Overview: Lung cancer kills more women than breast cancer and colorectal cancer combined. In the United States, approximately 70,000 women die each year from lung cancer and 30,000 die from breast cancer. Although smoking remains the most common cause of lung cancer in women, lung cancer caused by non-smoking factors is also gaining attention and the two types of lung cancer are treated differently. Factors such as genetics and hormones may be responsible for gender differences in lung cancer occurrence and outcomes. Lung cancer susceptibility may also be influenced by genetic polymorphisms that encode enzymes that metabolize tobacco carcinogens. In addition, smoking-related lung cancer among women is associated with a high rate of KRAS mutations, and treatment efficacy is influenced by the level of DNA repair enzyme expression. In conclusion, lung cancer survival is longer in women compared to men, and a number of factors, such as longer life expectancy in women and greater prevalence of non-smoking lung adenocarcinoma in women, can play a role in influencing survival. There are significant gaps in our understanding of the differences between male and female lung cancer presentations, and more rigorous studies are needed in the future to define the exact gender differences. Huijuan Wang, Department of Internal Medicine, Henan Cancer Hospital
Key points.
1. In the United States, approximately 70,000 women die of lung cancer and 30,000 die of breast cancer each year.
Worldwide, more than 50% of newly diagnosed non-smoking lung cancers in developing countries are in women.
Levels of smoking-associated DNA adducts are higher in women’s lung cancer tissues, regardless of the level of smoking.
4. Older women have a survival advantage after surgical resection of early-stage lung cancer compared to male sex.
5. Whether the causes of lung cancer-related mortality affecting NSCLC in the progressive stage are attributable to gender remains unknown.
During the 20th century, the dramatic increase in demand for tobacco among women in the United States led to a substantial increase in lung cancer incidence and mortality. Since the mid-1880s, lung cancer has been the leading cause of cancer death among women in the United States. Approximately 20% of lung cancers in women are in nonsmokers, and 60% of nonsmoking lung cancers are in women. In addition, women account for 65% of the annual lung cancer deaths in the United States from secondhand smoke. Despite the controversy, the results of many studies show that women are more sensitive than men to the carcinogenic factors of smoking and that hormone levels may also contribute to the increased risk of lung cancer. In conclusion, women survive longer than men after lung cancer treatment, especially in early stage disease.
Incidence
This section will briefly discuss lung cancer incidence and risk factors. The main content is derived from a paper and references published by Egleston et al. In the United States, the age-adjusted incidence of lung cancer in women peaked in 1998 at 52.9 cases per year in 100,000 women and has remained stable over the last decade, with the most recent figure being 51.6 cases per year in 100,000 women. Non-Hispanic white women had the highest incidence rate (59.0/100,000), followed by black women (54.7/100,000), followed by American Indian and Alaskan women (39.8/100,000) and Asian Pacific Islander women (28.1/100,000), and Hispanic white women had the lowest (25.3/100,000). Worldwide, the picture is similar in developed countries, i.e., decreasing incidence in males and increasing or stable incidence in females. In less developed regions, the incidence of lung cancer in women is relatively low, but smoking is becoming more prevalent. In the recent Global Youth Tobacco Survey, 747,603 students aged 13-15 years from more than 100 countries had higher smoking rates among males than females, but notably, this result was close to the adult male and female smoking rates in that country. This suggests an increase in smoking-related diseases in the future, including lung cancer, for which the U.S. male to female mortality risk ratio was 1.1 (95% CI: 1.0-1.1) among individuals born in the 1960s-1970s by gender.
In 2009, 85%-90% of the 219,440 new lung cancer diagnoses in the United States were in smokers or former smokers, and approximately 22,000-33,000 were in nonsmokers. Specific data on smoking history are difficult to obtain from medical records, and population registries do not include smoking status, making it difficult to describe risk in this population. Results from six recent large prospective studies suggest that women are more likely than men to develop nonsmoking-related lung cancer (14.4-20.8 cases per 100,000 and 4.8-13.7 cases per 100,000, respectively.) In contrast, data from the two American Cancer Prevention Study Groups show that although age-standardized lung cancer mortality rates are higher in nonsmoking men than in nonsmoking women, these data cannot be used to compare incidence rates. It should be worth noting that differences in lung cancer risk between men and women who are current and former smokers in these studies are difficult to observe. Worldwide, more than 50% of female lung cancer patients in developing countries are nonsmokers. As smoking patterns change globally, standardized collection of smoking history will be critical for future epidemiological and clinical studies.
