Fibrotic Response to Neoadjuvant Therapy Predicts Survival in Pancreatic Cancer and Is Measurable with Collagen-Targeted Molecular MRI

Derek J. Erstad, Mozhdeh Sojoodi, Martin S. Taylor, Veronica Clavijo Jordan, Christian T. Farrar, Andrea L. Axtell, Nicholas J. Rotile, Chloe Jones, Katherine A. Graham-O’Regan, Diego S. Ferreira, Theodoros Michelakos, Filippos Kontos, Akhil Chawla, Shen Li, Sarani Ghoshal, Yin Ching Iris Chen, Gunisha Arora, Valerie Humblet, Vikram Deshpande, Motaz QadanNabeel Bardeesy, Cristina R. Ferrone, Michael Lanuti, Kenneth K. Tanabe*, Peter Caravan, Bryan C. Fuchs

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: To evaluate the prognostic value of posttreatment fibrosis in human PDAC patients, and to compare a type I collagen targeted MRI probe, CM-101, to the standard contrast agent, Gd-DOTA, for their abilities to identify FOLFIRINOX-induced fibrosis in a murine model of PDAC. Experimental Design: Ninety-three chemoradiation-treated human PDAC samples were stained for fibrosis and outcomes evaluated. For imaging, C57BL/6 and FVB mice were orthotopically implanted with PDAC cells and FOLFIRINOX was administered. Mice were imaged with Gd-DOTA and CM-101. Results: In humans, post-chemoradiation PDAC tumor fibrosis was associated with longer overall survival (OS) and disease-free survival (DFS) on multivariable analysis (OS P = 0.028, DFS P = 0.047). CPA increased the prognostic accuracy of a multivariable logistic regression model comprised of previously established

PDAC risk factors [AUC CPA (-) = 0.76, AUC CPA (+) = 0.82]. In multiple murine orthotopic PDAC models, FOLFIRINOX therapy reduced tumor weight (P < 0.05) and increased tumor fibrosis by collagen staining (P < 0.05). CM-101 MR signal was significantly increased in fibrotic tumor regions. CM-101 signal retention was also increased in the more fibrotic FOLFIRINOX-treated tumors compared with untreated controls (P = 0.027), consistent with selective probe binding to collagen. No treatment-related differences were observed with Gd-DOTA imaging. Conclusions: In humans, post-chemoradiation tumor fibrosis is associated with OS and DFS. In mice, our MR findings indicate that translation of collagen molecular MRI with CM-101 to humans might provide a novel imaging technique to monitor fibrotic response to therapy to assist with prognostication and disease management.

Original languageEnglish (US)
Pages (from-to)5007-5018
Number of pages12
JournalClinical Cancer Research
Volume26
Issue number18
DOIs
StatePublished - Sep 15 2020
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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