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Supplementary Figure from Precision Medicine in Pancreatic Cancer: Patient-Derived Organoid Pharmacotyping Is a Predictive Biomarker of Clinical Treatment Response

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posted on 2023-03-31, 23:54 authored by Toni 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 Figure 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

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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

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