A prospective feasibility trial to challenge patient-derived pancreatic cancer organoids in predicting treatment response

Introduction Pancreatic cancer (PC) is characterized by a high inter- and intratumor heterogeneity and a considerable variation in responses to antitumor therapies, yet reliable models to predict effectiveness of treatment strategies are not established. Patient-derived pancreatic cancer organoids (PDOs) exhibit features of the parental tumor and may thereby represent a powerful preclinical tool to predict drug response. Real-time isolation, propagation and pharmacotyping of PDOs may enable treatment response prediction and thereby improve survival outcome.

Methods PDOs were isolated from 54 patients with suspected or confirmed PC in the framework of a prospective feasibility trial. Drug response of single agents of standard of care chemotherapeutics was determined by a viability assay. Areas under the curves (AUCs) were clustered for each drug and a prediction score was developed for combined regimens.

Results Pharmacotyping profiles were obtained from 28 PDOs (efficacy 63.6%) of PC patients after a median of 53 days (range 21-126 days). PDOs exhibited heterogenous responses to standard of care drugs and were classified into high, intermediate or low responder categories. Our developed prediction model allowed a successful response prediction in treatment-naïve patients with an accuracy of 91.1% for first-line and 80.0% for second-line regimen, respectively. The power of prediction declined in pretreated patients to an accuracy of 60.0%, particularly with more than one prior line of chemotherapy. Progression-free survival (PFS) was significantly longer in previously treatment-naïve patients receiving a predicted tumor sensitive compared to a predicted tumor resistant regimen (mPFS 141 vs. 46 days; p=0.0048).

Conclusion Generation and pharmacotyping of PDOs from untreated and pretreated PC patients is feasible in clinical routine. Implementation of PDOs into clinical practice may personalize treatment strategies in the perioperative and metastatic setting and thereby improve survival.

Publication History

Article published online:
07 September 2021