Correlation between drug sensitivity profiles of circulating tumour cell-derived organoids and clinical treatment response in patients with pancreatic ductal adenocarcinoma

Yuan-Hung Wu; Yi-Ping Hung; Nai-Chi Chiu; Rheun-Chuan Lee; Chung-Pin Li; Yee Chao; Yi-Ming Shyr; Shin-E Wang; Shih-Chin Chen; Sheng-Hsuan Lin; Yi-Hsuan Chen; Yu-Mei Kang; Shih-Ming Hsu; Sang-Hue Yen; Jeng-You Wu; Kuan-Der Lee; Huey-En Tseng; Jia-Ruey Tsai; Jui-Hsiang Tang; Jeng-Fong Chiou; Thierry Burnouf; Yin-Ju Chen; Peng-Yuan Wang; Long-Sheng Lu

doi:10.1016/j.ejca.2022.01.030

Correlation between drug sensitivity profiles of circulating tumour cell-derived organoids and clinical treatment response in patients with pancreatic ductal adenocarcinoma

Eur J Cancer. 2022 May:166:208-218. doi: 10.1016/j.ejca.2022.01.030. Epub 2022 Mar 17.

Authors

Yuan-Hung Wu¹, Yi-Ping Hung², Nai-Chi Chiu³, Rheun-Chuan Lee³, Chung-Pin Li⁴, Yee Chao⁵, Yi-Ming Shyr⁶, Shin-E Wang⁶, Shih-Chin Chen⁶, Sheng-Hsuan Lin⁷, Yi-Hsuan Chen⁸, Yu-Mei Kang⁵, Shih-Ming Hsu⁹, Sang-Hue Yen¹⁰, Jeng-You Wu¹¹, Kuan-Der Lee¹², Huey-En Tseng¹³, Jia-Ruey Tsai¹³, Jui-Hsiang Tang¹³, Jeng-Fong Chiou¹⁴, Thierry Burnouf¹⁵, Yin-Ju Chen¹⁶, Peng-Yuan Wang¹⁷, Long-Sheng Lu¹⁸

Affiliations

¹ Division of Radiation Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 11217, Taiwan; School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
² School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
³ School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; Department of Radiology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
⁴ School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; Division of Clinical Skills Training, Department of Medical Education, Taipei Veterans General Hospital, Taipei 11217, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
⁵ Division of Radiation Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 11217, Taiwan; School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
⁶ School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
⁷ Institute of Statistics, National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan; Institute of Data Science and Engineering, National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan.
⁸ Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan.
⁹ Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
¹⁰ Division of Radiation Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 11217, Taiwan; Department of Radiation Oncology, Taipei Municipal Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan.
¹¹ Department of Radiation Oncology, Taipei Municipal Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan.
¹² Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan; Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
¹³ Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan.
¹⁴ Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of Radiation Oncology, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan.
¹⁵ Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan; International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan.
¹⁶ Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan; Department of Radiation Oncology, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan; International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan; Department of Medical Research, Taipei Medical University Hospital, Taipei 11031, Taiwan.
¹⁷ Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Oujiang Laboratory, Wenzhou, Zhejiang 325000, China.
¹⁸ Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan; Department of Radiation Oncology, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan; International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan; School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan; International Ph.D. Program for Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Biomedical Materials and Tissue Engineering, Taipei Medical University, Taipei, Taiwan. Electronic address: lslu@tmu.edu.tw.

PMID: 35306319
DOI: 10.1016/j.ejca.2022.01.030

Abstract

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive and has poor prognosis. There are few biomarkers to inform treatment decisions, and collecting tumour samples for testing is challenging.

Methods: Circulating tumour cells (CTCs) from patients with PDAC liquid biopsies were expanded ex vivo to form CTC-derived organoid cultures, using a laboratory-developed biomimetic cell culture system. 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 Tumours (RECIST) version 1.1 criteria at the time of blood sampling and 3 months later. The correlation between CTS and clinical response was then assessed.

Results: A total of 41 liquid biopsies (87.8% from patients with Stage 4 disease) were collected from 31 patients. The 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 the surface marker analysis. All patients had received a median of two lines of treatment prior to enrolment 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.

Conclusions: CTCs were expanded from patients with PDAC liquid biopsies 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.

Keywords: Antitumour drug screening assays; Circulating tumour cells; Liquid biopsy; Medical oncology; Pancreatic ductal carcinoma; Personalised medicine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / metabolism
Carcinoma, Pancreatic Ductal* / pathology
Humans
Neoplastic Cells, Circulating* / pathology
Organoids / metabolism
Pancreatic Neoplasms* / pathology
Prospective Studies

Substances

Biomarkers, Tumor