Abstract:

Objective:

To analyze the differences in the clinico-pathological and molecular characteristics of non-small cell lung cancer (NSCLC) as well as the clinical outcome of patients by sex and hormonal status.

Materials and methods:

We performed a retrospective study among 1 104 NSCLC patients. Clinic-pathologic data was recorded and survival outcomes were compared between male and female sex patients, and further by pre and postmenopausal status in females.

Results:

Women were significantly more likely to be non-smokers (p<0.001), had higher frequency of wood-smoke exposure (p<0.001), EGFR-sensitizing mutations (p<0.001), had better performance status (p=0.020) and had a better overall survival (OS) compared to men (p=0.021). Differences were found also by hormonal status, postmenopausal women had a longer OS compared to premenopausal women (31.1 vs. 19.4 months p=0.046).

Conclusion:

Our results support the differences in lung cancer presentation by sex and also by hormonal status.

Keywords:
lung carcinoma, non-small-cell; men; women; postmenopausal; premenopausal

Resumen:

Objetivo:

Analizar las diferencias en las características clínico-patológicas, moleculares y en la evolución del cáncer de pulmón de células no pequeñas (CPCNP) por sexo y estadio hormonal.

Material y métodos:

Estudio retrospectivo (N=1 104) en pacientes con CPCNP. Se recabaron datos clínico-patológicos y desenlaces de sobrevida y se compararon entre hombres y mujeres, y entre mujeres pre y postmenopáusicas.

Resultados:

Las mujeres de este estudio tuvieron significativamente mayor probabilidad de ser no fumadoras (p<0.001), tener exposición a humo de leña (p<0.001), mutaciones en EGFR (p<0.001), mejor estado funcional (p=0.020), y una mejor sobrevida global (SG) en comparación con los hombres (p=0.021). Estas diferencias también se encontraron en cuestión al estatus hormonal, con las mujeres postmenopáusicas presentando una mayor sobrevida en comparación con las premenopáusicas (31.1 vs. 19.4 meses; p=0.046).

Conclusión:

Los presentes resultados apoyan las diferencias en la presentación del CPCNP de acuerdo con el sexo y estatus hormonal.

Palabras clave:
cáncer de pulmón de células no pequeñas; hombres; mujeres; premenopausia; postmenopausia

