2602 Background: A CLIA-certified organoid based drug sensitivity assay (a cancer organogram) has been developed for all solid tumors. An actionable report of organogram sensitivities to endocrine, chemotherapy and targeted agents, produced a drug sensitivity score as a tool to inform therapy decision making. Objectives: To evaluate the success rate of organoid derivation, the organogram drug responses across cancer types and to analyze the impact of the organogram report on therapeutic decision making. Methods: From 2016 to 2020, 628 cancer organograms were performed, with 513 tumor samples from 419 cancer patients. Within 48 hours of collection, fresh samples of tumor cells obtained from core biopsies, surgical excisions, or fluids were cultured, the majority as 3D organoids. Drug screens were performed with a library of up to 220 drugs, and dose-response was evaluated across a range of concentrations for each drug. Organogram sensitivity was ranked as response in five categories based on SPM Score: Exceptional (SPM15/14), Good (13/12), Moderate to Low (11/9), and None( < 9). 118 drugs on average were tested per screen (range: 68-152), so in a total of 628 organograms, more than 70,000 individual drug trials have been performed. The median turnaround time was 28 days (range: 19.5-51.5). Results: Of the 513 collected samples, 314 were fresh specimens: 96 core biopsies, 151 surgical specimens, and 67 fluids (pleural effusions or ascites), with an organoid derivation success rate of 58.3%, 78%, and 88%, respectively. Overall success rate in organoid derivation was 70.2%. Samples with poor viability and low tumor cell count (22%) were rejected. The primary cancer types tested were ovarian (n = 92, 17.9%), breast (n = 73, 14.2%), colorectal (n = 70, 13.6%), pancreatic (n = 51, 9.9%), cholangiocarcinoma (n = 42, 8.1%), and other solid tumors (n = 185, 36%). Median age of patients was 56 years old (range: 5-83), most of them heavily pretreated. 20.45% of drugs screened had exceptional and good responses (SPM score 15-12) (SD: 17.92%). We reviewed genomic data from 374 third-party genomic reports. The most frequent genomic alterations found were TP53 (n = 143, 38.2%), BRCA1 and BRCA2 (n = 47, 12.5%) CDKN2A (n = 42, 11.2%), FGFR1/2/3/4 (n = 41, 10.9%), and PIK3CA (n = 38, 10.1%). Post-test treatment information is available for a subset of 61 patients. The treating physician made an organogram-guided therapeutic decision in 32/44 patients with post test treatment drugs scored (72%). Conclusions: The cancer organogram test has a high rate of success in generating an actionable report that identifies therapies for patients with limited therapeutic options, including those with no known genomic biomarkers. The organogram guided selection of therapeutics for a significant subset of patients, nearly 4 times the rate reported with genomic testing alone.

3630 Background: Precision medicine integrates genetic, molecular, and clinical information to optimize therapy selection for cancer patients. Ex vivo drug testing has the potential to match the right drug to the right patient. We developed a CLIA-certified functional drug assay for all solid tumors which provides an actionable report of organoid sensitivity to targeted, endocrine and chemotherapy agents as a tool for therapeutic decisions. Objectives: To establish the predictive power of the test in relation to well-known genomic biomarkers as well as prior treatments to identify drug sensitivity. To demonstrate that functional drug testing increases the actionability of genomic reports. Methods: From 2016 to 2019, 240 organoids from cancer patients were subjected to functional testing at SEngine Precision Medicine. Patients with advanced primary or metastatic cancer (solid tumors) who were treatment naïve or had previous therapies fail. Fresh samples of tumor cells from core biopsies, surgical excisions, or fluids arrived <48 hrs following collection and were cultured as 3D organoids. They were evaluated using a multi-dose response format with a library of up to 130 compounds. Drug sensitivity was quantified using a score that combines sensitivity and personalization of each patient’s response relative to a reference population. Known genomic actionability from levels of evidence 1-2 from MSKCC OncoKB were queried against results for correlation. Results: Organoids were derived from breast (18.7%), ovarian (18.3%), colorectal (17.9%), pancreatic (6.7%), and others solid tumors (38,3%). Median age of patients was 53 (r5-83). 68 drugs on average were tested per patient with a mean turnaround time of 18 days (r9 -37). A mean of 7 drugs per patient were identified as top scoring drugs. In 75 patients with genomic data, we found high concordance of drug sensitivity with known genomic anchors (e.g., inhibitors of BRCA1/ PARP, ERBB2/HER2, FGFR1-2/FGFR, KRAS, PIK3CA/PI3K), measured as sensitivity to drugs among this targeted groups. However, several patient samples demonstrated sensitivity to targeted agents in the absence of known genomic biomarkers. Most important, analysis of previous treatments indicated >90% of retrospective concordance. Conclusions: Organoid based drug testing exhibits strong concordance with genomic and retrospective clinical evidence. In addition, functional testing identifies candidate therapies in patients with no known biomarkers and can identify the significance of variants currently not validated.

