Towards the clinical validity of tumor organoid drug screens: Establishing a framework for organoid disease models.

Abstract

e15037 Background: Despite advances in biomarker-directed cancer therapies to predict tumor response to treatment, precision oncology remains an imprecise science. Tumor organoid drug screens present an opportunity to test multiple potentially effective therapies simultaneously before exposing a patient to treatment toxicities. Preliminary studies have established the analytic validity; however, the clinical validity of the tumor organoid response to a drug to predict the tumor response in patients is unclear. Methods: In order to establish the clinical validity of an organoid drug screen, a clinical disease model should have the following features to enable comparison of the tumor’s clinical response to treatment and the organoid’s response to the same treatment. First, a fresh tissue biopsy (non-bone) needs to be obtained for organoid development prior to the start of systemic treatment. Priority should be given to tumors known to successfully grow organoids. Disease models where the standard of care systemic treatment is a single cytotoxic or targeted agent would best assess correlation between the drug screen and patient response, such as metastatic breast, cervical, or prostate cancer. This would often lead to enrolling patients on later line systemic therapies. Studies should avoid drugs whose mechanism of action leverages the patient metabolism or tumor microenvironment (e.g. immunotherapy, aromatase inhibitors, VEGF inhibitors). Patient should have measurable disease that can be measured clinically, radiographically, or pathologically and using standardized response evaluation criteria (e.g. RECIST). Next generation sequencing would assess genomic concordance between the tumor in the patient and organoid. These studies would determine the feasibility and timeliness of prospectively developing tumor organoids that is sufficient to perform a drug screen. Results: We propose two research models to evaluate the clinical validity of tumor organoid drug screens: a metastatic solid tumor and neoadjuvant solid tumor disease model. Metastatic disease models provide an opportunity to assess response across multiple cancer types at the time of progression and initiation of next line of therapy. The efficacy of chemotherapy can be determined using objective data from radiologic response (RECIST). In neoadjuvant models, pathologic (pCR) and radiologic response can provide objective data for organoid response. These study design features will lay the framework for determining the clinical utility of organoid drug screens. Conclusions: We call for clinical studies assessing the clinical validity of tumor organoid drug screens and determining their concordance with patient response to systemic therapy. Advancements in clinically validated tumor organoids have the potential to fundamentally shift clinical paradigms and improve patient outcomes in cancer treatment.