Introduction

Lung cancer remains the leading cause of cancer-related deaths among males and has increased in women in the last decades.¹1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108. https://doi.org/10.3322/caac.21262 Lung cancer in women has become an important health problem, surpassing mortality from breast cancer and being the first cause of cancer-related death in EEUU and in some countries from Europe.¹1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108. https://doi.org/10.3322/caac.21262^,22. Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, Jemal A. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177-93. https://doi.org/10.3322/caac.21395
https://doi.org/10.3322/caac.21395... ^,33. Islami F, Torre LA, Jemal A. Global trends of lung cancer mortality and smoking prevalence. Transl Lung Cancer Res. 2015;4(4):327-38. https://doi.org/10.3978/j.issn.2218-6751.2015.08.04
https://doi.org/10.3978/j.issn.2218-6751... ^,44. Eilstein D, Eshai K. Lung and breast cancer mortality among women in France: future trends. Cancer Epidemiol. 2012;36:(6)e341-8. https://doi.org/10.1016/j.canep.2012.07.008
https://doi.org/10.1016/j.canep.2012.07.... ^,55. Malvezzi M, Bertuccio P, Levi F, La Vecchia C, Negri E. European cancer mortality predictions for the year 2012. Ann Oncol. 2012;23:(4)1044-52. https://doi.org/10.1093/annonc/mds024
https://doi.org/10.1093/annonc/mds024... Interestingly, a higher incidence among young women compared to men has been observed in the last decades in EEUU, however, this increase in incidence among women cannot be attributed solely to an increase in tobacco use, due to the fact that young women and men show a similar pattern in terms of smoking behavior, nonetheless the increased incidence of lung cancer in women is notorious.⁶6. Jemal A, Miller KD, Ma J, Siegel RL, Fedewa SA, Islami F, et al. Higher lung cancer incidence in young women than young men in the United States. N Engl J Med. 2018;378:1999-2009. https://doi.org/10.1056/NEJMoa1715907
https://doi.org/10.1056/NEJMoa1715907... Moreover, an increased incidence of lung cancer has also been reported in Latin American women, who present a lower smoking index compared to European and American women.⁷7. Pineros M, Sierra MS, Forman D. Descriptive epidemiology of lung cancer and current status of tobacco control measures in Central and South America. Cancer Epidemiol . 2016;44(suppl 1): S90-9. https://doi.org/10.1016/j.canep.2016.03.002
https://doi.org/10.1016/j.canep.2016.03.... ^,88. Raez LE, Cardona AF, Santos ES, Catoe H, Rolfo C, Lopes G, et al. The burden of lung cancer in Latin-America and challenges in the access to genomic profiling, immunotherapy and targeted treatments. Lung Cancer. 2018;119:7-13. https://doi.org/10.1016/j.lungcan.2018.02.014
https://doi.org/10.1016/j.lungcan.2018.0... These data suggest that even though tobacco use remains an important risk factor for developing lung cancer, women face other risk factors, which also appear to play an important role in lung carcinogenesis. Furthermore, a higher percentage of women who develop lung cancer are never smokers compared to the low percentage of non-smoking men who present with this pathology (53 vs. 15%).⁹9. Jenks S. Is lung cancer incidence increasing in never-smokers? J Natl Cancer Inst. 2016;108(1). https://doi.org/10.1093/jnci/djv418
https://doi.org/10.1093/jnci/djv418... ^,1010. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin . 2011;61:69-90. https://doi.org/10.3322/caac.20107
https://doi.org/10.3322/caac.20107... Other risk factors that might partially explain the increased incidence of lung cancer in women include: wood smoke exposure,¹¹11. Arrieta O, Campos-Parra AD, Zuloaga C, Aviles A, Sanchez-Reyes R, Manriquez ME, et al. Clinical and pathological characteristics, outcome and mutational profiles regarding non-small-cell lung cancer related to wood-smoke exposure. J Thorac Oncol. 2012;7:(8)1228-34. https://doi.org/10.1097/JTO.0b013e3182582a93
https://doi.org/10.1097/JTO.0b013e318258... cooking oil fumes exposure¹²12. Kim C, Gao YT, Xiang YB, Barone-Adesi F, Zhang Y, Hosgood HD, et al. Home kitchen ventilation, cooking fuels, and lung cancer risk in a prospective cohort of never smoking women in Shanghai, China. Int J Cancer. 2015;136:632-8. https://doi.org/10.1002/ijc.29020
https://doi.org/10.1002/ijc.29020... or second hand exposure to cigarette smoke,¹³13. Kim CH, Lee YC, Hung RJ, McNallan SR, Cote ML, Lim WY, et al. Exposure to secondhand tobacco smoke and lung cancer by histological type: a pooled analysis of the International Lung Cancer Consortium (ILCCO). Int J Cancer. 2014;135:1918-30. https://doi.org/10.1002/ijc.28835
https://doi.org/10.1002/ijc.28835... however exposure to these risk factors does not fully explain the increased incidence of lung cancer in women. In the last years, it has been reported that estrogen and progesterone play an important role in lung cancer in women, mainly in the adenocarcinoma subtype, activating carcinogenic pathways.¹⁴14. Rodriguez-Lara V, Hernandez-Martinez JM, Arrieta O. Influence of estrogen in non-small cell lung cancer and its clinical implications. J Thorac Dis. 2018;10(1):482-97. https://doi.org/10.21037/jtd.2017.12.61
https://doi.org/10.21037/jtd.2017.12.61... ^,1515. Marquez-Garban DC, Mah V, Alavi M, Maresh EL, Chen HW, Bagryanova L, et al. Progesterone and estrogen receptor expression and activity in human non-small cell lung cancer. Steroids. 2011;76(9):910-20. https://doi.org/10.1016/j.steroids.2011.04.015
https://doi.org/10.1016/j.steroids.2011.... Also, several studies have shown that hormone replacement therapy based on estrogen and progestin can increase lung cancer incidence and mortality.¹⁶16. Greiser CM, Greiser EM, Doren M. Menopausal hormone therapy and risk of lung cancer-Systematic review and meta-analysis. Maturitas. 2010;65(3):198-204. https://doi.org/10.1016/j.maturitas.2009.11.027
https://doi.org/10.1016/j.maturitas.2009... ^,1717. Chlebowski RT, Wakelee H, Pettinger M, Rohan T, Liu J, Simon 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):10-7e1. https://doi.org/10.1016/j.cllc. 2015 .09.004
https://doi.org/10.1016/j.cllc. 2015 .09...