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.

Background: Clinically approved targeted therapies for ovarian cancer patients are currently limited to PARP inhibitors and bevacizumab. To improve treatment outcomes, a precision medicine approach is crucial to match effective drugs to patient-specific genetic features and vulnerabilities. This study aimed to: (1) demonstrate the feasibility of performing high-throughput drug screens on fresh patient organoids using a CLIA-approved assay, (2) assess concordance of responses with genomic and clinical information, and (3) reveal novel biomarkers of response to approved/experimental drugs and insights into ovarian cancer biology. Methods: From 2015 to 2020, 76 ovarian tumor samples were collected from 60 patients. To date, 50 evaluable samples were successfully screened at SEngine Precision Medicine. Drugs tested include a range of chemotherapies and targeted therapies that are FDA-approved or in clinical development, with an average of 61 drugs screened per assay (range: 6-135). Somatic and/or germline DNA sequencing is currently available for 30 samples. Sample collection, screening, and sequencing is ongoing. Results: The cohort included ovarian cancer patients with high grade serous (65%), low grade serous (7%), unknown grade serous (7%), clear cell (7%), carcinosarcoma (5%), stromal (5%), endometrioid (2%) subtypes, and one of unknown pathology. Whole genome mutational analysis of 5 tumor-derived organoids and their original tumors demonstrated a high degree of similarity between the tumor-organoid pairs. We present prospective and retrospective evidence from at least 18 cases that organoid drug screening can accurately predict clinical response to chemotherapy and targeted therapies. We also report a patient with platinum resistant serous carcinoma who responded to ibrutinib treatment after screening identified the drug as having excellent response in this patient's organoids. Three months into treatment, the patient's CA125 level was reduced from 250 to 125U/ml. In samples with available genomic information, we demonstrate high concordance between drug sensitivity and known biomarkers, e.g. 83% of samples with known BRCA1/BRCA2 mutation or high HRDetect showed sensitivity to a PARP inhibitor. Further, organoid screening can identify unique targets for every patient beyond established genomic biomarkers. Subsets of patients responded exceptionally to BET (41%), HDAC (28%), WEE1 (24%), and BTK (11%) inhibitors, indicating potential for these targeted therapies in ovarian cancer. Conclusions: The genomic and histopathological heterogeneity of ovarian cancer points to a need to evolve and prioritize the personalization of treatment. Our data demonstrates the utility of organoid based drug screening to nominate therapeutic options for individual patients with or without known genomic biomarkers. Citation Format: Goldie Lui, Anne Richardson, Payel Chatterjee, Madison Pollastro, Mia Lints, Danielle Peretti, Rachele Rosati, Lauren Appleyard, Grace Durenberger, Robert Diaz, Kay Gurley, Isabella Stork, Adam Whitney, Katannya Kapeli, Hallie Swan, Yasin Memari, Helen Davies, Serena Nik-Zainal, Kalyan Banda, Heidi Gray, Barbara Goff, Elizabeth Swisher, Astrid Margossian, Christopher Kemp, Carla Grandori. Functional drug screening of organoids from ovarian cancer patients demonstrates clinical and genomic concordance and identifies novel therapeutic vulnerabilities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 534.