS studies in female never-smokers, combining data from 14 studies including approximately 14,000 Asian women (6600 with lung cancer and 7500 without lung cancer), found variations at 3 locations in the genome—two on chromosome 6 and one on chromosome 10—that were associated with lung cancer in Asian female never-smokers. The variation at chromosome 10 had never been reported in prior GWAS of lung cancer in Asian or white populations.
Infections
Human papilloma virus (HPV) oncoproteins E6 and E7 disrupt epithelial differentiation and DNA synthesis, causing genomic instability that can lead to malignant transformation. Using polymerase chain reaction (PCR) and in-situ hybridization, HPV DNA was found in tumors of 49% of women with lung cancer who also had a history of high-grade cervical intraepithelial neoplasia. Similarly, in a study of 141 patients with lung cancer and 60 controls, HPV DNA was found in 55% of patients with lung cancer compared with 27% of controls. Stratification by age, gender, and smoking status indicated a higher prevalence of HPV-16 and HPV-18 in nonsmoking women older than 60 years. A meta-analysis including 1094 patients with HPV-positive lung cancer and 484 noncancer controls found a strong association with HPV-infected lung cancers compared with noncancer controls (OR 5.67, 95% CI: 3.09–10.4, P <.001), an association with HPV-16 and 18 and lung cancer (OR 6.01, 95% CI: 3.32–11.28, P <.001), significant association with squamous cell carcinoma (OR 9.78, 95% CI 6.28–15.11, P <.001), and a lower prevalence of HPV in normal lung tissue adjacent to HPV-positive lung cancer indicating that HPV likely plays a role in lung carcinogenesis. In contrast, one small study of 32 squamous cell carcinomas and 15 cervical cancers found negative HPVPCR in the lung cancer cases.
Nontuberculous mycobacteria (NTM) are a family of bacteria commonly found in water and soil that cause a variety of infections. Incidence of NTM in the general population is 1.0 to 1.8 per 100,000, with the most common isolate in the United States being Mycobacterium avium complex (MAC). Infection occurs more often in patients with compromised immune systems and chronic lung diseases causing structural abnormalities and in women. , MAC infection and associated chronic inflammatory microenvironment within the lung parenchyma may lead to cellular dysplasia and a predisposition to develop lung cancer; however, factors that make patients susceptible to NTM infection such as derangements in cellular immunity and underlying chronic systemic inflammation may independently increase the risk of lung cancer. A retrospective study evaluating patients with respiratory cultures positive for MAC and newly diagnosed lung cancer showed that 25% of patients diagnosed with lung cancer had MAC in respiratory cultures. When compared with a control group of lung cancer without MAC, female patients with lung cancer who had MAC were more likely to be nonsmokers. A retrospective study from Japan reviewed 1382 patients with lung cancer who underwent bronchoscopy with culture evaluation of NTM and found an association between MAC-positive cultures and female sex (OR 0.388; 95% CI, 0.175–0.860; P = .0198) and advanced age. Higher incidence of concomitant lung cancer and NTM diagnoses in women suggests women with NTM infection maybe at increased risk of developing lung cancer.
Breast Cancer and Radiation Therapy
Radiation therapy (RT) for breast cancer has been associated with an increased risk of second primary lung cancer (SPLC). A meta-analysis of patients with breast cancer (N = 631,021) in North America and Europe found that those treated with RT following lumpectomy or mastectomy had a higher risk of SPLC (RR, 1.23; 95% CI, 1.07–1.43), which increased with duration of time following diagnosis. In a study of Asian women with breast cancer, the overall occurrence of SPLC was much higher in the RT group compared with the non-RT group (2.25% vs 0.23%, respectively). After adjusting for age, comorbidities, and location of care, patients with breast cancer treated with RT have a significantly higher risk (hazard ratio [HR] increased 10.078-fold) for lung cancer compared with the non-RT group. A recent meta-analysis estimated the absolute risk of lung cancer following breast cancer with modern RT (average RT doses were 5.7 Gy for whole lung). A lung cancer IRR greater than 10 years after radiotherapy of 2.10 (95% CI, 1.48–2.98; P <.001) was found based on 134 cancers, indicating 0.11 (95% CI, 0.05–0.20) cause-specific mortality and excess IRRs per Gy whole-lung dose. Estimated absolute risk of lung cancer from modern RT for breast cancer was approximately 4% for long-term continuing smokers and 0.3% for nonsmokers, leading the investigators to conclude that the absolute risk of modern RT for breast cancer may outweigh the benefits in women who are long-term smokers.