Additionally, lung cancer presentation, behavior and response to treatment seem to differ between women and men. For instance, the median age for lung cancer diagnosis in women is lower compared to men. Women with lung cancer more often have no history of smoking and the predominant subtype is adenocarcinoma, frequently associated with mutations in epidermal growth factor receptor gene (EGFR). In addition, women show better response to chemotherapy and longer overall survival, regardless of the clinical stage at diagnosis, compared to men.¹⁸18. De Matteis S, Consonni D, Pesatori AC, Bergen AW, Bertazzi PA, Caporaso NE, et al. Are women who smoke at higher risk for lung cancer than men who smoke? Am J Epidemiol. 2013;177(7):601-12. https://doi.org/10.1093/aje/kws445
https://doi.org/601-12https://doi.org/10... ^,1919 . Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361:958-67. https://doi.org/10.1056/NEJMoa0904554
https://doi.org/10.1056/NEJMoa0904554... Recently, it has been observed that non-small cell lung cancer (NSCLC) tumors are more immunogenic in men and consequently male patients respond better to immunotherapy compared to women.²⁰20. Conforti F, Pala L, Bagnardi V, De Pas T, Martinetti M, Viale G, et al. Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis. Lancet Oncol. 2018;19(6):737-46. https://doi.org/10.1016/S1470-2045(18)30261-4
https://doi.org/10.1016/S1470-2045(18)30... All these differences in lung cancer by sex suggest a role of sexual hormones in lung cancer; however, differences by hormonal status in women (premenopausal/postmenopausal) have been poorly studied. Nevertheless, when characteristics of premenopausal women have been analyzed, they show that these patients are diagnosed in advanced stages, with less differentiated tumors, distant metastases and worse prognosis compared to postmenopausal women. This information suggests that lung cancer is not only influenced by sex, but also by hormonal status.²¹21. Albain KS, Unger J, Gotay CC, Davies M, Edelman M, Herbst RS, et al. Toxicity and survival by sex in patients with advance non-small cell lung carcinoma (NSCLC) on modern Southwest Oncology Group (SWOG) trials. J Clin Oncol. 2007;25(suppl 18):7549. https://doi.org/10.1200/jco.2007.25.18_suppl.7549
https://doi.org/10.1200/jco.2007.25.18_s... ^,2222. Rodriguez-Lara V, Pena-Mirabal E, Baez-Saldana R, Esparza-Silva AL, Garcia-Zepeda E, Cerbon Cervantes MA, et al. Estrogen receptor beta and CXCR4/CXCL12 expression: differences by sex and hormonal status in lung adenocarcinoma. Arch Med Res. 2014;45(2):158-69. https://doi.org/10.1016/j.arcmed.2014.01.001
https://doi.org/10.1016/j.arcmed.2014.01...

Several studies have focused on reporting the differences by sex and despite this information, these differences are poorly understood, and the results of studies are contradictory. The controversy in these studies might be due to the inherent characteristics of the population analyzed, differences in the main risk factors, mutational tumor profile, genetic characteristics of patients and hormonal status. With a better understanding about the role of sexual hormones in lung cancer, it is important to investigate differences by hormonal status in Latin America population.²³23. Wong MCS, Lao XQ, Ho KF, Goggins WB, Tse SLA. Incidence and mortality of lung cancer: global trends and association with socioeconomic status. Sci Rep. 2017;7:14300. https://doi.org/10.1038/s41598-017-14513-7
https://doi.org/10.1038/s41598-017-14513...

Nowadays, it is recognized that sex and sexual hormones influence lung cancer. Due to the impact that these differences have in future treatment strategies, it is important to comprehensively characterize them. In this study, we sought to investigate the differences in clinical features and survival of NSCLC patients by sex and hormonal status, in a Mexican population.

Materials and methods

Patient selection

We retrospectively reviewed demographic, clinical, molecular and pathological data of 1 104 NSCLC who attended at the National Cancer Institute of Mexico (Incan) between May 2008 through March 2017. All included patients had a histologically confirmed diagnosis of NSCLC and molecular genotype available in their clinical file (EGFR and Kirsten rat sarcoma virus oncogene [KRAS] mutation status). Information including sex, age, and menopausal status at diagnosis was collected. Menopause was defined according to the international menopause guideline²⁴24. Lumsden MA, Davies M, Sarri G, for the Guideline Development Group for Menopause: Diagnosis and Management (NICE Clinical Guideline No. 23). Diagnosis and Management of Menopause: The National Institute of Health and Care Excellence (NICE) Guideline. JAMA Intern Med. 2016;176(8):1205-6. https://doi.org/10.1001/jamainternmed.2016.2761
https://doi.org/10.1001/jamainternmed.20... as the permanent cessation of menses for 12 or more months in the absence of chemotherapy. Patients who had undergone oophorectomy were excluded from this study. According to standardized guidelines for smoking measurement,²⁵25. World Health Organization. Guidelines for Controlling and Monitoring the Tobacco Epidemic. Geneva: WHO, 1998. we defined any patient who smoked 100 or more cigarettes in his or her lifetime and those who currently smokes, as a smoker. A person was defined as a non-smoker if he or she had either never smoked at all, or had never been a daily smoker and had smoked less than 100 cigarettes in his or her lifetime. Smoking index was obtained by multiplying the number of cigarettes smoked per day by the number of years the patient reported that he/she had smoked [(# cigarettes per day)(years smoking)/20) and reported as pack-year]. Self-reported wood-smoke exposure while cooking was recorded and the wood smoke exposure index was calculated by multiplying the number of daily hours exposed by the number of years’ exposure.¹¹11. Arrieta O, Campos-Parra AD, Zuloaga C, Aviles A, Sanchez-Reyes R, Manriquez ME, et al. Clinical and pathological characteristics, outcome and mutational profiles regarding non-small-cell lung cancer related to wood-smoke exposure. J Thorac Oncol. 2012;7:(8)1228-34. https://doi.org/10.1097/JTO.0b013e3182582a93
https://doi.org/10.1097/JTO.0b013e318258...

