Seppälä, Toni T, Zimmerman, Jacquelyn W, Suri, Reecha, Zlomke, Haley, Ivey, Gabriel D, Szabolcs, Annamaria, Shubert, Christopher R, Cameron, John L, Burns, William R, Lafaro, Kelly J, He, Jin, Wolfgang, Christopher L, Zou, Ying S, Zheng, Lei, Tuveson, David A, Eshlemann, James R, Ryan, David P, Kimmelman, Alec C, Hong, Theodore S, Ting, David T, Jaffee, Elizabeth M, Burkhart, Richard A (April 2022) Precision medicine in pancreatic cancer: Patient derived organoid pharmacotyping is a predictive biomarker of clinical treatment response. Clinical Cancer Research. ISSN 1078-0432
Abstract
RATIONALE: Patient-derived organoids (PDOs) 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). METHODS: 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. RESULTS: Clinical sequencing pipelines often fail to detect PDAC-associated somatic mutations in surgical specimens that demonstrate a good pathological 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, CA-19-9 and favorable RECIST imaging response. CONCLUSION: PDOs establishment 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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders Investigative techniques and equipment diseases & disorders > neoplasms Investigative techniques and equipment > biomarker Investigative techniques and equipment > cell culture > cancer organoids Investigative techniques and equipment > cell culture diseases & disorders > cancer > drugs and therapies > chemotherapy diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > drugs and therapies > patient outcomes diseases & disorders > cancer > drugs and therapies > precision medicine diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Tuveson lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 1 April 2022 |
| Date Deposited: | 07 Apr 2022 14:03 |
| Last Modified: | 17 Jan 2024 14:59 |
| PMCID: | PMC9357072 |
| URI: | https://repository.cshl.edu/id/eprint/40566 |
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