Juan Wisnivesky

M.D., DrPH

Icahn School of Medicine at Mount Sinai

Professor of Medicine

PLCO (Learn more about this study)

PLCO-460

Mar 25, 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. The literature is conflicting as to whether women have increased incidence of lung cancer compared to men after adjusting for smoking, but 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. From a mechanistic perspective, there have been published molecular reasons that support an increased lung cancer susceptibility in women, including increased hydrophobic DNA adduct formation and the effect of estrogen.

Apart from gender itself, it is intriguing to ponder what reproductive variables (menarche, menopause, parity) and exogenous estrogen (oral contraceptive pills OCPs, hormone replacement therapy HRT) may affect a woman’s risk for lung cancer. An analysis of the Women’s Health Initiative trial found that low parity and late menopause lowered lung cancer risk, while young age at first birth increased the risk. (1) Analysis of the Shanghai Women’s Health Study showed similar results regarding menopause, but found that higher parity was associated with a reduced risk of lung cancer. (2) An analysis of large cohort from Singapore also found that higher parity correlated with reduced risk of lung cancer, but found that age at menopause had no effect. (3) in contrast, a study of the NIH-AARP showed that parity had no association with lung cancer. (4) Thus publications in the literature are often conflicting, causing difficulty in reaching a consensus.

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

Specifically in the PLCO cohort, we intend to examine 1) if age at menarche, age at menopause (natural or surgical) and number of pregnancies are associated with lung cancer risk, and 2) whether this risk is associated with estrogen blockade via tamoxifen/raloxifene, or estrogen addition via OCPs/HRT.


References:
1. Schwartz, A. et al. Hormone Use, Reproductive History, and Risk of Lung Cancer: The Women’s Health Initiative Studies. J. Thorac. Oncol. Off. Publ. Int. Assoc. Study Lung Cancer 10, p1004 (2015).
2. Weiss, J. et al. Menstrual and reproductive factors in association with lung cancer in female lifetime nonsmokers. Am. J. Epidemiol. 168, p1319 (2008).
3. Seow, A., Koh, W., Wang, R., Lee, H.-P. & Yu, M. C. Reproductive variables, soy intake, and lung cancer risk among nonsmoking women in the Singapore Chinese Health Study. Cancer Epidemiol. Biomark. Prev. Publ. Am. Assoc. Cancer Res. Cosponsored Am. Soc. Prev. Oncol. 18, p821 (2009).
4. Brinton, L. et al. Reproductive and hormonal factors and lung cancer risk in the NIH-AARP Diet and Health Study cohort. Cancer Epidemiol. Biomark. Prev. Publ. Am. Assoc. Cancer Res. Cosponsored Am. Soc. Prev. Oncol. 20, p900 (2011)

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