Outcome measurement

Clinical baseline characteristics included age, sex, hormonal status (premenopausal/postmenopausal), weight, histologic tumor type, disease stage, smoking status, wood-smoke exposure, exposure to asbestos, ECOG performance status, metastatic sites, and mutation profile for EGFR and KRAS. Overall survival (OS) was defined as the time from histological diagnosis until death or last follow-up.

Statistical analysis

For descriptive purposes, continuous variables were summarized as arithmetic means with standard deviations, while categorical variables were summarized as frequencies and percentages. The chi² or Fisher’s exact tests were used to assess the significance among categorical variables. The primary endpoint was OS, defined as the time from histological diagnosis until death or last follow-up. Median OS was estimated using the Kaplan-Meier’s method, whereas the log-rank test was used for making comparisons among subgroups. A multivariate Cox regression model was used to adjust for potential confounders and hazard ratios (HR) were calculated along with their corresponding 95%CI as a measure of association. Statistical significance was determined as p≤0.05 using a two-tailed test. SPSS software version 21 (SPSS Inc., Chicago, IL) was used for all statistical analysis.

Results

Characteristics for the entire population of NSCLC patients

Out of 1 104 patient records reviewed for this study, 582 (52.7%) were men and 522 (47.3%) women. The median age was 60.6 years (+12.9). According to risk factors, 55.7% were ever smokers, while 38.5% of the patients had history of wood smoke exposure, and 10.5% had exposure to asbestos; 72.9 % of all patients have an ECOG <1. Most patients had adenocarcinoma histology (84.3%) and 98.9% presented with advanced or metastatic disease (stages IIIB or IV) at diagnosis. Nearly thirty percent of patients (29.6%) had EGFR mutations and 10.2% had KRAS alterations (table I).

Characteristics of NSCLC patients according to sex

The relative frequency of obese patients was substantially higher in women (16%) than in men (9%), p=0.003, likewise, female patients showed a higher body mass index (BMI) in comparison with their male counterparts (24.6 vs. 25.1; p=0.036). In addition, women had higher frequencies of wood-smoke exposure (50 vs. 28.2%; p=<0.001), EGFR-sensitizing mutations (38.8 vs. 18.7%; p=<0.001) and better ECOG performance status (≤1) (76.2 vs. 69.9%; p=0.020). By contrast, men showed higher frequencies of tobacco smoking exposure compared to women (70 vs. 32%; p=<0.001). We did not find differences among men and women in terms of age, histology, disease stage or KRAS mutation status. Table I shows the clinic-pathological characteristics by sex.

Factors associated with the overall survival of patients

The median OS for the entire cohort was 21.6 months. The univariate analysis showed that the factors associated with OS were: sex, weight, smoking history, ECOG performance status, liver metastases and alterations in KRAS. The OS was prolonged in women compared to men (27.6 vs. 18.4 months, respectively [p=0.021]) (figure 1). Similarly, overweight patients had better results in terms of OS compared with normal weight or obesity (28.4 vs. 17.4 vs. 22.4 months, respectively; p=0.045). Patients with tobacco exposure had a shorter OS compared to never smoker patients (18.1 vs. 28.2 months; p=0.002). On the other hand, patients with an ECOG <2 (23.5 vs. 14.5 months; p=0.006), absence of liver metastases, and wild type KRAS (38.9 vs. 15.7 months; p<0.001) had better OS. The multivariate analysis showed that ECOG performance status (HR: 0.4, 95%CI (0.2-0.7); p=0.001) and KRAS mutation (HR: 2.1, 95%CI (1.1-3.8); p=0.017) were independently associated with OS (table II).

Characteristics of women with NSCLC by hormonal status

Among 522 female patients with NSCLC analyzed, 120 were premenopausal (23%) and 402 postmenopausal (77%). Table III shows the characteristics the female sex population according to hormonal status. The relative frequency of wood-smoke exposure was substantially higher in postmenopausal than premenopausal women (52.5 vs. 41.7%, p=0.037). Likewise, postmenopausal patients showed a higher wood-smoke exposure index (113.2 vs. 50.6; p=0.006) and tobacco smoking index (19.8 vs. 10.2; p=0.017) compared to premenopausal women. By contrast, premenopausal women showed higher frequencies of exposure to asbestos in comparison to postmenopausal patients (16.7 vs. 7.0%; p=0.001). We did not find differences among women according to their hormonal status in terms of BMI, tobacco exposure, histology, disease stage, ECOG performance status, sites of metastases (brain, lung, liver, bone, lymphatic nodes, and adrenal glands) nor by EGFR or KRAS mutation status (table III).

