Abstract 757: 17β-hydroxysteroid dehydrogenases 1 and 2: potential markers for breast cancer recurrence and tamoxifen resistance among premenopausal women diagnosed with breast cancer in Denmark

Abstract Background: Breast cancer is the most commonly diagnosed malignancy among women worldwide. Despite high survival rates, 20%-40% of women will experience a recurrence, with risks extending beyond 20 years after diagnosis. Premenopausal women diagnosed with estrogen receptor (ER) positive disease are prescribed 5-10 years of tamoxifen therapy to prevent a recurrence. 17β-hydroxysteroid dehydrogenase 1 and 2 expression (HSD17B1 and HSD17B2, respectively) regulate the relative concentrations of estrogen metabolites and may modify tamoxifen effectiveness. We evaluated the prognostic and predictive value of these biomarkers. Methods: Premenopausal women diagnosed during 2002-2011 with a first primary stage I-III breast cancer were identified in the Danish Breast Cancer Group database, and categorized based on ER status and receipt of tamoxifen (4600 ER+/TAM+ and 1359 ER−/TAM−). HSD17B1 and HSD17B2 were assayed by immunohistochemistry and scored using automated image analysis [Visiopharm (Hoersholm, Denmark)]. The biomarkers were assessed within ER/TAM strata, to differentiate the enzymes predictive of treatment response from enzymes prognostic for breast cancer recurrence. We used Cox proportional hazards regression and probabilistic bias analysis to account for mismeasurement of biomarker expression and baseline selection bias from tumor sample availability to calculate the hazard ratios (HRs) and 95% simulation intervals (SIs) associating each biomarker with recurrence. Results: 24% of ER+/TAM+ and 13% of ER−/TAM− breast cancers had any HSD17B1 expression. In the bias-adjusted analyses, women diagnosed with tumors positive for HSD17B1 expression had an increased rate of recurrence: HR=1.40 (95% SI: 1.02, 2.92) in the ER+/TAM+ stratum, and HR=1.32 (95% SI: 0.82, 2.74) in the ER−/TAM− stratum. A 10-unit increase in HSD17B2 expression corresponded with a decreased recurrence rate among women in the ER+/TAM+ (HR=0.85, 95% SI: 0.69, 1.05) stratum, but not among women in the ER−/TAM− stratum (HR=1.07, 95% SI: 0.82, 1.42). Conclusions: We observed that HSD17B1 expression was associated with a higher rate of recurrence among premenopausal women, and that HSD17B2 expression was associated with a lower rate of recurrence among premenopausal tamoxifen-treated women diagnosed with ER+ disease. HSD17B1 may be an important prognostic marker of breast cancer recurrence among premenopausal breast cancer patients and HSD17B2 may be predictive of response among tamoxifen-treated premenopausal women diagnosed with ER+ breast cancer. Citation Format: Lindsay Jane Collin, Anders Kjærsgaard, Thomas P. Ahern, Michael Goodman, Lauren E. McCullough, Lance A. Waller, Kristina B. Christensen, Per Damkier, Stephen J. Hamilton-Dutoit, Kristina Lauridsen, Peer M. Chistiansen, Bent Ejlertsen, Henrik Toft Sørensen, Deirdre Cronin-Fenton, Timothy L. Lash. 17β-hydroxysteroid dehydrogenases 1 and 2: potential markers for breast cancer recurrence and tamoxifen resistance among premenopausal women diagnosed with breast cancer in Denmark [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 757.