Abstract 765: Tobacco smoke exposure, hormonal history, and estrogen metabolism in women with EGFR-mutant non-small cell lung cancer (NSCLC)
Authors: Raza Ahmad , Treat Joseph , Krzizike Daniel D. , Vanderveer Lisa , Cheung Mitchell , Zawislak Carolyn , Etkins Lisa , Ross Eric , Flieder Douglas B. , Edelman Martin J. , Clapper Margie L. , Bodor J Nicholas 
Published: March 2024

Abstract
Introduction: The factors responsible for NSCLC development in never-smokers remain unclear, thus hindering prevention efforts. Our group is one of the first in the U.S. to build a registry of never-smokers with NSCLC to facilitate research to address this global problem. Given the high prevalence of women among cases, we are investigating the contribution of estrogen metabolism to this disease. CYP1B1 converts parent estrogens to the putative carcinogen 4-hydroxyestrogen (4-OHE), a process further accelerated by tobacco smoke exposure. In contrast, CYP1A1 generates 2-hydroxyestrogen (2-OHE), which may be converted to anti-proliferative derivatives. We determined previously that women with EGFR-mutant NSCLC enrolled in the registry have a 2-fold higher ratio of 4-OHEs to 2-OHEs, as compared to cancer-free controls. While EGFR-mutant NSCLCs are typically thought to be diagnosed in never-smokers, prior data indicate that a fraction of patients report some smoking history. The goal of this current study is to determine the smoking prevalence among women with EGFR-mutant NSCLC in our registry and explore the impact of smoking and hormonal history on estrogen metabolism.
Methods: The Lung Cancer in Never-Smokers Risk Registry (LCNS-RR) is recruiting patients with NSCLC who are never-smokers (&lt;100 cigarettes/lifetime) and/or have tumors with oncogenes characteristically present in never-smokers (e.g., EGFR, ALK). In addition to donating biospecimens (e.g., blood, urine), participants complete a survey on tobacco and environmental exposures, hormonal history, and other factors. Using UPLC-MS/MS, profiles of urinary estrogens (E1, E2, E3, 4-OHE1, 4-OHE2, 2-OHE1, 2-OHE2) were determined for 32 women with EGFR-mutant NSCLC in the LCNS-RR. The proportion of each estrogen species over total estrogen and the ratio of 4-OHEs to 2-OHEs were calculated. Medians were compared using the Wilcoxon rank-sum test.
Results: Among women in this EGFR-mutant cohort, none were current smokers, 16 were former smokers, and 16 were never-smokers. Among the former smokers, median pack-years was 11.6. The ratio of 4-OHEs to 2-OHEs was comparable in former- vs. never-smokers (0.51 vs. 0.49, p-value = 0.956). Twenty-three women (71.8%) had a history of oral contraception use, and 5 (15.6%) reported early menarche (&lt;12 years of age). However, neither of these factors correlated with 4-OHE production. Among 28 post-menopausal women, 7 (25%) reported estrogen use since menopause, an exposure that was not associated with 4-OHE levels.
Conclusion: This preliminary analysis suggests that smoking history, use of hormones, or early menarche do not enhance the production of 4-OHEs in women with EGFR-mutant NSCLC. Recruitment to the LCNS-RR is ongoing and will facilitate future analyses in a larger cohort. (Supported by a Ride Hard Breathe Easy Innovation Award)
Citation Format: Ahmad Raza, Joseph Treat, Daniel D. Krzizike, Lisa Vanderveer, Mitchell Cheung, Carolyn Zawislak, Lisa Etkins, Eric Ross, Douglas B. Flieder, Martin J. Edelman, Margie L. Clapper, J Nicholas Bodor. Tobacco smoke exposure, hormonal history, and estrogen metabolism in women with EGFR-mutant non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 765.