Gender differences in lung cancer

Tiziana Vavalà1, Annapaola Mariniello2, Maria Lucia Reale2, Silvia Novello2

1. Department of Oncology at ASL CN1, Cuneo, Italy;

2. University of Torino, Department of Oncology at San Luigi Hospital, Regione Gonzole 10, Orbassano (TO), Italy.

Received 24 August 2016; accepted 28 September 2016.

Summary. In the early 20th century, lung cancer was diagnosed in a few hundred cases, but the progressive spread of tobacco consumption caused an increasing incidence of this disease firstly among male and later among female smokers, and is now the leading cause of cancer death for both sexes in developed countries. The higher percentage of lung cancer in non-smoking women, as compared with non-smoking men, suggests distinctive biological aspects in female patients. Hormonal status is one of the possible explanations: estrogens are involved in lung tumorigenesis through cell proliferation induced by ligand-estrogen receptor (ER) interaction and cross-talks between ERs and growth factor receptors. From a prognostic point of view, mainly retrospective data evidence greater survival rates in women compared with men regardless of stage, histology or treatment modality, thus implying the need for gender-based prospective confirmative trials. Increasing knowledge of sex-differences in lung cancer pathogenesis and biology will be the background for further investigations aiming to identify genetic alterations or hormonal profiles, which could be targeted by personalized sex-based therapies.

Key words: lung cancer, women, gender differences, cigarette smoking, hormones.

Differenze di genere nel tumore del polmone

Riassunto. Agli inizi del XX secolo la neoplasia polmonare veniva diagnosticata raramente, tuttavia la progressiva diffusione del consumo di tabacco ne ha causato una crescente incidenza tra i fumatori prima e tra le fumatrici poi, e ora è la principale causa di morte per cancro in entrambi i sessi nei paesi sviluppati. Il maggior riscontro di neoplasia polmonare nelle non-fumatrici rispetto ai non-fumatori suggerisce inoltre un differente comportamento biologico della malattia e fra le possibili cause a supporto di questa condizione vi è sicuramente l’assetto ormonale. Gli estrogeni sono infatti coinvolti nella tumorigenesi attraverso la proliferazione cellulare indotta dall’interazione ligando-recettore estrogenico (ER) e cross-talks tra ERs e recettori del fattore di crescita. Dal punto di vista prognostico, dati principalmente retrospettivi riportano tassi di sopravvivenza maggiori nelle donne rispetto agli uomini, indipendentemente da stadio di malattia, istologia o trattamenti, e questo nuovamente indica differenze di genere sebbene con necessità di studi prospettici confermativi. Una più approfondita conoscenza delle differenze di genere nella patogenesi e biologia del tumore polmonare consentirà l’identificazione di alterazioni genetiche o ormonali, quali possibili bersagli di terapie personalizzate, genere-specifiche.

Parole chiave: neoplasia polmonare, donne, differenze di genere, fumo di sigaretta, ormoni.

Introduction

In the early 20th century, only a few hundred cases of lung cancers were diagnosed yearly, but the progressive huge spread of tobacco consumption caused an increased incidence of this disease first among men and then later among female smokers in Western countries1.

Nowadays, cigarette smoking accounts for more than 90% of lung cancers in men and 75-85% of them in women in the United States (US) and the European Union, being the most well-established risk factor for this disease2.

Furthermore, 20% of women with lung cancers have never smoked: it has been known that women have a 1 in 16 lifetime risk of developing lung cancer, regardless of smoking status and the higher percentage of lung cancer in non-smoking women, as compared with non-smoking men, suggests that lung cancer behaves differently in female patients3.

Literature data suggest gender differences concerning clinical presentation and biology of lung cancer, arguing that this disease should be considered a specific entity in women, where adenocarcinoma is the most common histological subtype and prognosis and response to treatment were described to be dissimilar4-7.

In line with these findings, hormonal receptors have been evaluated in lung cancer tissues: estrogen receptors (ERs) interaction with growth-factor-receptor signalling is an emerging area of investigation and, considering the potential impact of hormonal factors, lung carcinogenesis is hypothesized to have distinctive aspects in women8,9.

Despite these concerns, no “gender-driven” diagnostic or therapeutic approaches are currently available. Improving knowledge of lung cancer in women will permit to identify specific genetic alterations or hormonal profiles, which could be targeted by therapy, enhancing personalized sex-based investigations.

Epidemiology

In 2012, the estimated number of new lung cancer cases was 1.8 million, accounting for about 13% of total cancer diagnoses. Lung cancer was the leading cause of cancer death among males in both developed and developing countries; while, among females, it was the foremost cause of cancer death in more developed countries, and the second one in less developed countries, after breast cancer2.

In men, the highest lung cancer incidence rates (age-standardized per 100,000) were in Central and Eastern Europe (53.5), East Asia (50.4), Southern Europe (46.4) and North America (44.0), with a lower incidence in Middle and Western Africa (2.0 and 1.7 per 100,000 respectively). Among women, they were generally lower, mainly reflecting different historical exposure to tobacco smoking: the highest ones were evidenced in Northern and Western Europe (33.8 and 23.7), North America (33.8), Australia/New Zealand (21.7), Eastern Asia (19.2) while the lowest were described in Western and Middle Africa (1.1 and 0.8 respectively)2 (Figure 1).




Lung cancer was estimated to account for almost one in five cancer deaths (1.59 million deaths, 19.4% of the total), worldwide. Because of its high fatality (the overall ratio of mortality to incidence is 0.87) and the relative lack of variability in survival in different world regions, the geographical distribution of mortality followed the same incidence data: the highest lung cancer mortality was evidenced in Australia/New Zeland (age standardized rates: 43.3 for males, 15.4 for females), in Europe (40.3 and 11.3, respectively) and in females in America (15.5)2,10. Considering Asian Countries, lung cancer mortality rates were 14.2 for males and 5.2 for females: in East Asia, China presented the highest rates (18 per 100,000), even more elevated than those among women in some European countries (Germany: 14.5, France: 12.9, per 100,000 respectively) despite a relatively lower prevalence of female smoking. This is likely due to higher exposure to secondhand smoke, outdoor and indoor air pollution from unventilated combustion of coal used for heating and cooking purposes11-13.

