Project 1: Risk-Stratified Breast Cancer Screening with Quantitative Magnetic Resonance Imaging (MRI) as a Paradigm ShiftAim 1. Expand enrollment of high-risk women in a novel, biannual abbreviated magnetic resonance imaging (MRI) program to community partner sites in Chicago and develop a national multi-institutional study
- Determine the clinical effectiveness of a biannual abbreviated ultrafast MRI protocol
- Evaluate the cost effectiveness of implementing a biannual abbreviated ultrafast MRI protocol in high-risk women, in order to determine the optimal imaging protocol by risk profile
Aim 2. Use a randomized sub-study to evaluate the effect of a cognitive behavioral therapy (CBT) + hypnosis intervention in high-risk women
- Evaluate the effect of CBT+hypnosis on the short- and intermediate-term stress and anxiety levels by monitoring psychological and physiological biomarkers
- Evaluate the effect of CBT+hypnosis on the long-term adherence to screening regimen and the rate of opting for prophylactic mastectomy
Project 2: Optimizing Neoadjuvant Therapy for Aggressive HER2-Enriched and Triple-Negative Breast Cancer (TNBC) in Low-Resource Settings
Aim 1. Assess the response rate to biomarker-informed neoadjuvant therapy of breast cancer
- Validate the Xpert Breast Cancer STRAT4 Assay mRNA results for ESR1, PGR, ERBB2 and MKI67 relative to corresponding standard of care IHC/FISH in 200 well-annotated samples.
- Prospectively evaluate the pattern of response and mechanisms of resistance to neoadjuvant therapy based on STRAT4 mRNA levels in uniformly treated patients in Nigeria.
Aim 2: Examine breast tumor heterogeneity before and after neoadjuvant therapy and perform comparative analysis with results from European ancestry groups.
- Examine tumor heterogeneity in primary and residual tumors post neo-adjuvant therapy, using whole-exome sequencing and RNA-Seq, and identify genomic alterations including copy number changes contributing to treatment resistance
- Apply cost-effective ultra-low-pass whole-genome sequencing to estimate tumor fraction and monitor copy number changes in serial cell-free DNA
Aim 3: Profile protein activity signatures in breast tumors and single circulating tumor cells
- Conduct unbiased, quantitative proteomic profiling in primary tumor samples to identify biomarkers associated with therapeutic response and disease aggressiveness
- Apply an "on-chip” single-cell activity-dependent proximity ligation multi-enzyme panel to profile biomarker activity signatures in cells from breast primary tumor and serial circulating tumor cells from the same patient, and integrate novel pan-kinase activity probes to query essentially all of the validated proliferative signaling pathways that drive breast cancer aggressiveness and therapeutic resistance
Project 3: The Role of Glucocorticoid Receptor (GR) Blockade in Androgen Receptor (AR)-Positive TNBCAim 1: Identify AR and GR coordinated transcriptional pathways and phenotypes that are antagonized by AR-blockade (enzalutamide), or GR-blockade (mifepristone) versus combined AR/GR antagonism using in vitro models.
Aim 2: Identify in vivo GR (+/- AR-V7) driven pathways and tumor response following AR versus combined AR/GR blockade and establish TNBC AR+ PDX models through growth in mouse mammary gland duct (mammary intraductal or MIND models).
Aim 3: Determine whether AR and GR protein expression and their associated gene expression pathways are potential biomarkers of response to chemotherapy, enzalutamide monotherapy, or enzalutamide plus mifepristone combination therapy in AR+ TNBC. We will use a Phase II randomized trial as a platform for patient samples obtained at baseline (pre-treatment), on treatment (at 9 weeks), and at the time of disease progression.