Understanding Sex Disparities in Lung Cancer Incidence: are Women more at Risk?

Abstract

Keywords: adenocarcinoma • lung cancer epidemiology • lung cancer incidence • never-smokers • risk factors • lung cancer development • women Sex-based differences in global lung cancer incidence have dramatically shifted over the past 50 years. This is particularly evident in the western world, including in the USA, where women now have an increased risk relative to men of developing lung cancer, despite a decreasing incidence of lung cancer overall among both groups [1-5]. Sex-based disparities in lung cancer incidence are characterized primarily by rising rates of adenocarcinoma and are particularly magnified among younger women and never-smokers, two increasingly at-risk populations who we notably do not currently have screening guidelines for [4-7]. There are a number of endogenous and exogenous factors that may uniquely contribute to a woman's risk of developing lung cancer, suggesting that lung cancer may be increasingly characterized as a truly distinct disease process in women compared with men [1,8,9]. Further exploration of these sex-based differences will be of monumental importance, as we refine our risk stratification and screening processes to reflect the changing demographics of the lung cancer population. Changes in smoking habits, particularly in the last part of the 20th century, are partly responsible for the shifting demographics in lung cancer incidence. In the USA, for example, women did not begin smoking at high rates until after World War II, and therefore the decline in smoking rates that started in the late 1960s was delayed and much slower for women compared with men [10]. Lung cancer incidence thus peaked later for women (early 2000s) compared with men (1980s), and is now declining, but at a slower rate [9]. In contrast, in many developing nations where smoking rates are declining among men, they alarmingly continue to rise among women [3]. Despite these trends, the majority of women diagnosed with lung cancer globally today are still smokers and thus public health initiatives to address smoking behavior, particularly in women, are of ongoing importance [9]. From the early 1990s to present day, many have questioned whether women may be more susceptible to the carcinogens in tobacco than men and therefore at a higher risk of developing lung cancer at similar levels of exposure. A few large prospective cohort studies have not shown this to be the case [8,10,11]. However, some speculation remains as to whether women who smoke may harbor a different genetic profile than men who smoke that could predispose them to the development of lung cancer. For example, women who smoke have a higher frequency of a point mutation in the TP53 gene compared with women who do not smoke, a finding which does not apply to men [12]. Women also are more likely to have mutations in the GSTM1 gene, which normally functions to inactivate toxic metabolites and has been linked to the development of lung cancer in smokers [1,12]. Although variations in smoking patterns between sexes may explain the smoking-associated sex-based lung cancer incidence disparities particularly in western countries, it does not explain the disparities in the never-smoker population, for whom there are clearly additional factors at play.