In Europe, almost 75% of lung cancer deaths in men and over 80% in women were evidenced, with the majority of them (38% for men and 27% for women) in Central and Eastern Europe. The highest lung cancer mortality in women was observed in Northern and Western Europe (19.1 and 14.8, respectively), with the most elevated rates in Denmark (43) and Netherlands (36). In Southern Europe lung cancer mortality rates were lower: 39.1 for males and 10.0 for females2.

In Italy, according to “Pool Airtum 2007-2011” data, lung cancer is the second neoplasm in terms of incidence (after prostate cancer) in men, with a 1.4% decrease in the last few years; on the contrary, it ranked third (after breast and colorectal cancer) in women with a 2.7% increase in recent years (1996 to 2014)14. These data reflect a progressive reduction of tobacco consumption among males (from 55% to 28% between 1970-2011 - according to Istituto Nazionale di Statistica, ISTAT, data) with a constant increase among females (from 12% to 17% - according to ISTAT data). The highest density region for male smokers in Italy is Campania and the lowest is Trentino-Alto-Adige. For female smokers, the highest density region is Lazio, while the lowest ones are Basilicata and Calabria15.

Lung cancer death worldwide will increase from 1.6 million in 2012 to 3 million in 2035. It will almost double in both men (1.1 million in 2012 to 2.1 million in 2035) and women (0.5 million in 2012 to 0.9 million in 2035). A progressive increase is predicted worldwide, but its scale is different: the lowest increase is expected for Europe (37%); in the Western Pacific Region, America and South-East Asia it is predicted to double (by 97%, 91% and 95%, respectively), while in the East Mediterranean region and Africa the estimated increase is expected to be the highest (123% and 108%, respectively)2.

Smoking trends and lung cancer risk

The observed variations in lung cancer rates and trends across countries or between males and females within each country, largely reflect differences in tobacco spread and consumption. In US, California has been a leader in introducing public policies designed to reduce cigarette smoking. It was the first state in the US to establish a comprehensive state-wide tobacco-control program in 1988 through increased excise taxes on cigarettes, and as early as the mid-1970s, issued local government ordinances for smoke-free work places. As a result, progress in reducing smoking prevalence and mortality associated with smoking-related diseases, including lung cancer, was evidenced and it was much greater in California than in the rest of the US16.

Some Northern European countries were able to substantially reduce smoking prevalence in both men and women; consequently, in some of them, such as the United Kingdom and Denmark, lung cancer mortality rates decreased for several decades, first among men and then later among women. Many other high-income nations in Europe, such as Germany and the Netherlands experienced a major decrease in prevalence of smoking in men, but with only a recent and modest decrease in female smoking17,18.

Italy was among the first large European States to introduce a comprehensive smoking ban, in 2005: this resulted in a further acceleration of a decreasing trend of smoking prevalence in both sexes with an estimated reduction from 27.6% in 2010 to 23.1% in 2025, among men, and from 17.6% in 2010 to 16.3%, in the same projected year, for women19,20,21.

By contrast, in those countries where tobacco epidemic has been established more recently and smoking has just peaked or continues to increase, such as in China, Indonesia, or several countries in Africa, lung cancer rates will probably rise at least for the next few decades without interventions to accelerate smoking cessation and avoid initiation2.

Considering previous data, tobacco smoking is confirmed as the most well-established risk factor for lung cancer; however, if women are more or equally susceptible to the carcinogenic effects of cigarette smoke on the lungs compared with men, is still a matter of controversy22.

Several case–control studies suggested a higher relative risk among women compared with men for the same level of smoking exposure23-26. By contrast, other cohort studies did not evidence any higher smoking-related risks, suggesting that the incidence of lung cancer among female smokers was about the same as that of male smokers, after standardizing for the amount smoked27-29.

In this context, the ICARE study, a multicenter case-control study, compared lung cancer risks associated with smoking between genders, suggesting that heavy smoking might confer to women a higher risk of lung cancer as compared with men. The study included 2276 male and 650 female cases and 2780 male and 775 female controls. Lifetime smoking exposure was represented by the comprehensive smoking index (CSI), which combines duration, intensity and time since cessation of smoking habits. Results varied according to histological type: overall lung cancer risk was similar among men and women, but women had a two-fold greater risk associated with a one-unit increase in CSI than men of developing either small cell carcinoma (Odds Ratio [OR] 15.9, 95% Confidence Interval [CI] 7.6-33.3 and 6.6, 95% CI 5.1-8.5, respectively; p <0.05) or squamous cell carcinoma (OR 13.1, 95% CI 6.3- 27.3 and 6.1, 95% CI 5.0-7.3, respectively; p <0.05)30.

Despite previous studies, De Matteis et al, with the evaluation of 2100 cases and 2120 controls, evidenced a negative female sex-smoking interaction (OR = 0.39, 95% CI: 0.24, 0.62; p <0.0001) in all subjects and no interaction (OR 0.63, 95% CI 0.29, 1.37; p = 0.24) among non-smokers31.

Moreover, a recent Chinese meta-analysis of 47 studies found that males had higher susceptibility for cigarette smoking-attributable lung cancer than females. Compared with non-smokers, male to female Relative Risk Ratio (RRR) was 1.61 (95% CI 1.37, 1.89) among current smokers. The analysis involved more than 400,000 individuals of which 44.8% were Asians and 35.8% were Europeans. The prevalence of smoking was higher in men than in women, particularly in Asians32. Estimates of the sex-specific associations between smoking and lung cancer varied across studies, possibly because of differences in study design, region, classification of smoking status, and adjustment for confounders. For examples, the number of cigarette packs smoked per year and the years of smoking were generally higher in males than in females. This might also result in overrating the risk of lung carcinoma in males. Additionally, a specific biomarker of nicotine absorption suggested that more females than males underreported their smoking behavior32.

