Our main finding was that never-smokers had better five-year survival rates than ever-smokers. This confirms the results of the other studies, which have shown survival benefits associated with a never-smoking status in NSCLC patients. Never-smoking status has been reported as an independent predictor of improved survival at five years (16% for current smokers, 23% for never-smokers),10
and a poorer survival outcome in patients with a history of smoking was described in a retrospective analysis.4
However, there is controversy regarding this finding in the current literature. Another study did not find differences in survival between NSCLC patients stratified according to their smoking status.11
In our study the presence of comorbidities did not differ between ever or never-smokers, although it has been described with tobacco-related disease. Conversely, in other studies the presence of comorbidities justified the worst survival among lung cancer patients.12
For a more comprehensive analysis, we performed a Cox proportional hazards regression adjusted for known prognostic factors. This multivariate analysis also confirmed that never-smokers exhibited a decreased risk of dying. As expected, early disease diagnosis, patient treatment and higher Karnofsky Performance Status scores were also favorable, independent predictors of survival. Interestingly, neither female gender nor having adenocarcinoma reached the specified significance level in the multivariate survival analyses, although both variables accounted for a significantly higher proportion of never-smoker patients in the univariate analysis.
Never-smokers constituted 24% of the NSCLC patients in our population. The literature supports the assertion that several characteristics are more commonly seen in NSCLC patients who are never-smokers. Our study found that women were more likely than men to have non-smoking-associated lung cancer (68%). The risk of developing lung cancer among women who smoke has been described as higher than that of men who are exposed to the same smoking rate.13-18
These results are still controversial, and the possibility that women have an increased susceptibility to the effects of smoking is not yet clearly defined. However, the predominance of females among never-smokers with tumors, even without exposure to cigarette smoke carcinogens, has been previously described, suggesting that aspects related to hormonal factors may interfere with tumor carcinogenesis.6,8,15
The role of estrogen in the carcinogenesis of other types of tumors in women is well established. Growing evidence indicates the effects of estrogen on lung cancer cells. The presence of estrogen receptors (ERs) in pulmonary tumor cells suggests that this hormone plays a role in the carcinogenesis of lung cancer.19-21
There are two main types of ERs in humans: ER-alpha and ER-beta. ER-beta receptors are the major mediators of estrogen activity in lung cells. They are active receptors in lung tissue and can contribute to the growth of neoplastic cells. Although the prevalence of ERs in tumor cells is similar in men and women, gender differences in survival exist.22,23
The mechanism underlying these sex-based differences is unclear, but genetic and metabolic factors, hormonal influences, and the presence of specific isoforms of ER-beta may be involved.
Another interesting finding is the predominance of adenocarcinoma among never-smoking patients, which is consistent with the results of previous studies.7,24,25
Although this histological variant is most commonly found in women, never-smoking men also showed a higher proportion of adenocarcinoma in our study, suggesting that a factor unrelated to sex is responsible for the predominance of adenocarcinomas in the never-smoking population. Several genetic alterations have been described that may contribute to the development of adenocarcinoma in nonsmokers. Two main pathways for the development of lung adenocarcinoma have been described: the KRAS and the epidermal growth factor receptor (EGFR)20
pathways. KRAS mutations are generally linked to tobacco consumption, and the EGFR pathway is generally associated with nonsmokers.26-28
Recent studies have indicated that patients with mutations in the EGFR gene respond better to treatment with EGFR tyrosine kinase inhibitors.29,30
Although KRAS mutations are historically considered to represent a tumorigenic pathway in smokers, their prevalence has been reported to be similar in smokers and nonsmokers; however, differences in mutation type have been reported.31
Though this is still controversial, molecular differences between groups may be responsible for distinct clinical manifestations and responses to treatment. As biomarkers may be used for risk stratification and treatment selection, new pathogenic pathways are being studied.32,33
In contrast to studies in Asian populations, we did not find differences in the age of diagnosis among never-smokers compared with ever-smokers.34
Our findings are consistent with the results of studies performed in Europe and the United States, where this disease occurs mainly in older adults. These differences may be explained by the hypothesis that indoor air pollutants, such as cooking fumes, play a role in lung carcinogenesis in developing countries, although there is some controversy surrounding this issue.35
Exposure to cooking fumes is common in Brazil; however, we lacked information regarding our participants' exposure levels to such fumes.
As lung cancer is considered a disease of smokers,36,37
never-smoker patients may experience either late presentation or late diagnosis on the part of physicians. The majority of our patients presented with the disease at later stages; however, when the group of never-smokers was analyzed for gender associations, we found that women were more likely than men to have lung cancer diagnosed at a more advanced stage. It is noteworthy that we did not find differences in extrathoracic disease between never-smokers and ever-smokers. Consequently, the clinical threshold for investigating symptomatic never-smokers must be lower.
The limitations of our study are related to the lack of information about passive smoking and cooking fume exposure as well as molecular analyses of the tumors. However, the epidemiological behavior of our never-smoker sample confirmed that even a racially varied population, as found in Brazil, follows the same model as that of never-smokers in other parts of the world.
In conclusion, the vast majority of never-smoker lung cancer patients were female and exhibited adenocarcinoma as the predominant histological type. Additionally, the female never-smoker patients showed a higher proportion of advanced disease, although the proportion with extrathoracic metastasis was similar to that of male never-smokers. Among NSCLC patients, after adjusting for age, female gender and adenocarcinoma, being a never-smoker with early treatment of the disease and having a higher Karnofsky Performance Status Scale were associated with a better prognosis. Lung cancer in never-smokers has a different clinical profile, with a distinctly lower mortality rate compared to lung cancer among smokers, which reflects a singular clinical behavior and natural history.