Risk factors and behaviors
For nearly 60 years, smoking has been considered the factor most associated with lung cancer. In addition to smoking, several factors have been associated with lung cancer, including: exposure in smoking environments, occupational and residential radon exposure, asbestos exposure, and air pollution. These risk factors are described in detail in the following sections.
Smoking
From 1991 to 2005, new diagnoses of lung cancer in the United States increased by 0.5% per year in women and 1.8% in men. In the past 40 years, smoking among men has declined by half; however, smoking among women has only declined by 25%. According to the Centers for Disease Control and Prevention, at least 500,000 female teens smoke. Girls and women smoke in part because of the belief that smoking will help them lose weight and because of advertising aimed at women who need it.
Reproductive factors
The discovery of estrogen receptor (ER) expression in lung cancer provides the scientific basis for exploring hormone exposure as a risk factor for lung cancer. Most epidemiological studies have included current smokers, former smokers, non-smokers; women of different ages and menopausal status; but usually without sufficient validity. In China, the Shanghai Women’s Health Research Institute prospectively studied nonsmoking women and found that late menopause was a protective factor for lung cancer; a long childbearing history and high birth rate were associated with lung cancer development. The Singapore Chinese Health Research Society, which studied smoking and nonsmoking women, did not find an association between age at menarche or menopause and lung cancer occurrence. The two largest American women’s research societies, the Nurses’ Health Research Society and the Women’s Health Organization, are also currently conducting research on these issues.
Hormone Replacement Therapy
The use of hormone replacement therapy (HRT) has declined rapidly worldwide since the publication of the results of the Women’s Health Research Organization’s randomized controlled clinical study in 2002. An early case-control study suggested that smokers who applied HRT had a 33-fold increased risk of developing lung adenocarcinoma compared to those who did not smoke and did not have HRT. In contrast, in a case-control study that included approximately 500 patients, a decreased risk of lung cancer was found with estrogen replacement therapy alone compared to combination therapy, especially in current smokers. Another large case-control study showed that application of HRT was associated with a decreased risk of lung cancer, but the strongest effect was seen in former smokers.
Human papillomavirus (HPV)
The majority of nonsmokers with lung cancer have adenocarcinoma of the lung, which has prompted research into the unique risk factors for this population. A recent meta-analysis of secondary tumorigenesis after treatment for cervical cancer showed a 2-fold increased risk of lung cancer. Although in the past lung HPV infection rates have varied across populations, recent technology allows detection of transcripts of the oncogenes E6 and E7 for HPV16 and HPV18, thus supporting a role for HPV in lung adenocarcinogenesis. Much work remains to be done to determine the route of transmission, to understand the HPV-associated lung cancer genes, and to regulate the role of sex in potential risk factors.
Pathology
A review of differences in marker expression between males and females published by Planchard et al. provides a reference for this topic. Of interest is the fact that at any level of smoking, smoking-related DNA adducts are higher in female lung cancer tissue. Polyaromatic cyclic hydrocarbons in tobacco are oxidized by cytochrome P450 enzymes, which convert polycyclic aromatic hydrocarbons to phenols and epoxides, ultimately affecting DNA adduct formation. class II enzymes, such as glutathione reductase and nicotinamide adenine phosphate dinucleotide (NADPH)-quinone oxidoreductase, bind intermediate reactants to more hydrophilic compounds. In NSCLC patients, CYP1A1 expression levels in paracancerous tissues were significantly higher in female smokers than in male smokers (p=0.01). Germline mutations in stage I and II lung cancer genes may alter the activity of their encoded enzymes. a study by Dressler et al. found that the combined effect of CYP1A1 exon 7 and GSTM1 dummy site polymorphisms only increased the risk of lung cancer in women compared to wild-type genes at the same locus (risk ratio = 6.54; 95% CI: 1.07-40.00).