Environmental tobacco smoke and additional risk factors

Passive smoking is also another established risk factor for lung cancer: approximately 20% of women with lung cancer are non-smokers and women married to men who smoke have been shown to have a 25%-29% increased risk of developing lung cancer33-37.

Wang et al recently evaluated the relationships between active and passive smoking with lung cancer incidence in a prospective cohort of more than 90,000 US postmenopausal women, the Women’s Health Initiative Observational Study (WHI-OS). Compared with non-smokers, lung cancer incidence was greatly higher in current (Hazard Ratio [HR] 13.44, 95% CI 10.80–16.759) and former smokers (HR 4.20, 95% CI 3.48–5.08) in a dose-dependent manner. Current and former smokers had a significantly increased risk for all lung cancer subtypes, particularly small-cell and squamous cell carcinomas. In WHI-OS study, among non-smokers, lung cancer incidence did not differ between non-smokers with passive exposure compared with non-smokers without passive exposure (HR 0.88, 95% CI 0.52-1.49). However, borderline significant increased lung cancer risk was seen in non-smokers with adult home exposure ≥ 30 years when compared with women with no adult home exposure (HR 1.61, 95% CI 1.00-2.58)38.

In a cohort of 91.540 Japanese non-smoking wives, women with smoker husbands were at a higher risk (Rate Risk, [RR] 1.8) for lung cancer when compared to women with non-smoker husbands39.

Environmental tobacco smoke exposure is one of the most important risk factors for non-smoking females, but it is only one of a well-characterized set of risk factors that include: occupational exposure to lung carcinogens such as asbestos, pesticides, radon, outdoor and indoor air pollution (e.g. coal-fuelled stoves and cooking fumes), diet, pre-existing lung disease, family history and infections12,40,41.

A case-control study carried out in Missouri on occupational risk factors in never-smoking women, described an increased risk for lung cancer among women exposed to asbestos (OR 3.5; 95% CI 1.2-10) and pesticides (OR 2.4; 95% CI 1.1-5.6)42.

Exposure to high levels of radon is also associated with an enhanced risk for developing lung cancer. In fact, radon, the first identified environmental cause of lung cancer, is not only of concern for underground miners, but for the population generally, as a ubiquitous contaminant of indoor air43.

In non-smokers, smoke from domestic fuel (i.e., coal, wood, biomass) used for cooking and heating has been associated with lung cancer, particularly among Asian females using coal44. In addition, housing characteristics related to poor ventilation - including less window area, absence of a separate kitchen, lack of a ventilator and limited time with windows open - were associated with lung cancer in a Chinese case-control study. This study included 399 lung cancer cases and 466 controls, of which 164 cases and 218 controls were female non-smokers45.

A protective effect against lung cancer has been suggested for consumption of vegetables, fruit and β-carotene among never-smoking women46,47. A cohort study of Finnish men and women found an inverse relation between Vitamins E, C and β-carotene and lung cancer risk in non-smokers48. However, other cohort studies from US found non-significant decreased risks for fruit consumption among non-smokers and no association between Vitamins E, C, carotenoids, or vegetable and fruit intake and lung cancer risk among non-smokers49,50. More recently, over 71,000 Chinese women with no history of smoking or cancer at baseline were prospectively evaluated for their dietary intake with a follow-up time exceeding 11 years. Dietary riboflavin intake was inversely associated with lung cancer risk (HR 0.62; 95% CI 0.43–0.89; p trend = 0.03 for the highest quartile, compared with the lowest)51.

Pre-existing lung diseases such as asthma and chronic obstructive pulmonary diseases can represent additional potential risk factors for lung cancer52. Even after controlling for active and passive tobacco exposure, some studies have shown an increased risk for lung cancer among these patients53. Literature studies showed that people with tuberculosis had as much as a 50% increase in lung cancer risk: interestingly, a study by Hinds et al, examining lung cancer risk among smokers and non-smokers with tuberculosis, found that female non-smokers with tuberculosis had approximately an eightfold increase in lung cancer risk, whereas there was no association among female smokers54. Wu et al. found that the risk for lung cancer was increased for non-smoking women with previous lung disease (adjusted OR 1.56; 95% CI 1.2-2.0) and this finding was mainly driven by the prevalence of tuberculosis in this population55.

Patients with a family history of lung cancer have an increased incidence of lung cancer, even in non-smoking families. It has been shown that non-smoking women in non-smoking families with a history of lung cancer have a greater risk in the development of lung cancer compared with non-smoking men with a similar family history56.

Finally, Human Papillomavirus (HPV) is known to be associated with different types of cancer and has been proposed to be also one of the etiological factors for lung cancer, especially in Asia57. Since the virus infects the oral mucosa and subsequently the larynx and bronchial tissue, this may be the main source of HPV detected in the lungs58. A meta-analysis on HPV in non-smokers with Non-Small-Cell-Lung Cancer (NSCLC) evaluated 46 articles, of which 23 were from Asian countries. The prevalence of the virus in non-smokers was significantly higher in East Asia (33.9%; 95% CI, 29.2–38.9, N = 392) than in Europe (14.8%; 95% CI, 6.6–27.1, N = 58, p = 0.005). While HPV prevalence in East Asia was similar between never- and ever- smokers (33.9% vs 39.2%, p = 0.080), it was significantly higher in never-smokers than in ever-smokers (14.8% vs 2.9%, p <0.001) in Europe59. A recent population-based study showed a significant increase in lung cancer risk among Taiwanese women, who were exposed to HPV infection. The study included 24.162 individuals with HPV infection from 2001 to 2004 and 1.026.986 uninfected individuals. Lung cancer incidence among infected and uninfected individuals was compared using univariate and multivariate regression models. After adjusting for age, gender, low income, residential area, and comorbidity, the risk of lung cancer was higher in women (HR 1.26; 95% CI 1.01-1.57), while all cancer risks were high in both men and women with corresponding HR of 1.16 (95% CI, 1.08-1.24) and 1.24 (95% CI 1.15–1.33), respectively. Cigarette smoking, the modifiable risk factor for lung cancer, was not adjusted, due to the lack of this information in the database60. However, other studies have yielded different results. In a retrospective evaluation of 223 lung cancer cases, HPV infection had no role in the pathogenesis of primary lung cancer, whereas HPV positivity was indicative of pulmonary metastasis from a primary HPV-associated cancer elsewhere in the body61. Considering controversial data emerged from literature studies, this information needs further confirmations.

