Systematic functional drug testing in patient-derived models reveals ex vivo sensitivities associated with clinical outcome in rare solid tumors

Abstract Rare cancers are individually uncommon but collectively represent a substantial share of cancer burden, with limited systemic treatment options for many entities. Molecular profiling identifies targetable alterations, but actionable findings are limited and responses can vary despite a matched target. This motivates complementary approaches that directly assess tumor drug response. Here, we establish a biopsy-compatible ex vivo drug sensitivity testing platform optimized for low input and reproducibility. Patient-derived material was tested either directly or following ex vivo expansion. Functional profiling was performed within clinically relevant timelines across models from 126 patients with rare advanced solid tumors. Drug responses were consistent between model types. In most samples, we identified at least one potentially active compound, supporting feasibility at biopsy-scale. High in vitro sensitivity was associated with clinical benefit and progression-free survival. These findings support functional drug sensitivity testing as a complementary component in precision oncology for adults with rare cancers. Statement of Significance This study presents a biopsy-compatible drug sensitivity testing platform for phenotype-based therapy stratification in rare cancers. It identifies actionable ex vivo drug responses and shows associations with clinical outcome in patients treated with screened therapies. These findings support functional testing as a complementary additional layer of stratification for therapeutic prioritization.