Pilot ENDORSE study evaluates response-guided systems medicine report for endocrine-pathway targets (ESR1/PIK3CA/mTOR/HER2)

This pilot, single-arm feasibility study at City of Hope tests whether a biology-guided therapy recommendations report can be delivered on time and be usable in routine decision-making for progressive HR+/HER2- unresectable or metastatic breast cancer. The intervention is not a drug; it is a tumor-tissue–derived “report” that integrates an ENDORSE signature score plus biomarker readouts (including ESR1 and PIK3CA mutations, HER2 mutation/expression, and an mTOR signature) to predict ongoing sensitivity or resistance to endocrine-based strategies, then suggests treatment options that the treating physician may or may not follow. Mechanistically, the report is aimed at matching patients to established target classes: ER pathway blockade (for ESR1-driven endocrine resistance), PI3K pathway inhibition (PIK3CA-mutant tumors are common in HR+ disease, roughly ~30–40%), mTOR pathway inhibition, and (when present) HER2 pathway targeting even within nominally HER2-negative disease. Clinically, today’s care typically starts with endocrine therapy plus a CDK4/6 inhibitor, then moves to biomarker-guided agents such as alpelisib for PIK3CA-mutant disease, elacestrant for ESR1-mutant disease, or everolimus-based regimens, before chemotherapy and antibody–drug conjugates in later lines—this study tests whether a structured, response-guided “systems medicine” layer can better prioritize those choices.