Ross, Jeff

Abstract Objective: The established link between estrogen and breast cancer occurs via both estrogen receptor (ER)-mediated and non ER-mediated mechanisms. The term genotoxic estrogens describes mutagenic metabolites, including estrogen catechols and quinones, which have been linked to breast carcinogenesis in post-menopausal women. Recent data showed that childhood obesity is associated with significantly higher levels of genotoxic estrogens in the blood compared with lean children, raising the possibility of a potential pathogenic roles of these metabolites in breast cancer starting even prior to the onset of puberty (Mauras et al: J Clin Endocrinol Metab. 100:2322, 2015). A finding of higher levels of genotoxic estrogens associated with oral estradiol may have breast cancer prevention implications.We hence aimed to assess if the route of administration of 17β estradiol (E2) affects the accumulation of genotoxic estrogen metabolites in a model of ovarian failure in young girls with Turner Syndrome. Methods: Stored plasma were used from 40 adolescents with Turner's who participated in a previous 12 months randomized controlled trial of the metabolic impact of E2 orally (2mg/d) vs. transdermally (100μg/d). The doses of oral and transdermal E2 were determined to result in similar plasma levels of unconjugated E2. Previously we had reported that despite the similar plasma levels of unconjugated E2, the oral E2 administration route was associated with higher levels of biologically active estrogen activity than the transdermal route (Torres-Santiago L et al:J Clin Endocrinol Metab. 98:2716, 2013). In this study, we measured 12 estrogen metabolites (conjugated and unconjugated) using a highly sensitive LCMSMS assay. Results from 48 normally menstruating adolescents were used for comparison. Results: After treatment, least square mean (SE) total (conjugated plus unconjugated) E2 and estrone (E1) concentrations were higher in the oral vs. transdermal group (p<0·0001), as were catechol-estrogens 4-OH-E2 (149 vs. 28 (49) pmol/L), 2-OH-E2 (300 vs 76 (52)), 4-OH-E1 (450 vs 105 (113)), 2-OH-E1 (304 vs 740 (684)) and 16α-OH-E1 (3007 vs 157 (534)) (<0·001 between groups). Levels were much closer to controls in the transdermal group. Conclusions: Common feminizing doses of oral estradiol for 12 months result in greater accumulation of unphysiologic, genotoxic estrogens than transdermal estradiol, expanding concerns about oral estrogens' first hepatic passage contributing to the accumulation of these metabolites. These metabolites have the potential for inducing breast cancer in post-menopausal women. These results suggest the potential benefit of preferential use of transdermal versus oral estrogens as replacement and possibly contraceptive options, in the prevention of breast cancer. Further studies to assess long-term risks of these metabolites in women taking different forms of estrogen replacement are needed. Citation Format: Colon-Otero G, Torres-Santiago L, Santen R, Mericq V, Ross J, Damaso L, Hossain J, Wang Q, Mesaros C, Blair IA, Mauras N. Impact of route of administration of estradiol (oral vs. transdermal) on genotoxic estrogens concentrations in girls with ovarian failure due to Turner syndrome: Potential implications for breast cancer prevention [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-14.

Abstract OBJECTIVES: Mutations in ESR1 that are acquired following treatment with aromatase inhibitors commonly underlie resistance to endocrine therapy in breast cancer. ERa-LBD mutations, especially at ESR1 Y537 and D538, confer constitutive activity and partial resistance to selective estrogen receptor modulators (SERMs), such as tamoxifen, and degraders (SERDs) such as fulvestrant in transcription assays. Some ovarian tumors also respond to anti-hormone therapy, and a subset which initially respond subsequently become resistant. The mechanisms of resistance to hormone therapy in ovarian cancer have not been previously described. Comprehensive genomic profiling (CGP) of ovarian tumors was used to analyze ESR1 and correlate responsiveness to aromatase inhibitors in a subset of these patients. METHODS: DNA was extracted from tumor specimens and sequenced using hybridization-capture (FoundationOne) targeting up to 315 genes, plus select introns frequently rearranged in cancer. Demographic and clinicopathologic data will be presented for a subset of patients whose tumors harbor ERa-LBD mutations associated with activation and resistance.. RESULTS: CGP of 3,641 ovarian and peritoneal carcinomas revealed 31 (0.9%) samples with amplification of ESR1 and 16 (0.4%) samples with acquired or de novo mutations affecting the ERa-LBD: Y537S (10), Y537N (1), D638G (4), and S341L (1). Within the 16 samples, ovarian serous carcinoma (10), ovarian endometrioid adenocarcinoma (3), ovarian epithelial carcinoma NOS (2), and peritoneal serous carcinoma (1) were represented. In cases of acquired mutations following prior hormone therapy, there was evidence of clinical benefit to SERM/SERDs. CaseAgeDiseaseESR1 MutationPrior HRTAcquiredSERM/SERD (*post mut if acquired)Clinical Benefit SERM/SERD159Ov serousY537SYYNN/A258Papillary serousY537NNNYY344Endometrioid ov adenoY537SNNYY445HG ov serousD538GNUYU564Endometrioid ov adenoY537SYUNU646LG ov serousY537SYUYU739Papillary serousY537SYUNN/A827LG ov serousY537SYYYY CONCLUSIONS: Acquired activating mutations in ESR1, previously described in breast cancer, can occur in ovarian serous carcinomas and endometrioid carcinomas initially responsive to hormone therapy and suggest a similar mechanism for acquired aromatase inhibitor resistance. However, ERa mutations can occur in gynecologic malignancies even in the absence of prior endocrine therapy. Tumors harboring these mutations may remain responsive to SERM/SERDs. Citation Format: J. A. Elvin, L. Gay, G. Colon-Otero, M. Jorgensen, L. Havrilesky, D. Zajchowski, L Shawver, F. A. Valea, S Aithal, J. S. Ross, M. Markman, S. Gaillard. CONSTITUTIVELY ACTIVE ESTROGEN RECEPTOR–ALPHA LIGAND BINDING DOMAIN (ERA–LBD) MUTATIONS IN OVARIAN CARCINOMA [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-056.