A20 Estrogen Metabolism in Patients with EGFR-Mutated and ALK-Mutated Non-Small Cell Lung Cancer (NSCLC)

Prior studies have shown that the human lung can extensively metabolize estrogen to reactive catechols. Of greatest concern is 4-hydroxyestrogen (4-OHE), a putative carcinogen, produced by cytochrome P450 1B1 (CYP1B1). In contrast, CYP1A1 metabolizes parent estrogens to 2-hydroxyestrogen (2-OHE), which are less reactive and converted to derivatives that may be antiproliferative. Data from this group strongly suggest that 4-OHE contributes to lung tumorigenesis, though its role in driver-mutated NSCLC has not been investigated. This study assessed estrogen metabolite profiles in EGFR-mutated and ALK-mutated NSCLC patients as compared to cancer-free subjects. Advanced-stage NSCLC patients with tumors that possessed either an EGFR (n = 14) or ALK (n = 8) mutation and cancer-free subjects (n = 17) were recruited from Fox Chase Cancer Center. Tumor mutation status of NSCLC patients was determined by tissue biopsy. All study participants were 50 years of age or older to circumvent any confounding influence of young age or premenopausal status on estrogen levels. NSCLC patients included 14 females and 8 males. Cancer-free subjects serving as controls were never-smoking women. Urine specimens were collected from study participants and urinary estrogen species (E1, E2, E3, 4-OHEs, 2-OHEs, 2-OMEs) were quantified using UPLC-MS/MS. Medians were calculated and the Wilcoxon rank-sum test was used to compare estrogen metabolite measures (4-OHEs/total estrogen, 2-OHE/total estrogen, and the ratio of 4-OHEs/2-OHEs) between NSCLC patients and control subjects. EGFR-mutated NSCLC patients had a significantly higher proportion of 4-OHEs/total estrogen (0.18 vs. 0.05, p-value = 0.048) and a trend towards lower 2-OHEs/total estrogen (0.18 vs. 0.26, p-value = 0.084) as compared to cancer-free control subjects. The ratio of 4-OHEs/2-OHEs was higher in EGFR-mutated NSCLC patients as compared to cancer-free controls (0.90 vs. 0.16, p = 0.053). Differences were not seen between ALK-mutated NSCLC patients and cancer-free subjects for the measures of 4-OHE/total estrogen (0.09 vs. 0.05, p-value = 0.842), 2-OHE/total estrogen (0.20 vs. 0.26, p-value = 0.238), and the ratio of 4-OHEs/2-OHEs (0.34 vs. 0.16, p-value = 0.669). The greater relative level of 4-OHE to 2-OHE in EGFR-mutated NSCLC patients suggests that enhanced production of 4-OHE may contribute to the development of EGFR-mutated lung tumors. Targeting CYP1B1, the enzyme responsible for 4-OHE production, may be of therapeutic interest. Research is ongoing to validate these findings in a larger cohort of EGFR-mutated NSCLC patients.