Abstract 5174: Organoids to predict treatment response in metastatic colorectal cancer (OPTIC)

Abstract Introduction: The inability to predict treatment response results in unnecessary toxicity, decreased efficacy and survival. There is a clinical need for an effective biomarker to select patients for cancer treatment. A promising biomarker for treatment efficacy is response testing on patient-derived organoids (PDOs). For metastatic colorectal cancer (mCRC), larger prospective studies are needed to evaluate the predictive value of standardized PDO screens. Methods: OPTIC is an ongoing prospective multicenter trial (NL61668. 041. 17, started 2018) that will evaluate the value of tumor PDOs in therapy response prediction. We establish PDOs for mCRC patients from newly obtained biopsies, prior to the start of treatment. We compare PDO sensitivity (area under drug response curve) with patient response measured by changes in biopsied metastatic lesion size on CT scans. Secondary outcome measures are RECIST response and progression-free survival. We evaluate the feasibility of using PDOs as a biomarker by examining drug screen availability in a clinically relevant timeframe of 4 weeks. From 2020 onwards, we incorporated whole genome sequencing (WGS) on fresh-frozen biopsies to correlate drug response in vitro and in vivo, to genetic tumor characteristics. Additionally, PDO screens with experimental drugs based on genetic alterations identified by WGS could be performed. Trial inclusion will continue until 85 PDOs from clinically evaluable patients for standard of care (SOC) treatment are established, with expected completion in Q1 2024. Results: Currently, 206 patients were included in 5 hospitals and 180 biopsies were taken. PDO establishment success gradually increased from 22% in 2018-2020 to 75% in 2023, yielding an overall success rate of 50% (n=84 PDOs and 13 in culture). Critical factors in optimizing culture success were replacement of several growth factors in the culture medium, reducing time to processing and more frequent handling of biopsies. We have established PDOs for comparing with patient response for the following treatment categories: 5-fluorouracil (n=4), CAPOX/FOLFOX (n=23), irinotecan/FOLFIRI (n=11), FOLFOXIRI (n=12), trifluridine/tipiracil (n=14), panitumumab (n=14), encorafenib-cetuximab (n=2), non-SOC drugs (n=4). We have successfully screened the first 8 PDOs in consistent technical triplicates and biological duplicates (R0. 88, p0. 02). WGS succeeded in 76% (n=75), primarily failing when tumor percentage was 20%. Conclusion: We improved PDO establishment success to 75% which is essential to facilitate the implementation of PDOs in clinical treatment. OPTIC will enhance the clinical application of PDOs by defining thresholds for PDO sensitivity and analyzing the diagnostic power for different treatments. To enable personalized treatment in clinical practice, PDO screening should guide mCRC treatment and result in enhanced chance of response and reduced over- and mistreatment. Citation Format: Lidwien P. Smabers, Emerens Wensink, Carla S. Verissimo, Mayke Doorn, Tao Yang, Timo Voskuilen, Yasmine Abouleila, Maarten A. Huismans, Liselot Valkenburg-van Iersel, Geert A. Cirkel, Elske C. Gootjes, Frank J. Jeurissen, Guus M. Bol, Hilde H. Nienhuis, Manon M. Braat, Bas Penning de Vries, Sjoerd G. Elias, Edwin Cuppen, Robert G. Vries, Onno Kranenburg, Miriam Koopman, Sylvia F. Boj, Jeanine M. Roodhart. Organoids to predict treatment response in metastatic colorectal cancer (OPTIC) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5174.