Histologic distribution of lung cancer in women
Adenocarcinoma is the most common histologic subtype of NSCLC. Female smokers are more likely to develop adenocarcinoma, whereas male smokers are more likely to develop squamous cell carcinoma, likely due to differences in tar content of cigarettes as well as mode of inhalation. , , Rates of small cell lung cancer are similar between men and women (14.8% in women and 13% among men), but case control studies have reported that women smokers have higher OR for development of small cell lung cancer than squamous cell lung cancer. , ,
Treatment response, complication, and outcomes
Women are diagnosed with less advanced lung cancer than men, and when adjusted for age, stage, and selected histologic subgroups they have improved outcomes after treatment of lung cancer. Following surgery for stage I NSCLC, mortality rates are reported to be lower among women, , and 5-year overall survival (OS) rates range from 83% to 91% in women compared with 53% to 74% in men. , In a National Cancer Database study of lobectomy versus sublobar resection performed between 2003 and 2006 in 11,990 patients with clinical stage IA NSCLC, female sex was associated with long-term survival with a multivariable-adjusted HR in women compared with men of 0.76 (95% CI, 0.72–0.80, P <.0001). In a meta-analysis of randomized trials in advanced NSCLC, women had a higher response to chemotherapy (42% versus 40%, P = .01) and longer survival than men (median OS 9.6 vs 8.6 months, HR 0.86%, P = .002); however, this survival advantage is confined to patients with adenocarcinoma. The increased frequency of EGFR mutations in women with lung adenocarcinoma may explain the improved OS in women with advanced stage NSCLC. In contrast, a recent meta-analysis including 11,351 patients, 7646 men and 3705 women, with advanced cancer treated with immunotherapy (32% melanoma, 31% had NSCLC) found a pooled overall survival HR of 0.72 (95% CI, 0.65–0.79) in men and 0.86 (95% CI, 0.79–0.93) in women, consistent with a statistically significant decrease in efficacy of immune checkpoint inhibitor in women compared with men ( P = .0019).
Women experience higher rates of grade 2 or higher-radiation pneumonitis after stereotactic radiotherapy compared with men (16% vs 13%, respectively; adjusted OR 1.30 [95% CI, 0.53–3.10]).
Combined HRT has been shown to negatively affect lung cancer survival and is associated with a lower age at cancer diagnosis. , Postmenopausal women in the Women’s Health Initiative treated with estrogen monotherapy did not have increased death rate from lung cancer compared with placebo (HR of death 1.07; 95% CI 0.66–1.72, P = .79).
Lung cancer screening
The US Preventive Services Task Force (USPSTF) recommends low-dose CT (LDCT) screening in current or former (quit within the last 15 years) smokers aged 55 to 80 years with at least a 30 pack-year smoking. However, use of age and smoking history alone may exclude potentially high-risk patients. In a retrospective study from 2005 to 2011, the proportion of patients with lung cancer who smoked more than 30 pack-years declined and the proportion of former smokers, especially those who had quit smoking more than 15 years before lung cancer diagnosis, increased. The relative proportion of patients meeting USPSTF criteria for LDCT screening was 56.8% from 1984 to 1990 and decreased to 43.3% from 2005 to 2011 ( P <.001). When stratified by sex, over time, a more notable decline was found in women meeting lung cancer screening criteria (52.3%–36.6%, P = .005) compared with the decline in men (60%–49.7%, P = .3). The reduced risk of dying from lung cancer following LDCT screening has been shown to be more favorable in women than in men (39%–61% versus 26%, respectively).
Impact of tobacco cessation
A prospective study assessed the benefits of prolonged smoking cessation at various ages among 1.3 million women and found that women who have smoked cigarettes throughout adult life have 3 times the overall mortality rate of women of the same age who have never smoked or who stopped well before middle age. The excess mortality is mainly due to smoking-related diseases; RR for lung cancer is 21.4 (95% CI 19.7–23.2). Quitting smoking before age 40 years avoids more than 90% of the excess mortality and about 97% if quit before age 30 years. Among smokers who stopped smoking permanently at ages 25 to 34 years or at ages 35 to 44 years, the RRs for lung cancer mortality were significantly reduced at 1.84 (CI 1.45–2.34) and 3.34 (CI 2.76–4.03), respectively, underscoring the critical importance of smoking cessation counseling and treatment in women.
Summary
Lung cancer is a major women’s health problem worldwide, with increasing incidence and mortality rates. It is not clear if women are more susceptible to the carcinogenic effects of tobacco; women smokers tend to be younger when diagnosed with lung cancer, and women nonsmokers are more likely to be diagnosed with lung cancer than men nonsmokers. Women may be more susceptible to the influences of hormonal, environmental, and molecular factors. Although research on sex-based differences in the biology, natural history, and response to therapy in lung cancer has been promising, more efforts are needed to better understand the impact of these factors in order to design future trials of therapy and screening in lung cancer. Without doubt, the most effective form of intervention aimed at stopping the lung cancer epidemic in both women and men is to reduce smoking rates to zero. As such, extensive support should be given to campaigns of smoking prevention in all individuals.
Disclosure
The authors have nothing to disclose.
References
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