Hormonal influences

Hormonal status is one of the potential explanations for differences in lung cancer between men and women. Estrogens may be involved in lung tumorigenesis through numerous mechanisms, such as cell proliferation induced by ligand-estrogen receptor interaction and the cross-talk between ERs and other growth factor receptors (i.e. epidermal and insulin growth factor receptors)62.

As for ER-β, immunohistochemical positivity has been commonly observed for both the nucleus and cytoplasm in lung cancer. ER-β nuclear positivity has been related with a favorable clinical outcome in most studies, whereas the opposite is true for cytoplasmic positivity63. Compared with ER-β, ER-α shows great variability in its expression frequency. ER-α positivity is more usually observed in the cytoplasm than the nucleus, and ER-α cytoplasmic positivity has been related with poor clinical outcome63.

The presence of ERs on lung cancer cells raises the question of exogenous estrogen influence on lung cancer presentation. At present, it is still unclear whether or not exposure to oral contraceptives (OC), hormone replacement therapy (HRT) or hormonal therapy may influence positively lung cancer incidence and survival (Table 1).




The International Lung Cancer Consortium (ILCCO) meta-analysis results revealed an interaction between hormone use and lung cancer risk in women (1961 cases, 2609 controls): a reduced lung cancer risk for both oral OC use and HRT was found, independent of smoking status64. A reduced risk of lung cancer was also observed in an EAGLE study for HRT (OR 0.63, p = 0.03) and OC use (OR 0.67, p = 0.05)65. While in the Maryland Lung Cancer Study (n = 1041) no significant associations for OC or HRT use, including long-term use, and NSCLC cancer risk were evidenced66.

A recent meta-analysis of 14 cohort studies did not show a statistically significant association between HRT and lung cancer risk in women67. However, a significant increase in lung cancer incidence associated with HRT use was observed in the Vitamins and Lifestyle (VITAL) study (n = 36.000 postmenopausal women). The use of an estrogen plus progesterone (E+P) combination for more than 10 years was associated with an increased risk of lung cancer in comparison with no use of HRT (HR 1.48, p = 0.03)68.

The Women’s Health Initiative, a randomized, placebo-controlled trial, in which more than 16,000 postmenopausal women received placebo or daily HRT for 5 years, reported a strong negative effect on survival after a lung cancer diagnosis in women on the HRT arm in 2009, and recently, after 6 years’ additional post intervention follow-up, the increase in lung cancer deaths was found to be attenuated (p = 0.042) after discontinuation of combined hormone therapy69.

Finally, in the California Teachers Study (CTS) (n = 133.479), no effect of E+P use on female lung cancer was observed. Decrease of lung cancer mortality rates was determined among women who used estrogen-only therapy (ET) compared to non-users. The median survival time of lung cancer patients and ET users was 20.2 months vs 15.6 months for ET non-users (p = 0.008)70. In the Katcoff H et al study, E+P use was associated with a significantly improved survival for women with NSCLC taking combined HRT for 11 years or longer (p <0.0001)71.

With regard to the expression of specific gene alterations, there are relevant sex differences and correlations with hormonal status. Molecular details of the interaction between ER and Epidermal Growth Factor Receptor (EGFR) are emerging, suggesting that a reciprocal control mechanism exists between the two pathways: EGFR protein is down-regulated in response to estrogens and is up-regulated in response to anti-estrogens72. Estrogen can directly stimulate the transcription of estrogen-responsive genes in the nucleus of lung cells and can also transactivate growth factor signaling pathways, such as EGFR pathway72. He et al. evidenced, in a recent meta-analysis, a correlation between high nuclear expression of ER-β and EGFR mutations in NSCLC and no significant correlation with ER-α or progesterone73.

Finally, several reports found little or no progesterone Receptor (PR) in NSCLC and there are also data indicating lower PR levels in lung tumors compared to matched normal lung tissue74-76. Skjefstad et al. analyzed PR expression in 335 stage I–IIIA lung cancer and found that positive PR expression in stromal tissue correlates with favorable survival, on the contrary positive PR expression in tumor tissue correlates with poor survival in females77.

Enzymes capable of synthesizing PR were also detected in many NSCLC tumors. A positive correlation was observed between intratumoral levels of progesterone and the presence of three enzymes participating in progesterone synthesis. Progesterone treatment led to growth inhibition of tumor xenografts and induction of apoptosis, in agreement with clinical data suggesting that the presence of PR was correlated with longer overall survival in NSCLC patients75.

Genetic alterations, innovative evaluations and research approaches

It is now well known that sex differences influence specific gene alterations: EGFR mutation is found at a much higher frequency in adenocarcinomas, women, Asians and non-smokers78. Mazieres et al observed differential genetic alteration repartition in women, according to their tobacco status: 50.8% of non-smokers displayed an EGFR mutation versus 10.4% of smokers (p <0.001)79.

Ongoing research has been adding new data towards specificities of lung cancer in women.

Although the Human Epidermal growth factor Receptor 2 (HER2) is well-known as a prognostic and predictive marker in patients with breast cancer, its role in lung cancer patients is far less understood35. In NSCLC, HER2/neu gene mutations occur in exons 18-21 of the tyrosine kinase domain, they are not seen in breast cancer and occur mostly in lung adeno­carcinoma80. These mutations are identified in approximately 2% of NSCLC and in a recent publication, Mazierès et al. identified a high proportion of women (45 women versus 20 men; 69%) and a high proportion of non-smokers (n = 34; 52.3%)81.

V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations have been primarily observed in smokers and are historically associated with male sex, but Dogan et al. genotyped 3026 lung adenocarcinomas for the major EGFR (exon 19 deletions and L858R) and KRAS (G12, G13). From these data emerged that KRAS G12C, the most common G >T transversion mutation in smokers, was more frequent in women (p = 0.007) and these women were younger than men with the same mutation (median 65 versus 69, p = 0.0008) and had smoked less82.

