A Prospective Feasibility Trial to Challenge Patient–Derived Pancreatic Cancer Organoids in Predicting Treatment Response

Abstract

Real-time isolation, propagation, and pharmacotyping of patient-derived pancreatic cancer organoids (PDOs) may enable treatment response prediction and personalization of pancreatic cancer (PC) therapy. In our methodology, PDOs are isolated from 54 patients with suspected or confirmed PC in the framework of a prospective feasibility trial. The drug response of single agents is determined by a viability assay. Areas under the curves (AUC) are clustered for each drug, and a prediction score is developed for combined regimens. Pharmacotyping profiles are obtained from 28 PDOs (efficacy 63.6%) after a median of 53 days (range 21–126 days). PDOs exhibit heterogeneous responses to the standard-of-care drugs, and are classified into high, intermediate, or low responder categories. Our developed prediction model allows a successful response prediction in treatment-naïve patients with an accuracy of 91.1% for first-line and 80.0% for second-line regimens, respectively. The power of prediction declines in pretreated patients (accuracy 40.0%), particularly with more than one prior line of chemotherapy. Progression-free survival (PFS) is 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). In conclusion, generation and pharmacotyping of PDOs is feasible in clinical routine and may provide substantial benefit.

Organoid Models for Cancer Research—From Bed to Bench Side and Back

“…For 16 patients, a correlation of preclinical results to performance was possible with a prediction accuracy of 91.1% in treatment-naïve patients for first-line regimen and of 80% in second-line therapy setting. For pretreated patients, the accuracy dropped to 40%, especially if more than one chemotherapeutic regime was administered before [ 96 ].…”

“…Colorectal cancer Showing for the first time potential of organoids to predict clinical response; shown for metastatic CRC, gastroesophageal and cholangiocellular cancer [90] APOLLO trial-first interventional trial; drug screening and next generation sequencing in organoids from peritoneal metastases of CRC; providing organoid-screening stratified therapy for 2 patients [89] single-arm, single-center prospective intervention trial in metastatic CRC that missed to show feasibility of optimal therapy selection by organoid based drug screen [98] ClinCare study-evaluating the predictive value of PDOs from 80 therapeutically naive locally advanced rectal cancer patients for patients clinical response to standard of care chemo(radio)therapy; sensitivity data of 68 organoids matched clinical outcome of the patients , only 12 did not match [103] retrospective correlation of treatment response of 7 rectal PDOs to corresponding patients clinical performance regarding 5-FU or FOLFOX treatment [56] Pancreatic cancer prospective trial evaluating and correlating PDOs from primary or metastatic tissue as predictors of clinical drug response, mainly including ductal adenocarcinoma but also less frequent subtypes [96] correlating treatment efficiency in PDOs to clinical results of the corresponding four patients for gemcitabine treatment demonstrating an overall correlation [74] performing therapeutic profiling (pharmacotyping) in 66 PDOs for five mainly used chemotherapeutic agents in PDAC and retrospectively correlating patients outcome to their corresponding PDO performance demonstrating good correlation; longitudinal organoid sampling reflected patients individual clinical courses [75] evaluating individual response of one patient with metastatic pancreatic cancer to PDO selected chemotherapy; PDO insensitivity to initial chemotherapeutic regime was represented in clinical setting as well as good response to PDO sensitive agents [104] Liver cancer no study correlating PDO response to clinical performance…”

Organoids at the PUB: The Porcine Urinary Bladder Serves as a Pancreatic Niche for Advanced Cancer Modeling

“…Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest and most difficult to treat cancers among all tumor entities, with rising incidence and projection to be the second most common cause of cancer-related death by 2030. [1] Despite intensive research and ongoing implementation of a variety of personalized medicine approaches including genome sequencing and organoid-based decision making into treatment regimens, [2][3][4] the 5-year overall survival of patients remains poor as it ranges between 39% in the minority of patients with localized disease to only 3% in patients with distant metastatic disease. [5] Most recently, others and we demonstrated that the generation of human pluripotent stem cell (PSC)-derived pancreatic duct-like organoids (PDLOs) and pancreatic acinus-like organoids (PALOs) enable the investigation of pancreatic disease onset and carcinogenesis in a welldefined and easily customizable genetic background.…”

“…[7][8][9]11] Complementary, patientderived PDAC organoids (PDOs) represent a valuable resource to study late-stage cancer and provide the unique opportunity to reconstruct tumor biology, as well as drug response predictions with direct implications for patient treatment. [2,12,13] Thus, PSCbased and patient-derived pancreatic organoid systems have i) fundamentally advanced the understanding of pancreatic development and disease evolution [14] and ii) substantially extended the toolbox to investigate PDAC by a plethora of perspectives.…”

“…Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest and most difficult to treat cancers among all tumor entities, with rising incidence and projection to be the second most common cause of cancer‐related death by 2030. [ 1 ] Despite intensive research and ongoing implementation of a variety of personalized medicine approaches including genome sequencing and organoid‐based decision making into treatment regimens, [ 2–4 ] the 5‐year overall survival of patients remains poor as it ranges between 39% in the minority of patients with localized disease to only 3% in patients with distant metastatic disease. [ 5 ]…”