Factors associated with overall survival among women NSCLC patients

Median OS for women was 27.6 months; in the univariate analysis the factors associated with a better OS were hormonal status (postmenopausal vs. premenopausal) (31.1 vs. 19.4 months; p=0.046) (figure 2), tobacco exposure (never vs. ever) (32.1 vs. 18.5 months; p=0.037), ECOG performance status (<2 vs. 2+) (27.9 vs. 18.5 months; p=0.022), adrenal glands metastases (no vs. yes) (27.6 vs. 10.7; p=0.023) and KRAS mutation status (absent vs. present) (37.6 vs. 15.8 months; p=0.007). In the multivariate analysis, the independently associated factors with OS were tobacco exposure (HR: 1.4, 95%CI (1.0-1.9); p=0.031), ECOG performance status (HR: 01.7, 95%CI (1.2-2.4); p=0.005) and KRAS mutation status (HR: 2.1, 95%CI (1.1-4.0); p=0.022) (supplementary table I).²⁶26. Arrieta O. Suppl files characteristics of non-small cell lung cancer. Differences by sex and hormonal status in a Mexican population. Dataverse 2019. https://doi.org/10.7910/DVN/PAVQ3T
https://doi.org/10.7910/DVN/PAVQ3T...

NSCLC among EGFR (+) women by hormonal status

Among 522 female patients, only 219 patients were tested for EGFR mutation status, among them only 85 (38.8%) patients harbored an EGFR mutation (17 [20%] were premenopausal and 68 [80%] were postmenopausal women). We did not find any differences between premenopausal and postmenopausal EGFR-mutated women in terms of BMI, tobacco, wood-smoke and, asbestos exposure, histology, disease stage, ECOG performance status, sites of metastases (brain, lung, liver, bone, lymphatic nodes, and adrenal glands) nor by KRAS mutation status (supplementary table II).²⁶26. Arrieta O. Suppl files characteristics of non-small cell lung cancer. Differences by sex and hormonal status in a Mexican population. Dataverse 2019. https://doi.org/10.7910/DVN/PAVQ3T
https://doi.org/10.7910/DVN/PAVQ3T...

Factors associated with the overall survival among EGFR- mutated women

Median OS for women harboring EGFR mutations was 32.4 months; in the univariate analysis the factors associated with a better OS included a good ECOG performance status (<2 vs. 2+) (38.9 vs. 12.9 months; p=0.012) and absence of adrenal glands metastases (no vs. yes) (32.4 vs. 8.3; p=0.009). We did not find differences in OS when evaluating by hormonal status, age, BMI, tobacco exposure, wood-smoke exposure, exposure to asbestos, disease stage, sites of metastases (brain, lung, liver, bone, lymphatic nodes, and adrenal glands) nor by KRAS mutation status. None of the previously mentioned characteristics were independently associated with OS in the multivariate analysis (supplementary table III).²⁶26. Arrieta O. Suppl files characteristics of non-small cell lung cancer. Differences by sex and hormonal status in a Mexican population. Dataverse 2019. https://doi.org/10.7910/DVN/PAVQ3T
https://doi.org/10.7910/DVN/PAVQ3T...

NSCLC among wt-EGFR women by hormonal status

Among 522 female patients, only 219 were tested for EGFR mutation status; among them, 134 had wt-EGFR (32 [23.9%] premenopausal and 102 [76.1%] postmenopausal). Premenopausal wt-EGFR women were more likely to have a history of exposure to asbestos (25% vs. 3%; p<0.001). We did not find differences among premenopausal and postmenopausal wt-EGFR women by the other analyzed variables (supplementary table IV).²⁶26. Arrieta O. Suppl files characteristics of non-small cell lung cancer. Differences by sex and hormonal status in a Mexican population. Dataverse 2019. https://doi.org/10.7910/DVN/PAVQ3T
https://doi.org/10.7910/DVN/PAVQ3T...

Factors associated with the overall survival among wt-EGFR women with NSCLC

Median OS for women without an EGFR mutation was 32.1 months. In the univariate analysis the factors associated with OS were liver metastases (no vs. yes) (27.9 vs. 18.7 months; p=0.044) and KRAS mutation status (absent vs. present) (37.6 vs. 15.8 months; p=0.002). We did not find any significant differences in OS for the other analyzed factors. None of the characteristics were independently associated with OS in the multivariate analysis (supplementary table V).²⁶26. Arrieta O. Suppl files characteristics of non-small cell lung cancer. Differences by sex and hormonal status in a Mexican population. Dataverse 2019. https://doi.org/10.7910/DVN/PAVQ3T
https://doi.org/10.7910/DVN/PAVQ3T...

