Gender Disparity in Lung Cancer

Lung cancer is a significant global health challenge because of its prevalence, high mortality rate, and underlying gender disparities. It is the leading cause of cancer-related death in many countries, with most cases diagnosed at advanced stages.1 Interestingly, gender-based differences in lung cancer incidence have emerged during the past few decades. Historically, lung cancer predominantly affected men, with a higher overall lifetime risk of developing lung cancer compared to women.1 However, recent epidemiological data underscore a concerning trend worldwide: women are increasingly bearing a disproportionate burden of lung cancer incidence and mortality. Multiple factors, some uniquely affecting women, contribute to this gender disparity and warrant attention to implement tailored interventions to further minimize the gender gap.

Understanding the Gender Disparity in Lung Cancer

Differences in lung cancer incidence between men and women arise from the complex interplay of biological, environmental, and sociocultural factors. Variables such as genetics, hormones, and pre-existing medical conditions suggest lung cancer is a biologically different disease in women, particularly in the population of women who have never smoked tobacco.2

For example, germline mutations in tumor suppressor genes such as TP53, DNA repair pathway genes such as BRCA1, BRCA2, and cytochrome p450 are most correlated with  early onset lung adenocarcinoma in young women who never smoked.3 Driver mutations for lung cancer, specifically EGFR, ALK, and KRAS, are more common in women regardless of cigarette smoking status.4 In one study population, KRAS G12C-associated lung cancers occurred more frequently in women who had objectively smoked fewer cigarettes than  men in the same population.5

Studies have also demonstrated the effects of estrogen and progesterone on lung cancer. In one large study of 16,000 women, higher mortality rates from lung cancer were noted in patients receiving hormone replacement therapy (0.11%) compared to placebo (0.06%).6 This was attributed to increased lung carcinogenesis through free radical production or increased cancer cell proliferation and invasion after endogenous exposure to or exogenous use of estrogen.7 Female patients with prior lung disease, such as COPD, were two times more likely than men to develop lung cancer.8 Infection with HPV16/18 may also contribute to increased risk of lung cancer, particularly for Asian women who do not smoke.2

Environmental exposures such as air pollution increase lung cancer risk. Women are more commonly exposed to indoor gases such as coal and radon—both of which are associated with lung cancer pathogenesis—while performing household chores such as cooking. This is even more pronounced among socioeconomic classes and cultures that emphasize women in more domesticated roles.9 Asbestos is a common occupational hazard found in textile mills that predominantly affected men’s risk in developing lung cancer; however one meta-analysis suggests women are at a higher risk of developing lung cancer from non-occupational exposures to asbestos.10 Radiation exposure from breast cancer therapy is also associated with a higher incidence of lung cancer in the ipsilateral lung and overall incidence in the general population.11

Tobacco is the most influential factor in the development of lung cancer, regardless of gender. Tobacco use through cigarettes increased in the mid 1900s. In the US, for example, smoking rates in men increased during World Wars I and II, while women began smoking at higher rates after the wars.12 The decline in smoking rates for women started in the late 1960s, after that of men, and therefore lung cancer incidence peaked later for women. Though both lung cancer and smoking rates are declining for both genders worldwide, the decline has been slower for women.13

Some evidence suggests that women are more sensitive to the effects of tobacco. For example, from a molecular standpoint, one study indicated that females who smoke have higher levels of CYP enzymes, which then break down hormones and smoke-derived compounds into carcinogenic compounds.14 In addition, secondhand smoke exposure, another risk factor for lung cancer, has been shown to have a greater impact on women.15

Gender-specific health behaviors also influence the incidence of lung cancer and the effects on individuals after a cancer diagnosis. Women are more likely to delay seeking healthcare than men due to their increased involvement in childcare needs and domestic tasks at home as well as economic constraints imparted by lower-paying occupations.16 Delays in diagnosis may lead to more advanced stage of lung cancer or worsening clinical condition at the time of diagnosis. Some studies have also shown a lower rate of smoking cessation among women due to anxiety- as well as depression-induced increase in cigarette smoking.17

Concern about fertility and ovarian function disproportionately affects women with lung cancer. Studies have shown that immunotherapies can decrease ovarian follicular reserve and increase peripartum complications such as premature delivery or stillbirth.18 Discussing fertility-preservation techniques appropriately will help mitigate stress regarding lung cancer treatment and encourage participation in clinical trials. Other aspects of survivorship include highly prevalent immunotherapy-induced sexual dysfunction in women, up to 77%.19Providers often fail to discuss sexual health with patients and when they do, they discuss it more with men than women.20 These differences can affect the trust women have in future treatment recommendations and their overall participation in healthcare decisions.

Gender-Specific Trends in Lung Cancer Incidence and Mortality

Over the years, significant differences have emerged in the incidence of lung cancer between men and women. In the last two decades, males had an overall higher age-adjusted incidence rate of lung cancer, though the incidence rate has  decreased more quickly for men than for women.21 Another study indicated  that males had a continuous decline in the incidence of lung cancer from 1986 to 2015 while the incidence increased from 1988 to 2006 and then decreased slowly from 2007 to 2015 in women.22 The decrease in incidence rate for women has slowed in recent years.21 Compared to men, women are also more likely to be diagnosed with adenocarcinoma, to be younger in age, and to have never smoked.13

Mortality from lung cancer remains the highest among all cancers worldwide.2 Recent studies have revealed differences in survival outcomes between genders. Generally, women diagnosed with lung cancer have slightly higher survival rates compared to men, though they present at more advanced stages of disease at the time of diagnosis.17 Several factors may contribute to these emerging survival patterns, including differences in tumor biology discussed above as well as treatment response and utilization.17 Women are more likely to undergo surgical resection compared to men, largely due to better overall state of health at time of diagnosis.17

Disparities in Lung Cancer Screening and Clinical Trial Representation

In one study, women were 32% less likely to discuss lung cancer screening with their doctor. Of all these women, non-Hispanic Black women were least aware of lung cancer screening tests, such as a low-dose CT scan.23 Regarding representation in clinical trials, within a composite of 269 NSCLC trials, women were underrepresented and comprised only 38.7% of all participants. Barriers to enrollment in clinical trials include lack of awareness of trials, distrust of healthcare institutions, and fear of decrease in quality of life after the trial.24 Female-specific factors due to increased household duties include time and financial cost associated with travel and being away from family.2

Nevertheless, awareness and encouragement of screening for lung cancer with low-dose CT scans is imperative, particularly in women who have had lower screening rates. The NELSON trial demonstrated a lower cumulative mortality rate from lung cancer for women (0.67) who were screened with a CT scan compared to that of men (0.76).26 A more unified screening program would benefit the overall lung cancer population, particularly women.15 As breast cancer and bone density screening have higher utilization, health systems should encourage healthcare practitioners to screen simultaneously with mammogram, DEXA scan, and low-dose CT scan.27

Future Directions

The increased burden of lung cancer on women underscores the necessity for gender-sensitive approaches in healthcare policy, research, and clinical practice. Neglecting this issue not only perpetuates health disparities but also fails to address societal norms surrounding women’s health behaviors and relative inaccessibility to healthcare women face. As healthcare providers and researchers, understanding historical themes and raising awareness through public campaigns is a step in the right direction to rectify differences in lung cancer care.

References

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