In addition to differences in sex-associated polymorphisms, there were also differences in sex on posterior alterations. A case-control study from Russia including 209 patients and 164 normal individuals found lower levels of RASSF1A methylation in women with lung cancer compared to men (p < 0.01).RASSF1A is a tumor suppressor gene and its silencing leads to hypermethylation. Studies on ER-α-promoted hypermethylation have shown that hypermethylation is more common in male lung cancer tissues. As more studies focus on acquired regulatory factors, it is increasingly important to determine whether sex is a regulator of DNA methylation.
ERs are present in normal and lung cancer tissues and are bound to estrogen. Several studies have shown that ER-β expression is associated with EGFR mutations in lung adenocarcinoma, while ER-Α has been found to be associated with EGFR mutations in NSCLC in some other studies. It is possible that earlier reports of differences in ER expression as a prognostic factor by gender were due to the inability to identify EGFR mutations. Future studies should focus on the relationship between sex differences in ER and other hormone receptor expression and EGFR mutations.
Lung cancers occurring in female smokers carry more smoking-related P53 mutations, mainly G:C to T:A substitutions, compared to males. Some reports suggest that EGFR activity mutations are associated with certain subtypes, such as female, adenocarcinoma, Asian and nonsmoking. Numerous studies have shown that the rate of EGFR mutations is higher in women than in men. However, Toyooka et al. stratified lung cancer patients according to smoking status to study the effect of gender on EGFR mutations. Comparing EGFR mutation status between smokers and nonsmokers in 1467 patients and stratifying by gender and smoking status, the study found no gender differences in EGFR mutations in nonsmokers. After adjustment for risk and histology, the rate of KRAS active mutations was higher in women compared to men after NSCLC surgery (26% vs 17%), suggesting a role for estrogen exposure not only in the initial but also in selective KRAS mutant clones.
Treatment and survival differences
Large observational and population-based studies have demonstrated an overall survival advantage for women with lung cancer. the largest study conducted by Fu et al. included 228,572 patients (from 1975-1999). In this study, 81,843 (36%) were women, and the 2-year survival and 5-year survival rates were better for women than for men at all stages (p < 0.0001). However, a recent observational study from Mayo Hospital showed no gender differences in lung cancer-related mortality for NSCLC diagnosed from 1997-2002. Subsequent studies have been highlighted as gender differences in lung cancer treatment. A further detailed report was published by Shafer and Albain.
Early resectable NSCLC: Outcomes and gender data after lung cancer surgery are primarily from retrospective studies with heterogeneity in type of surgery, neoadjuvant/adjuvant chemotherapy and radiotherapy. Survival data for women with lung cancer after surgery are available, with some findings suggesting longer survival, while others do not. Exceptionally, older women (older vs. 60 years) had better postoperative survival times than men in the control group. However, these data may be biased by the fact that women live longer. the results of the Minami et al. study suggest that women are younger at the time of lung cancer diagnosis, smoke less, have a higher incidence of adenocarcinoma, have smaller masses, and are more peripheral compared to men. the prospective study by Alexiou et al. included 833 patients with NSCLC treated surgically (1990-2000). Compared to female controls, male patients were more likely to have cardiac ischemic disease (p=0.03), had worse preoperative lung volumes, and were more likely to require lobectomy (p=0.0001). The predominant pathological type in men was squamous carcinoma while in women it was mainly adenocarcinoma (p<0.0001). Survival time was longer for women with non-squamous carcinoma (p=0.002) and longer for women with stage I lung cancer (p=0.01). In conclusion, the survival advantage of early surgical treatment for older female lung cancer patients was better than that of men. This may be influenced by several factors, smoking status, otherwise longevity, clinical and pathological features and extent of lung resection.
Adjuvant therapy for NSCLC: A recently published meta-analysis including 7,000 patients demonstrated that the application of adjuvant chemotherapy in postoperative NSCLC can benefit, extending overall survival by 2.5%-4.1%. Of these clinical studies of adjuvant chemotherapy, both the IALT and ANITA studies showed differences in survival by gender. In contrast, in the JBR1.0 study, there was a survival advantage for women with stage IB or II NSCLC, with or without adjuvant therapy, and men, older age and total lung resection were associated with poor survival (p=0.03).