Discussion

Lung cancer presentation, behavior and response to treatment depend on several factors including grading and staging of the disease, molecular and histological tumor features, and recently it have been proposed that sex and hormonal status are also associated with tumor behavior and survival of NSCLC patients, however, this information is still controversial. We reported differences in lung cancer presentation and OS according to the sex and hormonal status in a Mexican population of NSCLC.

We observed that women presented higher frequencies of wood-smoke exposure, EGFR sensitizing mutations, better ECOG performance, had a higher frequency of obesity and, as a result, higher BMI compared to men who instead exhibited a higher smoking index compared to women. OS was also higher in women compared to men, as well as in patients who were overweight, never smokers, had a good ECOG performance status, a wt-KRAS molecular status and were free of liver metastases.

In Mexico, as in other Latin-American countries, smoking habit does not appear to be the main risk factor for the development of lung cancer in women, since a higher percentage of women with NSCLC are never smokers. Previously it had been reported that wood-smoke exposure was an important risk factor to develop lung cancer in non-smoking Mexican women,²⁷27. Arrieta O, Martinez-Barrera L, Trevino S, Guzman E, Castillo-Gonzalez P, Rios-Trejo MA, et al. Wood-smoke exposure as a response and survival predictor in erlotinib-treated non-small cell lung cancer patients: an open label phase II study. J Thorac Oncol. 2008;3(8):887-93. https://doi.org/10.1097/JTO.0b013e31818026f6
https://doi.org/10.1097/JTO.0b013e318180... ^,2828. Hernandez-Garduno E, Brauer M, Perez-Neria J, Vedal S. Wood smoke exposure and lung adenocarcinoma in non-smoking Mexican women. Int J Tuberc Lung Dis. 2004;8(3):377-83. we observed that this factor remains relevant in the etiology of lung cancer in women to this day. In addition EGFR-mutations have also been associated with patients who are never smokers and women,²⁹29. Tseng CH, Chiang CJ, Tseng JS, Yang TY, Hsu KH, Chen KC, et al. EGFR mutation, smoking, and gender in advanced lung adenocarcinoma. Oncotarget. 2017;8:98384-93. https://doi.org/10.18632/oncotarget.21842
https://doi.org/10.18632/oncotarget.2184... which was also confirmed by our results. Nowadays patients with lung adenocarcinomas that exhibit EGFR sensitizing mutation are treated with targeted therapy based on Tyrosine Kinase Inhibitors (TKIs) which produce a high response rate as a first-line treatment.³⁰30. Nan X, Xie C, Yu X, Liu J. EGFR TKI as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer. Oncotarget. 2017;8:75712-26. https://doi.org/10.18632/oncotarget. 2009 5
https://doi.org/10.18632/oncotarget. 200... Moreover, obesity and high BMI were recently correlated with a reduced risk of death from lung cancer³¹31. Sepesi B, Gold KA, Correa AM, Heymach JV, Vaporciyan AA, Roszik J, et al. The influence of body mass index on overall survival following surgical resection of non-small cell lung cancer. J Thorac Onco l. 2017;12(8):1280-7. https://doi.org/10.1016/j.jtho. 2017 .05.010
https://doi.org/10.1016/j.jtho. 2017 .05... consistent with the data reported in the present study. The characteristics exhibited by women with lung cancer in our population, such as lower smoking index, higher frequency of EGFR sensitizing mutations, better ECOG performance status and higher frequency of obesity as well as high BMI, could explain the better OS we observe in women compared to men.

Analysis by hormonal status showed that postmenopausal women exhibited a higher wood smoke exposure and wood smoke exposure index as well as tobacco-smoking index compared to premenopausal women, who exhibited higher asbestos exposure. No differences were observed in tobacco exposure, BMI, histology, disease stage, ECOG performance status, sites of metastases and mutation in KRAS and EGFR by hormonal status. Nonetheless an interesting finding was the fact that postmenopausal women presented a better OS compared to their premenopausal counterparts. Older postmenopausal women survived a median of 31.1 months while younger premenopausal women survived only 19.4 months. The lower OS observed in premenopausal women could be explained by the differences in estrogen levels between premenopausal and postmenopausal women and the influence of this hormone in lung carcinogenesis.

