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

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. View inline Pre/Post Human Serum Adiponectin Levels.