Supplementary Data from Precision Medicine in Pancreatic Cancer: Patient-Derived Organoid Pharmacotyping Is a Predictive Biomarker of Clinical Treatment Response
posted on 2023-03-31, 23:54authored byToni T. Seppälä, Jacquelyn W. Zimmerman, Reecha Suri, Haley Zlomke, Gabriel D. Ivey, Annamaria Szabolcs, Christopher R. Shubert, John L. Cameron, William R. Burns, Kelly J. Lafaro, Jin He, Christopher L. Wolfgang, Ying S. Zou, Lei Zheng, David A. Tuveson, James R. Eshlemann, David P. Ryan, Alec C. Kimmelman, Theodore S. Hong, David T. Ting, Elizabeth M. Jaffee, Richard A. Burkhart
Supplementary Data from Precision Medicine in Pancreatic Cancer: Patient-Derived Organoid Pharmacotyping Is a Predictive Biomarker of Clinical Treatment Response
Funding
Sigrid Juselius Foundation
Instrumentarium Science Foundation
Emil Aaltonen Foundation
Jane and Aatos Erkko Foundation
Relander Foundation
Finnish Academy
NIH
NCI
SU2C-Lustgarten Foundation Pancreatic Cancer Interception Translational Cancer Research Grant
Entertainment Industry Foundation
American Association for Cancer Research
SU2C
History
ARTICLE ABSTRACT
Patient-derived organoids (PDO) are a promising technology to support precision medicine initiatives for patients with pancreatic ductal adenocarcinoma (PDAC). PDOs may improve clinical next-generation sequencing (NGS) and enable rapid ex vivo chemotherapeutic screening (pharmacotyping).
PDOs were derived from tissues obtained during surgical resection and endoscopic biopsies and studied with NGS and pharmacotyping. PDO-specific pharmacotype is assessed prospectively as a predictive biomarker of clinical therapeutic response by leveraging data from a randomized controlled clinical trial.
Clinical sequencing pipelines often fail to detect PDAC-associated somatic mutations in surgical specimens that demonstrate a good pathologic response to previously administered chemotherapy. Sequencing the PDOs derived from these surgical specimens, after biomass expansion, improves the detection of somatic mutations and enables quantification of copy number variants. The detection of clinically relevant mutations and structural variants is improved following PDO biomass expansion. On clinical trial, PDOs were derived from biopsies of treatment-naïve patients prior to treatment with FOLFIRINOX (FFX). Ex vivo PDO pharmacotyping with FFX components predicted clinical therapeutic response in these patients with borderline resectable or locally advanced PDAC treated in a neoadjuvant or induction paradigm. PDO pharmacotypes suggesting sensitivity to FFX components were associated with longitudinal declines of tumor marker, carbohydrate-antigen 19–9 (CA-19–9), and favorable RECIST imaging response.
PDOs established from tissues obtained from patients previously receiving cytotoxic chemotherapies can be accomplished in a clinically certified laboratory. Sequencing PDOs following biomass expansion improves clinical sequencing quality. High in vitro sensitivity to standard-of-care chemotherapeutics predicts good clinical response to systemic chemotherapy in PDAC.See related commentary by Zhang et al., p. 3176