Juan Wisnivesky

M.D., DrPH

Icahn School of Medicine at Mount Sinai

Professor of Medicine

NLST (Learn more about this study)

NLST-487

Mar 6, 2019

Gender-specific susceptibility and hormonal influence on lung cancer incidence

Identifying populations at increased risk of lung cancer has been a key endeavor of epidemiologic initiatives, in order to better target and utilize screening strategies. A key analysis of the International Early Lung Cancer Action Program (IELCAP) (1) showed that women, even after adjusting for age and smoking, had an increased odds of developing lung cancer, but had lower odds of a fatal outcome. Contrary to IELCAP, an analysis of the NIH-AARP Diet and Health study showed that except for never-smokers (among whom, women had a higher lung cancer incidence than men) there was no association between gender and the development of lung cancer.(2) Apart from these US studies, many international studies have shown conflicting results and thus a high amount of uncertainty exists in the literature; debate is still ongoing as to whether women have an increased incidence of and susceptibility to lung cancer. Nevertheless, multiple recent epidemiologic studies have shown that incidence rates for lung cancer are decreasing more slowly in women, and higher incidence rates of adenocarcinoma have now emerged in women. (3) A recent study published in the NEJM also showed that the historical rates of higher lung cancer incidence among men than women have reversed in non-Hispanic whites and Hispanics born since 1960s, and this is not fully explained by gender differences in smoking.(4) From a mechanistic perspective, there have been many published molecular reasons that support an increased lung cancer susceptibility in women, including increased hydrophobic DNA adduct formation and the effect of estrogen.

We intend to perform a 2-cohort project – involving the NLST and PLCO cohorts; PLCO analysis details to be reported separately – to further look into the relationship of female gender, female specific reproductive variables (such as age at menarche and menopause, parity, exogenous hormone use) and the incidence of lung cancer.

Specifically in the NLST cohort, we will examine 1) whether gender is an independent risk factor for lung cancer after adjusting for smoking and other known confounders (using Cox regression), 2) whether age modifies the above relationship (using an interaction variable), and 3) determine if adipose-produced estrogen (estimated by BMI) which is a principal source of estrogen in postmenopausal women affects lung cancer incidence.

References:
1. International Early Lung Cancer Action Program Investigators, Henschke, C. I., Yip, R. & Miettinen, O. S. Women’s susceptibility to tobacco carcinogens and survival after diagnosis of lung cancer. JAMA 296, 180–184 (2006).
2. Freedman, N. D., Leitzmann, M. F., Hollenbeck, A. R., Schatzkin, A. & Abnet, C. C. Cigarette smoking and subsequent risk of lung cancer in men and women: analysis of a prospective cohort study. Lancet Oncol. 9, 649–656 (2008).
3. Lewis, D. R., Check, D. P., Caporaso, N. E., Travis, W. D. & Devesa, S. S. US lung cancer trends by histologic type. Cancer 120, 2883–2892 (2014).
4. Jemal, A. et al. Higher Lung Cancer Incidence in Young Women Than Young Men in the United States. N. Engl. J. Med. 378, 1999–2009 (2018).

Specific aims encompass both the NLST and PLCO cohorts, even though this is the NLST application only.

1. Determine if in the NLST (National Lung Screening Trial) and PLCO (Prostate, Lung, Colon, and Ovarian Cancer Screening trial) cohorts of the NIH, the incidence of lung cancer is greater in women smokers compared to men smokers, after adjusting for extent of smoking and age. In the PLCO cohort only, perform additional separate analyses that include only i) never-smokers or ii) ever-smokers.

2. Determine if age modifies the gender-lung cancer association (eg: younger women have more susceptibility than men, but older women do not).

3. Determine if the menstruating period duration (including age at menarche and menopause), a period of higher exposure to estrogen/progesterone, and/or the number of pregnancies is associated with lung cancer incidence

4. Determine if estrogen in postmenopausal women, principally determined by adipose tissue and thus obesity/body mass index (BMI), affects lung cancer incidence

5. Determine if estrogen blockade via tamoxifen/raloxifene, or estrogen addition via oral contraceptive pills (OCP) or hormone replacement therapy (HRT), is associated with lung cancer incidence in women