Abstract 3262: Biomarkers of response to deslorelin in women at high risk of breast cancer

Abstract

Abstract Women with BRCA1 or BRCA2 mutations have a high breast cancer (BC) risk. Breast density is an independent biomarker of BC risk. We demonstrated that deslorelin (D), a gonadotropin-releasing hormone agonist (GnRHA), reduced mammographic breast density among BRCA1 carriers (Weitzel, CCR 2007). We report here on correlative studies in a Phase II chemoprevention study of intranasal D plus low-dose add-back estradiol and testosterone for 10 months in 10 premenopausal high-risk women. Pre- and post-study measures included mammographic and MRI breast density; serum hormone levels; breast tissue gene expression by Affymetrix GeneChip Human Genome U133 Plus 2.0 Array; Q-PCR to validate the top genes; analysis of sera by 2D-PAGE and LC-MS/MS Mass Spectrometry, validated by a marker specific ELISA. Nine of 10 participants showed a mean reduction in MRI volumetric breast density of 17.3% (p=0.045), a mean reduction in MRI fibroglandular volume of 15.1% (p=0.041) and a mean reduction in mammographic density of 31.9% (p=0.0033). The top five differentially expressed genes in breast tissue were: FOS, EGR1, FABP3, COL3A1 and COL1A1. From seven protein spots up-regulated following treatment, 65 sera proteins were initially identified as response biomarkers, with two of these, adiponectin and Vitamin D-binding protein, predicted by Ingenuity Pathway Analyses (IPA) to have a direct role in reducing breast density by possibly altering stromal and epithelial tissue viability and fat metabolism. FOS was identified through IPA in the Vitamin D-binding protein network and both COL3A1 and COL1A1 were identified in the adiponectin network. Of the nine subjects two had an increase of ≥ 5% BMI and two had a decrease of ≥ 5% BMI. There was no significant correlation between adiponectin level changes and BMI changes.Tissue micro-array gene expression and proteomic analyses of sera identified changes in biomarkers that correlated with reduced breast density among young high-risk women receiving a GnRHA-based chemoprevention regimen. Pre/Post Human Serum Adiponectin LevelsA_Pre: 0 MB_ Post: 10 MFold (Post/Pre)Log A (0M)Log B (10M)T-Test (p) pairedS10.4630.3860.835-0.335-0.4130.014S20.3760.4131.097-0.425-0.385S30.2620.3671.403-0.583-0.435S40.6640.8021.209-0.178-0.096S50.2450.6082.487-0.612-0.216S60.3150.7552.399-0.502-0.122S70.4130.7991.936-0.385-0.098S80.5750.6461.123-0.240-0.190S90.4360.7331.680-0.361-0.135Average1.574224 Citation Format: Jeffrey N. Weitzel, Michael F. Press, Sharon R. Sand, Lei Zhang, Catherine Klifa, Malcolm Pike, Giske Ursin, Darcy V. Spicer, AnnaMarie Daniels, Josef Herzog, Yunan Miao, Gerald Wuenschell, Chun Li, Robert Hickey. Biomarkers of response to deslorelin in women at high risk of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3262.