Previous studies which have considered hormonal status among women with lung cancer have reported that premenopausal women presented with more advanced stage-disease at the time of diagnosis, less differentiated tumors, distant metastases and had a worse prognosis²¹21. Albain KS, Unger J, Gotay CC, Davies M, Edelman M, Herbst RS, et al. Toxicity and survival by sex in patients with advance non-small cell lung carcinoma (NSCLC) on modern Southwest Oncology Group (SWOG) trials. J Clin Oncol. 2007;25(suppl 18):7549. https://doi.org/10.1200/jco.2007.25.18_suppl.7549
https://doi.org/10.1200/jco.2007.25.18_s... ^,2222. Rodriguez-Lara V, Pena-Mirabal E, Baez-Saldana R, Esparza-Silva AL, Garcia-Zepeda E, Cerbon Cervantes MA, et al. Estrogen receptor beta and CXCR4/CXCL12 expression: differences by sex and hormonal status in lung adenocarcinoma. Arch Med Res. 2014;45(2):158-69. https://doi.org/10.1016/j.arcmed.2014.01.001
https://doi.org/10.1016/j.arcmed.2014.01... compared to postmenopausal women and men. Although our results did not show significant differences in disease stage, ECOG performance status and metastatic site by hormonal status, premenopausal women exhibited a statistically significant lower OS compared to postmenopausal. In Mexico as in other countries, lung cancer continues to be diagnosed at advanced stages both in women and men; it is likely that this delay in diagnosis and therefore treatment, as well as other problems concerning hospital admission, as well as the low percentage of premenopausal women analyzed in this study could conceal the probable differences in lung cancer metastases and stage at diagnosis by hormonal status. However, our study supports that there are differences in lung cancer behavior, presentation and prognosis not only by sex but also by hormonal status, which can be explained by the response of lung cancer to steroid sexual hormones.¹⁴14. Rodriguez-Lara V, Hernandez-Martinez JM, Arrieta O. Influence of estrogen in non-small cell lung cancer and its clinical implications. J Thorac Dis. 2018;10(1):482-97. https://doi.org/10.21037/jtd.2017.12.61
https://doi.org/10.21037/jtd.2017.12.61... ^,3232. Niikawa H, Suzuki T, Miki Y, Suzuki S, Nagasaki S, Akahira J, et al. Intratumoral estrogens and estrogen receptors in human non-small cell lung carcinoma. Clin Cancer Res. 2008 ;14(14):4417-26. https://doi.org/10.1158/1078-0432.CCR-07-1950
https://doi.org/10.1158/1078-0432.CCR-07... ^,3333. Mah V, Marquez D, Alavi M, Maresh EL, Zhang L, Yoon N, et al. Expression levels of estrogen receptor beta in conjunction with aromatase predict survival in non-small cell lung cancer. Lung Cancer. 2011;74(2):318-25. https://doi.org/10.1016/j.lungcan.2011.03.009
https://doi.org/10.1016/j.lungcan.2011.0... Recently lung cancer is being considered as a hormone-dependent cancer, since NSCLC tissues and cell lines exhibited strong estrogen (ER) and aromatase enzyme expression;¹⁴14. Rodriguez-Lara V, Hernandez-Martinez JM, Arrieta O. Influence of estrogen in non-small cell lung cancer and its clinical implications. J Thorac Dis. 2018;10(1):482-97. https://doi.org/10.21037/jtd.2017.12.61
https://doi.org/10.21037/jtd.2017.12.61... ^,3232. Niikawa H, Suzuki T, Miki Y, Suzuki S, Nagasaki S, Akahira J, et al. Intratumoral estrogens and estrogen receptors in human non-small cell lung carcinoma. Clin Cancer Res. 2008 ;14(14):4417-26. https://doi.org/10.1158/1078-0432.CCR-07-1950
https://doi.org/10.1158/1078-0432.CCR-07... the estrogen pathway has been related to carcinogenic pathway activation and lung cancer progression.³⁴34. Deng F, Li M, Shan WL, Qian LT, Meng SP, Zhang XL, Wang BL. Correlation between epidermal growth factor receptor mutations and the expression of estrogen receptor-beta in advanced non-small cell lung cancer. Oncol Lett. 2017 ;13(4):2359-65. https://doi.org/10.3892/ol. 2017 .5711
https://doi.org/10.3892/ol. 2017 .5711... ^,3535. Chen XQ, Zheng LX, Li ZY, Lin TY. Clinicopathological significance of oestrogen receptor expression in non-small cell lung cancer. J Int Med Res. 2017 ;45(1):51-8. https://doi.org/10.1177/0300060516666229
https://doi.org/10.1177/0300060516666229... Probably the lower circulating estradiol levels present in postmenopausal women compared to premenopausal, explain the differences in terms of OS, however it is important to conduct a prospective study where hormonal biochemical characteristics (e.g. circulating estrogen level, exogenous estrogen intake, expression of estrogen receptor and aromatase in tumor) can be evaluated.

