Abstract P56: Prospective Functional Personalised Oncology For Metastatic Breast Cancer Patients Identifies Effective PI3K Inhibitors-based Combinations

Abstract

Breast cancer (BC) is the major cause of cancer-related death in women, with metastatic BC patients having a dismal 5-year survival rate of about 20%. The advent of functional precision oncology, leveraging on patient-derived models and functional assays, can provide patient-specific drug sensitivity information to guide patient treatment. As a functional drug combination screening platform, Quadratic Phenotypic Optimisation Platform (QPOP) ranks potential drug combination response in patient-derived avatars and has been successfully applied in several haematological malignancies. Here, we tested the feasibility of applying QPOP in the setting of metastatic BC in a Phase I clinical trial by leveraging on patient-derived breast cancer organoids (BCOs) from core biopsies. QPOP analyses were performed in 16 unique patient-derived lines to identify effective drug combinations with clinical potential. We identified unique QPOP-derived top-ranking combinations for individual primary breast cancer cells and BCOs. Three patients were prospectively treated with QPOP recommendations, with one patient exhibiting favourable clinical response. Interestingly, phosphoinositide 3-kinase (PI3K)-based combinations were identified as frequently top-ranking combinations. Validation of these combinations in a subset of PIK3CA-mutant luminal BCOs exhibited synergy and efficacy in vitro, highlighting their potential in a subpopulation of refractory BC patients. Global transcriptomic analysis in BCOs is currently underway to elucidate the molecular mechanisms underlying the efficacy of PI3K-based combinations. This study highlights that QPOP analysis on BDOs could identify prospectively effective novel combinations across different subtypes of refractory metastatic BC for functional personalised medicine. Furthermore, the identification of novel PI3K-based combinations as a potentially effective strategy has tremendous clinical applications, widening the treatment repertoire in subsets of BC patients.