Androgen Receptors in Luminal Breast Cancer: Effects on Response to Endocrine Therapy and an Immune-Suppressive Tumor Immune Microenvironment (TIME)
Abstract
This application addresses the following overarching challenges: (1) distinguish deadly from non-deadly breast cancers by determining how to better predict who will respond to anti-hormonal therapy; and (2) identify why some patient s breast cancers recur as metastatic disease. Every year, approximately 250,000 people in the U.S. are diagnosed with early (non-metastatic) breast cancer (BC). Three quarters of these patients have tumors whose growth are driven by the female sex steroid estrogen, so initial therapy includes drugs that shut down the estrogen receptor (ER). The most common treatment for early ER+ BC is a class of drugs called aromatase inhibitors (AI). AIs deprive tumors of estrogen by blocking the conversion of androgens (another sex hormone) to estrogens by a protein called aromatase in fat cells. Unfortunately, despite AI treatment working well and resulting in many years without metastatic disease, up to half (125,000 people annually) will ultimately develop recurrent metastatic breast cancer (MBC) that is resistant to AI therapy, 10 to 30+ years after the initial breast cancer diagnosis. Although androgens are thought of as a male hormone, women make adrenal androgens and 95% of ER+ BCs express AR. Furthermore, AR strongly increases in ER BC cells that are deprived of estrogen in cells that are invasive with the potential to metastasize. Such anchorage-independent BC cells can survive as they spread throughout the body, mimicking important features of MBC. We propose that when starved of estrogen, BC cells that are AR positive are poised to escape death by using androgens/AR to survive. In prostate cancer, AR is an established therapeutic target. We found that inhibiting AR action using the drug enzalutamide (an anti-androgen approved by the U.S. Food and Drug Administration for prostate cancer) completely blocked the ability of ER+ BC to metastasize in mice with their ovaries removed (estrogen-deprived conditions that mimic AI therapy) and inhibited outgrowth of established metastatic disease. The primary research investigator, Dr. Richer, and clinical partner, Dr. Anthony Elias recently completed two clinical trials that combined the anti-androgen drug, enzalutamide, to an ER degrader drug, fulvestrant, in AI-resistant MBC. They achieved promising results. They are therefore ideally suited to conduct these new studies because of their combined experience and expertise in hormone receptors and BC and breast medical oncology. Their research team includes two experienced patient/research advocates, and talented collaborators who are experts in tumor immunology and statistical analyses of complex immunohistochemistry to visualize multiple protein markers including hormone receptors and immune cells in BC tissue. They propose to measure steroid hormone receptor (SHR) differences in the primary tumor as a predictor of anti-estrogen resistance to guide therapy. AR, in both tumor cells and T cells, creates an immune-suppressive environment around the tumor. Therefore, we hypothesize that SHR differences in primary tumors impact anti-estrogen resistance, and specifically that a high AR:ER ratio drives resistance and creates an immune-suppressive environment around the tumor, making it less antitumor and more cancer permissive. Our specific aims will take advantage of knowledge gained from our two prior DOD-funded trials that targeted AR to inform further studies on those samples as well as biopsies from the I-SPY 2 Endocrine Optimization Protocol (EOP) and SWOG S0226 trials. We will also conduct a 5-year follow-up on the patients who were in our trial of neoadjuvant (prior to surgery) combination of fulvestrant with or without the anti-androgen drug, enzalutamide, to determine if this combined treatment will decrease disease recurrence. This approach maximizes patient participation in clinical research. If a higher AR:ER ratio correlates with decreased response to traditional endocrine
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310982
Entities
People
- Jennifer K Richer
Organizations
- United States Army
- University of Colorado Denver