On the other hand, hormonal status does not appear to influence EGFR mutational profile, since no differences were observed between premenopausal and postmenopausal women or by BMI, tobacco exposure, wood-smoke exposure, exposure to asbestos, histology, disease stage, ECOG performance status, sites of metastases and KRAS mutation status. Also no difference was observed in terms of the OS among EGFR-mutated women. Recently a functional relationship and a crosstalk between the estrogen and EGFR pathways in lung adenocarcinoma have been observed.³⁶36. Stabile LP, Lyker JS, Gubish CT, Zhang W, Grandis JR, Siegfried JM. 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(4):1459-70. https://doi.org/10.1158/0008-5472.CAN-04-1872
https://doi.org/10.1158/0008-5472.CAN-04... ^,3737. Giovannini M, Belli C, Villa E, Gregorc V. Estrogen receptor (ER) and epidermal growth factor receptor (EGFR) as targets for dual lung cancer therapy: not just a case? J Thorac Onco l. 2008 ;3(3):684-5. https://doi.org/10.1097/JTO.0b013e3181757aec
https://doi.org/10.1097/JTO.0b013e318175... NSCLC cells stimulated with estradiol resulted in EGFR pathway activation and EGFR activation also increased the expression and activity of the aromatase enzyme in NSCLC cells.¹⁴14. Rodriguez-Lara V, Hernandez-Martinez JM, Arrieta O. Influence of estrogen in non-small cell lung cancer and its clinical implications. J Thorac Dis. 2018;10(1):482-97. https://doi.org/10.21037/jtd.2017.12.61
https://doi.org/10.21037/jtd.2017.12.61... ^,3838. Marquez-Garban DC, Chen HW, Goodglick L, Fishbein MC, Pietras RJ. Targeting aromatase and estrogen signaling in human non-small cell lung cancer. Ann N Y Acad Sci. 2009 ;1155(1):194-205. https://doi.org/10.1111/j.1749-6632. 2009 .04116.x
https://doi.org/10.1111/j.1749-6632. 200... Although premenopausal women usually exhibit higher circulating estrogen level compared to postmenopausal women and men, it is probably that the level of estrogen in tumor microenvironment as well as the ER tumor expression are important factors to consider in terms of stimulating EGFR expression as previously reported.³⁸38. Marquez-Garban DC, Chen HW, Goodglick L, Fishbein MC, Pietras RJ. Targeting aromatase and estrogen signaling in human non-small cell lung cancer. Ann N Y Acad Sci. 2009 ;1155(1):194-205. https://doi.org/10.1111/j.1749-6632. 2009 .04116.x
https://doi.org/10.1111/j.1749-6632. 200... ^,3939. Nose N, Sugio K, Oyama T, Nozoe T, Uramoto H, Iwata T, et al. Association between estrogen receptor-beta expression and epidermal growth factor receptor mutation in the postoperative prognosis of adenocarcinoma of the lung. J Clin Oncol. 2009 ;27(3):411-7. https://doi.org/10.1200/JCO. 2008 .18.3251
https://doi.org/10.1200/JCO. 2008 .18.32... Accordingly, it is important to conduct a prospective study to evaluate the hormonal characteristics of each patient as well as hormone tumor status (aromatase and ER tumor expression, levels of estrogen in tumor microenvironment, etc.), in relation to EGRF expression, activity and mutation profile.

Finally, this study supports the differences by sex and also by hormonal status in lung cancer presentation and sustains the relevance that sexual hormones have in the course and prognosis of lung cancer, since women exhibited higher OS compared to men and premenopausal women showed a significantly lower OS compared to postmenopausal women. Due to the differences that lung cancer exhibited by sex and hormonal status it is important to consider not only women and men as it has previously been done, but also premenopausal and postmenopausal women in futures studies. Moreover the identification of hormonal markers in tumors from patients with lung adenocarcinoma would be relevant in order to design new treatment schemes based on anti-hormone therapy as has been recently proposed.⁴⁰40. Tang H, Liao Y, Zhang C, Chen G, Xu L, Liu Z, et al. Fulvestrant-mediated inhibition of estrogen receptor signaling slows lung cancer progression. Oncol Res. 2014;22(1):13-20. https://doi.org/10.3727/096504014X14077751730315
https://doi.org/10.3727/096504014X140777... ^,4141. Wen S, Fu X, Li G, He L, Zhao C, Hu X, et al. Efficacy of tamoxifen in combination with docetaxel in patients with advanced non-small-cell lung cancer pretreated with platinum-based chemotherapy. Anticancer Drugs. 2016;27(5):447-56. https://doi.org/10.1097/CAD.0000000000000350
https://doi.org/10.1097/CAD.000000000000... ^,4242. Rosell J, Nordenskjold B, Bengtsson NO, Fornander T, Hatschek T, Lindman H, et al. Long-term effects on the incidence of second primary cancers in a randomized trial of two and five years of adjuvant tamoxifen. Acta Oncol. 2017 ;56(4):614-7. https://doi.org/10.1080/0284186X.2016.1273547
https://doi.org/10.1080/0284186X.2016.12...

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