C-ros oncogene 1, receptor tyrosine kinase (ROS1) fusions have been identified in about 1-2% of lung adenocarcinomas83. Warth A. et al. analyzed a cohort of 1478 NSCLC patients and a significantly higher rate of ROS1 translocations was ob­served in females (1.3%) than in males (0.3%). ROS1 positivity in tumor (in 68/1478 cases) was significantly more likely in females with low pathologic tumor size (pT) (7.8%) than in males (3.2%, p <0.001)83.

To gain insights into the etiology of lung cancer in never-smoking women, the Female Lung Cancer Consortium in Asia (FLCCA) was founded including China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. A multi-stage genome-wide association study (GWAS) on this population (6,609 cases, 7,457 controls) identified novel susceptibility loci at 10q25.2, 6q22.2, 6p21.32, and confirmed two previously identified loci at 5p15.33 and 3q28.6. Lately, data from studies participating in FLCCA were analyzed with available information (n = 3; 1731 cases; 1349 controls) in order to evaluate the gene–household air pollution interactions associated with lung cancer in loci independent of smoking. The risk of lung cancer associated with coal exposure varied with the respective alleles for two SNPs (HLA Class IIrs2395185, p = 0.02; TP63 rs4488809 (rs4600802), p = 0.04) providing evidence that genetic variation in HLA Class II and TP63 may modify the association between household air pollution and lung cancer risk. The roles played in the cell cycle and inflammation pathways by the proteins encoded by these two genes provide biological plausibility for these interactions84. Furthermore, a meta-analysis of four imputed GWAS of lung cancer in never smoking Asian women has yielded three new genetic susceptibility alleles for lung cancer at loci 6p21.1, 9p21.3 and 12q13.1385.

Finally, recent studies investigated the role of telomere shortening in lung cancer. A 2015 report from FLCCA indicates that a genetic background that favors longer telomere length may increase lung cancer risk, consistently with earlier prospective studies relating longer telomere length with increased lung cancer risk. The dataset consisted of a sample of 5457 lung cancer cases and 4493 controls from a population of never-smoking Asian females. A genetic risk score, based on seven telomere-length associated variants, was used as instrumental variables to predict longer telomere length and it was associated with increased lung cancer risk (OR 1.51; 95% CI 1.34-1.69 for upper vs lower quartile of the weighted genetic risk score, p value = 4.54 x 10e14)86.

Prognostic implications

Women exhibit greater survival rates regardless of stage, histology, treatment modality, or smoking status, even after adjusting for gender-specific life expectancy87-89.

As for early-stage disease, data on a cohort of 10,908 patients with NSCLC (6665 men and 4243 women) from the Manitoba Cancer Registry showed a significantly better survival rate for women, independent of treatment, age, year of diagnosis, and histology (p <0.001). The adjusted HR for death for men compared with women was 1.13 (95% CI 1.04-1.23; p = 0.004). Sex modified the effect of surgical treatment on survival (HR 1.26; 95% CI 1.13 to 1.40]; p <0.001)90.

In a recent retrospective analysis on 8016 adults with NSCLC who underwent lobectomy with or without adjuvant chemotherapy for pathologic T2 tumors measuring at least 4 cm, with no lymph node involvement, gender appeared to be a significant factor in determining which patients would benefit from adjuvant chemotherapy. Data were obtained from the National Cancer Data Base, a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The cohort included 4617 men (58%) and 3399 women (42%). Overall, women had improved 5-year survival relative to men (60% vs 47%, p <0.0001). However, there were groups of older women who experienced no benefit from adjuvant chemotherapy: specifically, those older than age 72 years (5-year survival: 53% vs 56%, p = 0.57), and those aged 65–72 years with medical comorbidities (5-year survival: 51% vs 58%, p = 0.29). By contrast, all groups of men identified by recursive partitioning analysis demonstrated improved survivals with adjuvant chemotherapy91. In this setting, also the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) JBR.10 trial evidenced remarkable gender differences: in this trial, adjuvant chemotherapy was found to confer a significant survival benefit for patients with completely resected stage IB or II NSCLC. In a stratified analysis, male gender was predictive of poorer survival regardless of treatment (p = 0.03)92.

The Surveillance, Epidemiology, and End Results Database (31,226 patients) of lung cancer has been analyzed for prognostic factors and has identified the following as favorable prognostic factors: low-stage disease, surgical therapy, age <50 years, and female sex93.

A Polish population-based study, 77 of 20,561 cases of lung cancer between 1995 to 1998 revealed that female patients had a better prognosis than males regardless of treatment modality, with an RR of death of 1, compared to 1.21 (p <0.001) in male patients by univariate analysis. More women were non-smokers compared to men (18.8% vs 2.4%, p <0.001). A multivariate analysis of absolute survival in this series showed that the RR of death was significantly higher for men (1.15; p <0.001)94.

One potential explanation for better survival among women is a gender difference in DNA-repair capacities, which make tumors in women more responsive to platinum-based chemotherapies. DNA-repair machinery has been shown to be more defective in women, making them more susceptible to respiratory carcinogens but also more sensitive to DNA- interfering agents, however further prospective studies will clarify these suggestive hypotheses95-97.

Conclusions

All the exciting findings and progressive improvements in gender-based research discussed above will provide further evidence for the specificities of lung cancer in women. The differential expression of specific biomarkers, which could be targeted by therapy, will stimulate the development of further gender-based approaches and therapeutic tools which could be hopefully applied in clinical practice.




References

1. Giovino GA. Epidemiology of tobacco use in the United States. Oncogene 2002; 21: 7326-40.

2. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics 2012. CA Cancer J Clin 2015; 65(2): 87-108.

3. Marshall AL, Christiani DC. Genetic susceptibility to lung cancer--light at the end of the tunnel? Carcinogenesis 2013; 34(3): 487-502.

4. Ulas A, Tokluoglu S, Kos M, et al. Lung cancer in women, a different disease: survival differences by sex in Turkey. Asian Pac J Cancer Prev 2015; 16(2): 815-22.

