Correlation Between Drug Sensitivity Profiles of Ex Vivo Expanded Circulating Tumor Cells and Clinical Treatment Response in Pancreatic Ductal Adenocarcinoma Patients

Abstract

BackgroundPancreatic ductal adenocarcinoma (PDAC) is highly aggressive and has poor prognosis. There are few biomarkers to inform treatment decisions, and collecting tumor samples for genomic or drug sensitivity testing is challenging.MethodsCirculating tumor cells (CTCs) were prepared from the liquid biopsies of PDAC patients. These cells were subsequently expanded ex vivo to form CTC-derived organoid cultures, using a laboratory-developed biomimetic cell culture system. The CTC-derived organoids were tested for sensitivity to a PDAC panel of nine drugs, with tests conducted in triplicate, and a weighted cytotoxicity score (CTS) was calculated from the results. Clinical response to treatment in patients was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria at the time of blood sampling and 3 months later. CTS was then correlated with clinical response, and analyzed using 2 × 2 contingency tables.ResultsA total of 41 liquid biopsies were collected from 31 patients, with 87.8% of liquid biopsies from patients with Stage 4 disease. CTC-derived organoid expansion was achieved in 3 weeks, with 87.8% culture efficiency. CTC-derived organoid cultures were positive for EpCAM staining and negative for CD45 staining in surface marker analysis. All patients had received a median of two lines of treatment prior to enrollment, and prospective utility analysis indicated significant correlation of CTS with clinical treatment response. Two representative case studies are also presented to illustrate the relevant clinical contexts.ConclusionsIn this study, CTCs were expanded from the liquid biopsies of PDAC patients with a high success rate. Drug sensitivity profiles from CTC-derived organoid cultures correlated meaningfully with treatment response. Further studies are warranted to validate the predictive potential for this approach.Trial RegistrationTaipei Medical University Hospital Protocol Record N201803020, registered on July 10, 2018; ClinicalTrials.gov Identifier: NCT04972461, retrospectively registered on July 22, 2021.