The goal of precision medicine is to match the right drug to the right patient. However, every individual cancer carries a unique and complex mosaic of genetic and molecular changes making it difficult to identify the right drug based solely on genomic analysis. We developed a CLIA-certified functional drug assay (PARIS® test) for solid tumors which provides an actionable report of tumor derived organoid sensitivities to targeted, endocrine and chemotherapy agents as a tool for clinical therapeutic decisions. Objectives:1.To establish the concordance between organoid drug sensitivity with well-known genomic or immunohistochemical IHC biomarkers 2.To correlate organoid drug sensitivity with clinical outcomes.Methods: From 2015 to 2020, organoids from 410 tumor samples were subjected to functional testing at SEngine Precision Medicine, including 61 breast tumor samples from 48 patients. Fresh samples of tumor cells from core biopsies, surgical excisions, or from fluids arrived 90%.Conclusions: Organoid based drug testing exhibits strong concordance with genomic or IHC biomarkers and clinical response. In addition, functional testing identifies candidate therapies in patients lacking biomarkers and can nominate variants of unknown significance as candidate biomarkers. This study highlights the utility of functional assays to support clinical decision making in a genetically heterogenous cancer such as breast cancer. Citation Format: Astrid Margossian, Anne Richardson, Madison Pollastro, Michael Churchill, Franz Schaub, Shalini Pereira, Payel Chatterjee, Rachele Rosati, Lauren Appleyard, Grace Durenberger, Alex Federation, G. Adam Whitney, Hallie Swan, Trevor Ainge, Robert Diaz, Natasha Hunter, Eric Gamboa, Chris Kemp, Vijayakrishna Gadi, Carla Grandori. Clinical and genomic correlation of a CLIA certified organoid based functional test in breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-01.