5. Francisci S, Minicozzi P, Pierannunzio D, et al. EUROCARE-5 Working Group. Survival patterns in lung and pleural cancer in Europe 1999-2007: Results from the EUROCARE-5 study. Eur J Cancer. 2015; 51(15): 2242-53.

6. Lortet-Tieulent J, Soerjomataram I, Ferlay J, et al. International trends in lung cancer incidence by histological subtype: adenocarcinoma stabilizing in men but still increasing in women. Lung Cancer 2014; 84(1): 13-22.

7. Wakelee HA, Wang W, Schiller JH, et al. Eastern Cooperative Oncology Group. Survival differences by sex for patients with advanced non-small cell lung cancer on Eastern Cooperative Oncology Group trial 1594. J Thorac Oncol 2006; 1(5): 441-6.

8. Monica V, Longo M, Felice B, et al. Role of hormone receptor expression in patients with advanced-stage lung cancer treated with chemotherapy. Clin Lung Cancer 2012; 13(6): 416-23.

9. Siegfried JM, Stabile LP. Estrogenic steroid hormones in lung cancer. Semin Oncol 2014; 41(1): 5-16.

10. Globocan.iarc.fr [internet]. Globocan 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012 [update “unknown” cited 2016 July 30] Available from: http://globocan.iarc.fr

11. Secretan B, Straif K, Baan R, et al. A review of human carcinogens--Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol 2009; 10: 1033-4.

12. Sisti J, Boffetta P. What proportion of lung cancer in never-smokers can be attributed to known risk factors? Int J Cancer 2012; 131: 265-75.

13. Hamra GB, Guha N, Cohen A, et al. Outdoor particulate matter exposure and lung cancer: a systematic review and metaanalysis. Environ Health Perspect 2014; 122: 906-11.

14. Registritumori.it [internet]. I numeri del cancro in Italia 2015, AIOM-AIRTUM [update 2016 July, cited 2016 July 30]. Available from: www.registritumori.it

15. Banca dati tumori.net [internet]. Istituto Nazionale dei Tumori. SC Epidemiologia Analitica e Impatto Sanitario [update unknown, cited 2016 July 30]. Available from: http://www.tumori.net/it3/

16. Jemal A, Thun M, Yu XQ, et al. Changes in smoking prevalence among U.S. adults by state and region: estimates from the Tobacco Use Supplement to the Current Population Survey, 1992-2007. BMC Public Health 2011; 11: 512.

17. Eriksen MP, Mackay J, Schluger N, et al. The tobacco atlas. 5th ed. Atlanta: American Cancer Society, 2015.

18. Ng M, Freeman MK, Fleming TD, et al. Smoking prevalence and cigarette consumption in 187 countries, 1980-2012. JAMA 2014; 311: 183-92.

19. Gallus S, Zuccaro P, Colombo P. Effects of new smoking regulations in Italy. Ann Oncol 2006; 17: 346-47.

20. Tramacere I, Gallus S, Fernandez E, et al. Medium-term effects of Italian smoke-free legislation: findings from four annual population-based surveys. J Epidemiol Community Health 2009; 63: 559-62.

21. WHO.int [internet]. WHO global report on trends in tobacco smoking 2000-2025 [update unknown, cited 2016 July 30]. Available from: http://www.who.int/tobacco/publications/surveillance/reportontrendstobaccosmoking/en/

22. Khuder SA. Effect of cigarette smoking on major histological types of lung cancer: a meta analysis. Lung Cancer 2001; 31(2-3): 139-48.

23. Brownson RC, Chang JC, Davis JR. Gender and histologic type variations in smoking-related risk of lung cancer. Epidemiology 1992; 3(1): 61-4.

24. Harris RE, Zang EA, Anderson JI, et al. Race and sex differences in lung cancer risk associated with cigarette smoking. Int J Epidemiol 1993; 22(4): 592-99.

25. Risch HA, Howe GR, Jain M, et al. Are female smokers at higher risk for lung cancer than male smokers? A case control analysis by histologic type. Am J Epidemiol 1993; 138(5): 281-93.

26. Zang EA, Wynder EL. Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst 1996; 88(3-4): 183-92.

27. Bain C, Feskanich D, Speizer FE, et al. Lung cancer rates in men and women with comparable histories of smoking. J Natl Cancer Inst 2004; 96(11): 826-34.

28. Freedman ND, Leitzmann MF, Hollenbeck AR, et al. Cigarette smoking and subsequent risk of lung cancer in men and women: analysis of a prospective cohort study. Lancet Oncol 2008; 9(7): 649-56.

29. Kreuzer M, Boffetta P, Whitley E, et al. Gender differences in lung cancer risk by smoking: a multicentre case-control study in Germany and Italy. Br J Cancer 2000; 82(1): 227-33.

30. Papadopoulos A, Guida F, Leffondré K, et al. Heavy smoking and lung cancer: are women at higher risk? Result of the ICARE study. Br J Cancer 2014; 110(5): 1385-91.

31. De Matteis S, Consonni D, Pesatori AC, et al: Are women who smoke at higher risk for lung cancer than men who smoke? Am J Epidemiol 2013;177(7):601–12.

32. Yu Y, Liu H, Zheng S et al. Gender susceptibility for cigarette smoking-attributable lung cancer: a systematic review and meta-analysis. Lung Cancer 2014;85(3):351-60.

33. World Health Organization & International Agency for Research on Cancer. Tobacco Smoke and Involuntary Smoking: IARC Working Group in Lyon, 11-18 June 2002. Lyon, France 2004.

34. North CM, Christiani DC. Women and lung cancer: what is new? Semin Thorac Cardiovasc Surg 2013; 25(2): 87-94.

35. Paulus JK, Christiani DC: Environmental Exposures and Cancer, in Women and Health, ed 2. Waltham, MA: Academic Press 2012: 641-77.

36. Egleston BL, Meireles SI, Flieder DB, et al: Population-based trends in lung cancer incidence in women. Semin Oncol 2009; 36: 506-15.

37. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers-a different disease. Nat Rev Cancer 2007; 7: 778-90.

38. Wang A, Kubo J, Luo J, et al. Active and passive smoking in relation to lung cancer incidence in the Women’s Health Initiative Observational Study prospective cohort. Ann Oncol 2015; 26(1): 221-30.

39. Hirayama T. Non-smoking wives of heavy smokers have a higher risk of lung cancer: a study from Japan. BMJ 1981; 282: 183-5.

40. Alberg AJ, Wallace K, Silvestri GA, et al. Invited commentary: the etiology of lung cancer in men compared with women. Am J Epidemiol 2013; 177(7): 613-16.

41. Gordon SB, Bruce NG, Grigg J. Respiratory risks from household air pollution in low and middle income countries. Lancet Respir Med 2014; 2(10): 823-60.

42. Brownson RC, Alavanja MC, Chang JC. Occupational risk factors for lung cancer among nonsmoking women: a case-control study in Missouri (United States). Cancer Causes Control 1993; 4(5): 449-54.

43. Samet JM, Avila-Tang E, Boffetta P, et al. Lung cancer in never smokers: clinical epidemiology and environmental risk factors. Clin Cancer Res 2009; 15(18): 5626-45.

44. Hosgood HD, Wei H, Sapkota A, et al. Household coal use and lung cancer: systematic review and meta-analysis of case-control studies, with an emphasis on geographic variation. Int J Epidemiol 2011; 40: 719-28.

45. Mu L, Liu L, Niu R et al. Indoor air pollution and risk of lung cancer among Chinese female non-smokers. Cancer Causes Control 2013; 24(3): 439-50.

46. Candelora EC, Stockwell HG, Armstrong AW, et al. Dietary intake and risk of lung cancer in women who never smoked. Nutr Cancer 1992; 17: 263-70.

47. Brennan P, Fortes C, Butler J, et al. A multicenter case-control study of diet and lung cancer among non-smokers. Cancer Causes Control 2000; 11(1): 49-58.

48. Knekt P, Jarvinen R, Seppanen R, et al. Dietary flavonoids and the risk of lung cancer and other malignant neoplasms Am J Epidemiol 1997; 146(3): 223-30.

49. Fraser GE, Beeson WL, Phillips RL. Diet and lung cancer in California seventh-day Adventists. Am J Epidemiol 1991; 133(7): 683-93.

50. Yong LC, Brown CC, Schatzkin A, et al. Intake of Vitamins E, C, and A and risk of lung cancer: the NHANES 1 epidemiologic follow-up study. First National Health and Nutrition Examination Survey. Am J Epidemiol 1997; 146(3): 231-43.

51. Takata Y, Cai Q, Beeghly-Fadiel A, et al. Dietary B vitamin and methionine intakes and lung cancer risk among female never smokers in China. Cancer Causes Control 2012; 23: 1965-75.

52. Brownson RC, Alavanja MC. Previous lung disease and lung cancer risk among women (United States). Cancer Causes Control 2000; 11(9): 853-8.

53. Mayne ST, Buenconsejo J, Janerich DT. Previous lung disease and risk of lung cancer among men and women nonsmokers. Am J Epidemiol 1999; 149(1): 13-20.

54. Hinds MW, Cohen HI, Kolonel LN. Tuberculosis and lung cancer risk in nonsmoking women. Am Rev Respir Dis 1982; 125: 776-8.

55. Wu AH, Fontham ET, Reynolds P, et al. Previous lung disease and risk of lung cancer among lifetime nonsmoking women in the United States. Am J Epidemiol 1995; 141(11): 1023-32.

56. Wakelee HA, Chang ET, Gomez SL, et al. Lung cancer incidence in never smokers. J Clin Oncol 2007; 25: 472-8.

57. Lam WK, White NW, Chan-Yeung MM. Lung cancer epidemiology and risk factors in Asia and Africa. Int J Tuberc Lung Dis 2004; 8: 1045-57.

58. Smith EM, Ritchie JM, Summersgill KF, et al. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer 2004; 108: 766-72.

59. Hasegawa Y, Ando M, Kubo A, et al. Human papilloma virus in non-small cell lung cancer in never smokers: a systematic review of the literature. Lung Cancer 2014; 83(1): 8-13.

60. Lin FC, Huang JY, Tsai SC et al. The association between human papillomavirus infection and female lung cancer: A population-based cohort study. Medicine (Baltimore) 2016; 95(23): e3856.

61. Van Boerdonk RA, Daniels JM, Bloemena E, et al. High-risk human papillomavirus-positive lung cancer: molecular evidence for a pattern of pulmonary metastasis. J Thorac Oncol 2013; 8(6): 711-18.

62. Stabile LP, Dacic S, Lande SR, et al: Combined Analysis of Estrogen Receptor β-1 and Progesterone Receptor Expression Identifies Lung Cancer Patients with Poor Outcome. Clin Cancer Res 2011; 17(1): 154-64.

63. Kawai H. Estrogen receptors as the novel therapeutic biomarker in non-small cell lung cancer. World J Clin Oncol 2014; 5: 1020-7.

64. Pesatori AC, Carugno M, Consonni D, et al. Hormone use and risk for lung cancer: a pooled analysis from the International Lung Cancer Consortium (ILCCO). Br J Cancer 2013; 109: 1954-64.

65. Pesatori AC, Carugno M, Consonni D, et al. Reproductive and hormonal factors and the risk of lung cancer: the EAGLE study. Int J Cancer 2013; 132: 2630-9.

66. Meinhold CL, Berrington DA, Bowman ED, et al. Reproductive and hormonal factors and the risk of non small cell lung cancer. Int J Cancer 2011; 128: 1404-13.

67. Bae JM, Kim EH. Hormonal Replacement Therapy and the risk of lung cancer in women: An adaptive meta-analysis of cohort studies. J Prev Med Public Health 2015; 48(6): 280-6.

68. Slatore CG, Chien JW, Au DH et al. Lung cancer and hormone replacement therapy: association in the vitamins and lifestyle study. J Clin Oncol 2010; 28: 1540-6.

