Abstract PS4-01: Clinical and genomic correlation of a CLIA certified organoid based functional test in breast cancer patients
Authors: Margossian Astrid , Richardson Anne , Pollastro Madison , Churchill Michael , Schaub Franz , Pereira Shalini , Chatterjee Payel , Rosati Rachele , Appleyard Lauren , Durenberger Grace , Federation Alex , Whitney G. Adam , Swan Hallie , Ainge Trevor , Diaz Robert , Hunter Natasha , Gamboa Eric , Kemp Chris , Gadi Vijayakrishna , Grandori Carla 
Published: February 2021

Abstract
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 &lt;48 hrs following collection and were cultured as 3D organoids. Samples were evaluated using a multi-dose drug response format with a library of up to 130 oncology drugs. Drug sensitivity was quantified using the SPM score (1-15) that combines sensitivity and personalization of each patient’s response relative to a reference population. Known genomic anchors and IHC subtypes were compared to drug sensitivity to determine concordance.Results: 61 breast cancer samples from 48 patients were analyzed. The median age of patients was 53.4 (r26-76). 65 drugs on average were tested per patient with a mean turnaround time of 21 days (r9 -37). A mean of 6 drugs per patient were identified as top scoring sensitive drugs. In 42 patients with genomic or IHC data, we found high concordance of drug sensitivity with known biomarkers (e.g., HER2+ or ERBB2 amplification:HER2 or EGFR inhibitor, BRCA1 mutation: PARP inhibitor, FGFR1-2 mutation or amplification: FGFR inhibitor, PIK3CA mutation:PI3K inhibitor), measured as sensitivity to the cognate targeted drugs. For PIK3CAmut we found an 80% correlation of organoid sensitivity to alpelisib and taselisib. For HER2/ EGFRinh the correlation was 100%. We also found organoid sensitivity to targeted agents in the absence of known genomic or IHC biomarkers, for example tamoxifen and fulvestrant sensitivity in triple negative breast tumors, or HER2 inhibitor sensitivity in HER2 IHC negative tumors or PARP inhibitor sensitivity with BRCA2 variant of unknown significance (VUS). In a cohort of 18 analyzable patients, the retrospective and prospective correlation between organoid based drug sensitivity and clinical outcome was &gt;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.