Stage IIIA/IIIB NSCLC: A meta-analysis conducted by the Radiation Therapy Oncology Society in 2,000 patients with locally progressive NSCLC, although a multivariate analysis was used, women were predictors of improved overall survival. cefolio et al, evaluated 1,085 cases with stage I,II or III NSCLC. Overall age stage-adjusted 5-year survival favored females (60% vs. 50%; p < 0.001). Female patients were younger and more likely to have adenocarcinoma and early stage disease. In the Southwest Oncology Group study of neoadjuvant cisplatin and etoposide chemotherapy, combined with or without sequential surgery with radiotherapy, women were found to have a longer median survival time compared to men (21 months vs. 12 months; p=0.08). In terms of toxicities, a study of 148 patients reported that PS score status and females were predictive of radiation pneumonia. And another study including 83 patients with stage III NSCLC found no gender differences in radiographic pneumonia.
Stage IV NSCLC: The impact of gender on the prognosis of patients with progressive NSCLC in large randomized clinical trials is inconclusive, and several factors need to be considered when evaluating the role of gender on prognosis. In early stage NSCLC, women are mostly non-smoking related lung cancer. In addition, women are more often included in clinical studies compared to men. Table 1 summarizes the survival of women and different genders in large sex clinical studies of chemotherapy for progressive NSCLC in recent years. When women were included as part of the multivariate analysis, none of the other large clinical studies, except ECOG1594, suggested a significant difference in median survival time for patients.
EGFR inhibitor therapy in progressive NSCLC: Lynch et al. and others first found that specific EGFR mutations were associated with objective tumor remission rates with EGFR-TKI therapy. More than 50% of nonsmoking lung cancers have EGFR-active mutations. Identification of subgroups of patients more likely to have EGFR mutations can increase EGFR inhibitor efficacy. In 2 recent clinical studies, women accounted for 70% of patients initially treated with EGFR-TKI. median survival time recorded by Rosell et al. was 18 months for men compared with 29 months for women (p=0.05). In the IPASS study, gefitinib was not inferior to chemotherapy in terms of PFS. EGFR mutations were more common in women (59.7%), nonsmokers (66.6%), and adenocarcinoma (80.9%, p<0.001). However, female was not an independent prognostic factor for PFS benefit.
Small cell lung cancer: Individual patient data were obtained from six phase II/III chemotherapy studies involving 1,707 patients with SCLC. 44% were women. In univariate and multivariate analyses (p=0.04), female patients had longer survival times. The authors suggest that women had a slightly better survival time than men, but the toxicities of treatment were greater.
Conclusion
Although the incidence of female lung cancer has plateaued in the United States, the incidence of female lung cancer continues to rise in developing countries. Cultural changes have led to the emergence of large numbers of female smokers. The time lag between smoking and lung cancer incidence would predict increased lung cancer incidence and mortality in these countries.
Is lung cancer really different in women? The answer is complex and multifaceted. The information above defies the assumption that different diseases have different outcomes. Women who smoke may have an increased risk of lung cancer because of their cytochrome P450 gene differences. In addition, they may have a lower capacity for DNA repair. Hormonal factors, especially ER overexpression, may be consistent with the EGFR status described above. Indeed, there may be the same degree of molecular heterogeneity in smoking-associated NSCLC in women as in men.
Based on the results, a multivariate analysis in a large observational study, the survival advantage in women with lung cancer may come from surgical resection of early lung cancer. Controversy exists: whether this is because in women with lung cancer, nonsmokers predominate and may have fewer comorbidities such as cardiovascular and respiratory disease. The effect of gender has also had inconsistent results in clinical studies of advanced lung cancer. Some data suggest that women and men are disproportionately enrolled in clinical studies and that women have better PS status and may have reduced disease load. The results of improved survival in women in some studies may be biased by the inherent longevity advantage of women.
Non-smoking risk factor studies heavily favor women, with few data from studies of cooking fumes or passive smoking in men. Because nonsmoking tumor patients have reduced genetic complexity compared to tumor patients who smoke, these patients may be more dependent on one or several key signaling pathways for tumor survival, typically i.e. EGFR mutations/addiction. Although, there is a complex intrinsic link between gender and smoking in terms of mutation type, such mutations, in men and women are more likely to be affected by smoking status rather than gender.
Lung cancer is the leading cause of cancer death in women. Future hypotheses of differences or similarities mainly in pathogenesis and presentation will allow for more individualized treatment of lung cancer in women.
Translated by Peng Li, Henan Provincial Lung Cancer Treatment Center, Huijuan Wang