69. Chlebowski RT, Wakelee H, Pettinger M, et al. Estrogen plus progestin and lung cancer: Follow-up of the Women’s Health Initiative randomized trial. Clin Lung Cancer 2016; 17(1): 10-7.e1.

70. Clague J, Reynolds P, Henderson KD, et al. Menopausal hormone therapy and lung cancer-specific mortality following diagnosis: the California Teachers Study. PLoS One 2014; 9: e103735.

71. Katcoff H, Wenzlaff AS, Schwartz AG. Survival in women with NSCLC: the role of reproductive history and hormone use. J Thorac Oncol 2014; 9(3): 355-61.

72. Stabile LP, Lyker JS, Gubish CT, et al: Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects. Cancer Res 2005; 65: 1459-70.

73. He Q, Zhang M, Zhang J, et al. Correlation between epidermal growth factor receptor mutations and nuclear expression of female hormone receptors in non-small cell lung cancer: a meta-analysis. J Thorac Dis 2015; 7(9):1588-94.

74. Skov BG, Fischer BM, Pappot H. Oestrogen receptor b over expression in males with non-small cell lung cancer is associated with better survival. Lung Cancer 2008; 59(1): 88-94.

75. Ishibashi H, Suzuki T, Suzuki S, et al. Progesterone receptor in non-small cell lung cancer-a potent prognostic factor and possible target for endocrine therapy. Cancer Res 2005; 65 (14): 6450-8.

76. Abe K, Miki Y, Ono K, et al. Highly concordant coexpression of aromatase and estrogen receptor beta in non-small cell lung cancer. Hum Pathol 2010; 41(2): 190-8.

77. Skjefstad K, Richardsen E, Donnem T, et al. The prognostic role of progesterone receptor expression in non-small cell lung cancer patients: Gender-related impacts and correlation with disease-specific survival. Steroids 2015; 98: 29-36.

78. Mitsudomi T. Molecular epidemiology of lung cancer and geographic variations with special reference to EGFR mutations. Transl Lung Cancer Res 2014; 3(4): 205-11.

79. Mazières J, Rouquette I, Lepage B, et al. Specificities of lung adenocarcinoma in women who have never smoked. J Thorac Oncol 2013; 8(7): 923-9.

80. Mar N, Vredenburgh JJ, Wasser JS. Targeting HER2 in the treatment of non-smallcell lung cancer. Lung Cancer 2015; 7(3): 220-5.

81. Mazières J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol 2013; 31(16): 1997-2003.

82. Dogan S, Shen R, Ang DC, et al. Molecular epidemiology of EGFR and KRAS mutations in 3026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res 2012; 18(22): 6169-77.

83. Warth A, Muley T, Dienemann H, et al. ROS1 expression and translocations in non-small-cell lung cancer: clinicopathological analysis of 1478 cases. Histopathology 2014; 65(2): 187-94.

84. Hosgood HD 3rd, Song M, Hsiung CA, et al. Interactions between household air pollution and GWAS-identified lung cancer susceptibility markers in the Female Lung Cancer Consortium in Asia (FLCCA). Hum Genet 2015; 134(3): 333-41.

85. Wang Z, Seow WJ, Shiraishi K, et al. Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women. Hum Mol Genet 2016; 25(3): 620-9.

86. Machiela MJ, Hsiung CA, Shu XO, et al. Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia. Int J Cancer 2015; 137(2): 311-9.

87. Fu JB, Kau Y, Severson RK, et al. Lung cancer in women: Analysis of the national surveillance epidemiology, and end results database. Chest 2005; 127: 768-77.

88. Thomas L, Doyle LA, Edelman MJ: Lung cancer in women: emerging differences in epidemiology, biology, and therapy. Chest 2005; 128: 370-81.

89. Nakamura H, Ando K, Shinmyo T, et al: Female gender is an independent prognostic factor in non-small-cell lung cancer: A meta-analysis. Ann Thorac Cardiovasc Surg 2011; 17:469-80.

90. Pitz MW, Musto G, Navaratnam S. Sex as an independent prognostic factor in a population-based non-small cell lung cancer cohort. Can Respir J 2013; 20(1): 30-34.

91. Sandler BJ, Wang Z, Hancock JG, et al. Gender, age, and comorbidity status predict improved survival with adjuvant chemotherapy following lobectomy for non-small cell lung cancers larger than 4 cm. Ann Surg Oncol 2016; 23(2): 638-45.

92. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352(25): 2589-97.

93. Ramalingam S, Pawlish K, Gadgeel S. Lung cancer in young patients: analysis of a Surveillance, Epidemiology, and End Results Database. Am J Clin Oncol 1998; 16: 651-7.

94. Radzikowska E, Glaz P, Roszkowski K. Lung cancer in women: age, smoking, histology, performance status, stage, initial treatment and survival: population-based study of 20,561 cases. Ann Oncol 2002; 13:1087-93.

95. Wei Q, Cheng L, Amos CI, et al. Repair of tobacco carcinogen- induced DNA adducts and lung cancer risk: a molecular epidemiologic study. J Natl Cancer Inst 2000; 92: 1764-72.

96. Shen H, Spitz MR, Qiao Y, et al. Smoking, DNA repair capacity and risk of non small cell lung cancer. Int J Cancer 2003; 107: 84-8.

97. Berardi R, Verdecchi L, Di Pietro Paolo M, et al. Women and lung cancer: clinical and molecular profiling as a determinate for treatment decisions: a literature review. Crit Rev Oncol Hematol 2009; 69: 223-36.

98. Ganti AK, Sahmoun AE, Panwalkar AW et al. Hormone replacement therapy is associated with decreased survival in women with lung cancer. J Clin Oncol 2006; 24(1): 59-63.

99. Ayeni O, Robinson A. Hormone replacement therapy and outcomes for women with non-small-cell lung cancer: can an association be confirmed? Curr Oncol 2009; 16(3): 21-5.

100.  Huang B, Carloss H, Wyatt SW, et al. Hormone replacement therapy and survival in lung cancer in postmenopausal women in a rural population. Cancer 2009; 115(18): 4167-75.