TRLS-04 ENHANCING PRECISION MEDICINE THROUGH FUNCTIONAL DRUG TESTING FOR PATIENTS WITH BREAST CANCER BRAIN METASTASES.

Abstract Breast cancer brain metastases (BCBrMet) increase mortality among breast cancer patients. Our previous research confirmed the feasibility of real-time drug testing to guide personalized therapy for BCBrMet (Morikawa JCO Glo Onc suppl 2023). This study aims to characterize BCBrMet molecular profiles and examine responses to genomically matched drugs. Patient-derived organoids (PDOs) were established from BCBMet resected during clinically indicated surgery. Clinical and pathologic data were retrospectively collected. Each PDO was treated with up to 50 drugs and next generation sequencing (NGS) was conducted as previously published (Merrill Eur Uro 2024). We analyzed 21 PDOs from 19 patients (2 serial collections). The median age was 55 (range 30-72). Receptor subtypes included HR+/HER2+ (37%), HR-/HER2+ (21%), HR+/HER2- (16%), and HR-/HER2- (26%). Compared to the primary tumor, BCBMet showed increased HR negativity: ER-negative from 53% to 63% and PR-negative from 58% to 84%. HER2 status remained relatively unchanged. Post-resection survival data showed that 3 patients (16%) died within 1 month, and 7 (37%) within 1 year. PIK3CA mutations were associated with poor prognosis as all 4 patients with PIK3CA mutations died within 1 year, including 2 within the first month, irrespective of tumor subtype. Despite this, PDOs from these patients responded well to the PI3k pathway targeted drugs (Copanlisib, Gedatolisib, Alpelisib, GDC-0084). However, none of these patients received PIK3CA-targeted therapy in clinical practice. Functional screening of targeted matched therapies showed significant activity against PDOs, strongly supporting the use of precision medicine in BCBMet. Limited clinical use of targeted therapy partly reflects uncertainty about genomically matched drug activity beyond FDA indications. This study highlights the potential utility of integrating PDO drug testing with molecular profiling to guide precision medicine treatment strategies for BCBMet.