Abstract 6491: Temporal changes in circulating sex hormones and aromatase activity and associations with lung cancer survival in postmenopausal women
Authors: Zhao Yingya , Shu Xiao-Ou , Gao Yu-Tang , Kushnir Mark M. , Cai Qiuyin , Cai Hui , Lan Qing , Rothman Nathaniel , Zheng Wei , Yang Gong 
Published: April 2023

Background: Exogenous sex hormone supplements had been associated with increased lung cancer mortality in a large clinical trial. No study to date has evaluated temporal trajectories of circulating sex hormones and aromatase activity and their associations with lung cancer survival.

Objective: To characterize temporal changes in prediagnostic levels of circulating sex hormones and aromatase activity and to evaluate their associations with overall survival in lung cancer patients.

Methods: Included in the analysis were 385 incident lung cancer patients identified in a large prospective cohort among postmenopausal women who had never used cigarette products nor exogenous sex hormone supplements. Concentrations of sex hormones were quantitated using LC-MS/MS assays in prediagnostic plasma samples. The product-substrate molar ratio of estrone to androstenedione was used as an index of aromatase activity (IAA). A multivariable Cox model with restricted cubic spline functions was used to calculate hazard ratio (HR) for overall survival.

Results: Of 385 patients with lung cancer, 308 died during a median follow-up of 18.1 years. Initial analyses in all patients showed that higher levels of circulating estrone and IAA and lower levels of androstenedione and testosterone were associated with poorer overall survival after adjusting for nonclinical covariates. In analyses restricted to those with clinical data (n=281), stronger associations were found after further adjustment for tumor stage and treatment regimens. Compared with patients at the median level of IAA, adjusted HRs (95% CI) for total mortality in those at the 30th, 70th, 90th and 95th percentiles were 0.98 (0.84-1.13), 1.05 (0.94-1.16), 1.28 (1.06-1.54), and 1.64 (1.27-2.12), respectively, with P-overall &lt; 0.001. A similar positive association was observed for estrone. In contrast, inverse associations were seen for androgens. For example, compared with the median level of testosterone, HRs (95% CI) for those at the 5th, 10th, 30th, 70th percentiles were 2.10 (1.43-3.09), 1.69 (1.29-2.23), 1.45 (1.19-1.76), and 0.86 (0.78-0.94), respectively, with P-overall = 0.001. Further, we found that circulating levels of sex hormones changed during disease progression. The closer the hormone measurement to cancer diagnosis the higher the IAA and estrone levels (P-overall &lt; 0.001 for both), and the temporal change plateaued 10 years before cancer diagnosis (P-nonlinearity &lt; 0.001 for both). An opposite temporal pattern was found for testosterone. Moreover, the significant association between sex hormones and lung cancer survival was only observed when sex hormones were measured within 10 years before diagnosis.

Conclusions: Findings from our study, for the first time, demonstrate temporal changes in circulating sex hormones and their associations with lung cancer survival in postmenopausal women.

Citation Format: Yingya Zhao, Xiao-Ou Shu, Yu-Tang Gao, Mark M. Kushnir, Qiuyin Cai, Hui Cai, Qing Lan, Nathaniel Rothman, Wei Zheng, Gong Yang. Temporal changes in circulating sex hormones and aromatase activity and associations with lung cancer survival in postmenopausal women. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6491.