Sex Differences in Lung Cancer

Abstract

Sex disparities in the incidence and mortality of lung cancer have been observed since cancer statistics have been recorded. Social and economic differences contribute to sex disparities in lung cancer incidence and mortality, but evidence suggests that there are also underlying biological differences that contribute to the disparity. This review summarizes biological differences which could contribute to the sex disparity. Sex hormones and other biologically active molecules, tumor cell genetic differences, and differences in the immune system and its response to lung cancer are highlighted. How some of these differences contribute to disparities in the response to therapies, including cytotoxic, targeted, and immuno-therapies, is also discussed. We end the study with a discussion of our perceived future directions to identify the key biological differences which could contribute to sex disparities in lung cancer and how these differences could be therapeutically leveraged to personalize lung cancer treatment to the individual sexes.

Keywords: androgen; cancer immunology; estrogen; non-small cell lung cancer; progesterone; sex difference; smoking.

Figure 1

Sex differences in lung cancer growth and treatment. (A) There are distinct differences in lung cancer biology between men and women. Men have an overall increase in mortality from lung cancer and an increase in tumor grade at diagnosis compared to women. Due to increases in mutations in the EGFR pathway, women have a better response to EGFR inhibitors than men. Women also have a better response to chemotherapies compared to men, while men have a better response to immunotherapies compared to women. Some of these differences could be due to sex hormones. Estrogens can improve some aspects of the immune response to cancer; however, they can also promote tumor growth. Conversely, androgens suppress the T cell response, possibly contributing to lung cancer in men. (B) Several sex-relevant considerations must be accounted for when completing lung cancer clinical trials. These sex-relevant variables can impact treatment outcomes as described in this review. These include a sex-specific mutation status for tumors from men vs. women, the hormone status of both males and females, the inherent differences in therapy outcomes due to sex hormones, and any impacts which could result from gender affirmation therapies. (C) Estrogen is the best characterized sex hormone. It has several roles in both promoting and inhibiting lung cancer. Estrogens are a mitogen which promote (red arrow) the cell autonomous proliferation of lung cancer cells, a pro-cancer effect. Estrogens also enhance (green arrow) the cell autonomous response of cancer cells to cytotoxic chemotherapies. Lastly, there is significant literature that shows that the anti-tumor immune response is modulated by estrogen (green arrow), which could explain why women have a lower incidence and mortality for many cancers, not just lung cancer. Figure was created using Biorender.