Project Grant R37CA292075

PREDICTING ENDOCRINE THERAPY RESPONSE IN MALE BREAST TUMORS - PROJECT SUMMARY/ABSTRACT MALE BREAST CANCER IS CRITICALLY UNDERSTUDIED DUE TO BOTH THE RARITY OF THE DISEASE AND THE EXCLUSION OF MEN FROM BREAST CANCER TRIALS LEADING TO A SIGNIFICANT KNOWLEDGE GAP ABOUT HOW MALE BREAST TUMORS RESPOND TO THERAPY. THE EFFICACY OF EXISTING ENDOCRINE THERAPIES IN MEN WITH ER+/HER2- BREAST CANCER HAVE NEVER BEEN COMPARED PROSPECTIVELY, AND THIS IS THE GOAL OF THE ONGOING ETHAN TRIAL. IN THIS TRIAL, 60 PATIENTS ARE RANDOMIZED TO 3 ENDOCRINE REGIMENS FOR A 3-WEEK WINDOW PHASE, FOLLOWED BY BIOPSY, THEN A 4-MONTH NEOADJUVANT PHASE +/- THE CDK4/6 INHIBITOR ABEMACICLIB, FOLLOWED BY SURGICAL RESECTION. THE TRIAL IS WELL POWERED TO COMPARE DIFFERENCES IN RESPONSE RATES, MEASURED IN THE WINDOW PHASE BY A 50% REDUCTION IN KI-67, AND IN THE NEOADJUVANT PHASE BY RESIDUAL CANCER BURDEN INDEX. THIS DESIGN CREATES AN UNPRECEDENTED OPPORTUNITY FOR TRANSLATIONAL STUDIES USING SAMPLES FROM PRE AND POST TREATMENT TIMEPOINTS ANNOTATED WITH CLINICALLY RELEVANT RESPONSE ENDPOINTS. THE GOAL OF THIS PROPOSAL IS TO LEVERAGE PATIENT SAMPLES FROM THE ETHAN TRIAL TO UNDERSTAND AND PREDICT HOW MALE BREAST TUMORS RESPOND TO THERAPY. WE HYPOTHESIZE THAT MULTIGENE RESPONSE SIGNATURES WILL PREDICT RESPONSE TO ET IN MEN WITH ER+ BREAST TUMORS. TO TEST THIS HYPOTHESIS, IN AIM1 WE WILL DETERMINE ENDOCRINE THERAPY RESPONSE SIGNATURES USING WHOLE TRANSCRIPTOME SEQUENCING OF PRE AND POST TREATMENT SPECIMENS. WE WILL DETERMINE HOW EACH DRUG TREATMENT RESULTS IN CHANGES IN GENE EXPRESSION AND COMPARE THESE TO FEMALE PREDICTORS AND RESPONSE SIGNATURES. WE WILL PERFORM STRATIFIED ANALYSIS OF RESPONDERS AND NON-RESPONDERS TO DISCOVER BIOMARKERS WHICH WILL BE VALIDATED USING LARGE COHORTS OF PATIENTS WITH ER+/HER2- BREAST CANCER TREATED WITH ENDOCRINE THERAPY. IN AIM2, WE WILL UTILIZE OUR SINGLE CELL PROCESSING PIPELINE WHICH WE USED TO SHOW DISTINCT RESPONSES IN MALIGNANT CELL SUBPOPULATIONS WITHIN FEMALE ER+/HER2- BREAST TUMORS, TO DISSECT HETEROGENEITY IN ENDOCRINE THERAPY RESPONSE WITHIN MALE BREAST TUMORS. THIS ANALYSIS WILL DEFINE FEATURES OF LOW ABUNDANCE CELL POPULATIONS THAT MAY BE DRIVING THE RESISTANCE PHENOTYPE. FINALLY, IN AIM3, WE WILL ADDRESS A CRITICAL LACK OF EXPERIMENTAL MODELS OF MALE BREAST CANCER BY USING OUR ORGANOID INFRASTRUCTURE TO GENERATE MALE PATIENT DERIVED ORGANOIDS. WE WILL USE ORGANOIDS TO TEST ESTROGEN RECEPTOR GENE REGULATORY FUNCTION AND ASSESS THE PRECLINICAL EFFICACY OF TARGETED THERAPEUTIC STRATEGIES. CUMULATIVELY, THESE STUDIES WILL ADDRESS A SIGNIFICANT KNOWLEDGE GAP OF WHY THERAPIES ARE EFFECTIVE OR I NEFFECTIVE IN MEN WITH BREAST CANCER. THESE FINDINGS WILL GENERATE PREDICTORS OF RESPONSE, IDENTIFY PATHWAYS DRIVING RESISTANCE, AND GENERATE AND UTILIZE EXPERIMENTAL MODELS TO UNCOVER THE INTRINSIC BIOLOGY OF MALE BREAST TUMORS. IF SUCCESSFUL, THESE INSIGHTS WILL LEAD TO MORE PRECISE TREATMENT REGIMENS AND IMPROVE OUTCOMES FOR MEN WITH BREAST CANCER.