Abstract 2696: Catechol estrogen profiles of patients with EGFR- and ALK-positive non-small cell lung cancer (NSCLC)

Abstract Prior research from this group indicates that the human lung extensively metabolizes parent estrogens to reactive catechols. Estrone (E1) and estradiol (E2) are converted to the putative carcinogens, 4-hydroxyestrone (4-OHE1) and 4-hydroxyestradiol (4-OHE2), by cytochrome P450 1B1 (CYP1B1). In contrast, CYP1A1 metabolizes parent estrogens to 2-OHE1 and 2-OHE2, which may ultimately be converted to anti-proliferative derivatives. Our previous data strongly indicate that 4-OHEs contribute to lung tumorigenesis. However, their role in oncogene-driven NSCLC has not been investigated. The goal of this study was to compare the urinary profile of catechol estrogens in patients with EGFR- and ALK-positive NSCLC with those of cancer-free controls. The resulting levels of estrogen derivatives were correlated with genotypic variants in the estrogen metabolizing enzymes CYP1B1 and COMT. Patients with EGFR- and ALK-mutated NSCLC were recruited from the recently established Never-Smokers Lung Cancer Clinic at our institution. Study participants were 50 years of age or older to circumvent any confounding impact of pre-menopausal status on estrogen profiles. Mutation status was determined from tumor tissue biopsies. Cancer-free control subjects were Caucasian post-menopausal women with no prior smoking history. To date, 34 patients with tumors possessing EGFR mutations, 10 patients with ALK mutations, and 17 cancer-free control subjects have been enrolled. Urine specimens were collected from all participants and urinary estrogen species (E1, E2, E3, 4-OHE1, 4-OHE2, 2-OHE1, 2-OHE2, 16α-OHE1, 2-OME1, 4-OME1, OME2) were quantified using a newly established UPLC-MS/MS method. Blood lymphocytes, collected from NSCLC subjects, were genotyped for SNPs in CYP1B1 (L432V/rs1056836, R48G/rs10012, N453S/rs1800440) and COMT (V158M/rs4680) by real-time PCR. Preliminary investigation of the E1 metabolic pathway suggests a trend of higher ratios of 4-OHE1 to 2-OHE1 in patients with EGFR- and ALK-positive NSCLC as compared to cancer-free controls. Among NSCLC subjects, those possessing the high activity Leu432 variant of CYP1B1 (Leu/Leu + Leu/Val) tended to have higher ratios of 4-OHE1 to 2-OHE1 as compared to patients with the low activity Val/Val genotype. Early findings suggest enhanced production of C4 estrogen derivates may contribute to the development of oncogene-driven lung tumors. Targeting CYP1B1 may be of preventive and therapeutic interest. Recruitment of study participants is ongoing to validate these early findings in a larger cohort. (Supported by an In Vino Vita Award from Fox Chase Cancer Center) Citation Format: J. Nicholas Bodor, Joseph Treat, Daniel D. Krzizike, Carolyn L. Zawislak, Lisa Vanderveer, Sarah Eidbo, Eric A. Ross, Martin J. Edelman, Andrew J. Andrews, Margie L. Clapper. Catechol estrogen profiles of patients with EGFR- and ALK-positive non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2696.