Sex Differences in Lung Cancer Not Caused by Active Smoking
Even as the evidence coalesces around the absence of a smoking-by-sex interaction, greater interest in the broader question of a potential sex difference in the etiology of lung cancer is emerging. Among never smokers of cigarettes, men would be expected to have higher lung cancer rates than women based on the fact that typically the prevalence of exposure to lung carcinogens other than active cigarette smoking is higher in men than in women, largely because of occupational exposures. It is thus surprising that lung cancer incidence rates among never smokers appear to be greater in women than in men. In 3 cohort studies that included both sexes, lung cancer incidence rates among never smokers were 51%–200% greater in women than in men. In data from 35 cohort and cancer registry studies conducted worldwide, among never smokers lung cancer incidence rates were 15% greater in females than in males. If this is true, among never smokers, the greater observed lung cancer incidence rates in women than in men despite women's ostensibly lower risk profile raises the hypothesis that women may be more susceptible than men to lung malignancy that is not caused by active smoking.
A potential role of hormones in the etiology of lung cancer has emerged from varied lines of evidence. Estrogen has been observed to promote the growth of lung cancer cells. Estrogen receptor β is expressed in the majority of non-small-cell lung carcinoma cell lines. In women, a significantly increased risk of lung cancer (RR = 1.4, 95% CI: 1.03, 1.8) was observed in a meta-analysis of results from 2 large-scale randomized controlled trials of hormonal therapy that included an estrogen-plus-progestin formulation. The lung cancer risk associated with hormonal therapy may be specific to estrogen-plus-progestin formulations, since the results from 1 randomized trial were null for estrogen-only formulations. In a prospective cohort study, increased lung cancer risk was observed for estrogen-plus-progestin formulations, with null results for estrogen-only formulations, but when viewed as a whole, the heterogeneous results of observational studies do not lend themselves to such a clear-cut interpretation. Among lung cancer patients, use of hormone replacement therapy has been consistently associated with disease progression.