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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Companion Diagnostic, Pharmacogenomic, and Cancer Biomarkers

Prognostic and Predictive Biomarkers in Patients with Metastatic Colorectal Cancer Receiving Regorafenib

Yingmiao Liu, Jing Lyu, Kirsten Bell Burdett, Alexander B. Sibley, Ace J. Hatch, Mark D. Starr, John C. Brady, Kelli Hammond, Federica Marmorino, Daniele Rossini, Richard M. Goldberg, Alfredo Falcone, Chiara Cremolini, Kouros Owzar, Anastasia Ivanova, Dominic T. Moore, Michael S. Lee, Hanna K. Sanoff, Federico Innocenti and Andrew B. Nixon
Yingmiao Liu
1Department of Medicine, Duke University Medical Center, Durham, North Carolina.
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Jing Lyu
2Duke Cancer Institute, Durham, North Carolina.
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Kirsten Bell Burdett
2Duke Cancer Institute, Durham, North Carolina.
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Alexander B. Sibley
2Duke Cancer Institute, Durham, North Carolina.
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Ace J. Hatch
1Department of Medicine, Duke University Medical Center, Durham, North Carolina.
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Mark D. Starr
1Department of Medicine, Duke University Medical Center, Durham, North Carolina.
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John C. Brady
1Department of Medicine, Duke University Medical Center, Durham, North Carolina.
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Kelli Hammond
3The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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Federica Marmorino
4Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology, Azienda Ospedaliero- Universitaria Pisana, University of Pisa, Pisa, Italy.
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Daniele Rossini
4Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology, Azienda Ospedaliero- Universitaria Pisana, University of Pisa, Pisa, Italy.
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Richard M. Goldberg
5West Virginia University Cancer Institute, Morgantown, West Virginia.
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Alfredo Falcone
4Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology, Azienda Ospedaliero- Universitaria Pisana, University of Pisa, Pisa, Italy.
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Chiara Cremolini
4Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology, Azienda Ospedaliero- Universitaria Pisana, University of Pisa, Pisa, Italy.
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Kouros Owzar
2Duke Cancer Institute, Durham, North Carolina.
6Duke Department of Biostatistics & Bioinformatics, Durham, North Carolina.
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Anastasia Ivanova
3The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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Dominic T. Moore
3The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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Michael S. Lee
3The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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Hanna K. Sanoff
3The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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Federico Innocenti
3The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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Andrew B. Nixon
1Department of Medicine, Duke University Medical Center, Durham, North Carolina.
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  • For correspondence: anixon@duke.edu
DOI: 10.1158/1535-7163.MCT-20-0249 Published October 2020
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Abstract

Regorafenib is a tyrosine kinase inhibitor approved by the FDA for the treatment of patients with chemotherapy refractory metastatic colorectal cancer (mCRC). Regorafenib inhibits signaling through multiple receptors associated with angiogenesis, metastasis, and tumor immunity. Here, we report biomarker results from LCCC1029, a randomized, placebo-controlled, phase II trial of chemotherapy ± regorafenib in patients with second-line mCRC. A panel of 20 soluble protein biomarkers (termed the Angiome) was assessed in the plasma of 149 patients from the LCCC1029 trial both at baseline and along the treatment continuum. Baseline protein levels were analyzed for prognostic and predictive value for progression-free survival (PFS) and overall survival (OS). Changes in protein levels during treatment were analyzed for potential pharmacodynamic effects. Six markers (HGF, IL6, PlGF, VEGF-R1, OPN, and IL6R) were found to be prognostic for PFS. Nine markers (IL6, TIMP-1, PlGF, VCAM-1, ICAM-1, OPN, TSP-2, HGF, and VEGF-R1) were prognostic for OS. Higher baseline levels of OPN (Pintx = 0.0167), VCAM-1 (Pintx = 0.0216), and PDGF-AA (Pintx = 0.0435) appeared to predict for PFS benefit from regorafenib compared with placebo. VCAM-1 was also potentially predictive of OS benefit from regorafenib compared with placebo (Pintx = 0.0124). On-treatment changes of six markers reflected potential on-target effect of regorafenib. Consistent results were observed in an Italian cohort where 105 patients with late-stage mCRC received regorafenib monotherapy. The key findings of this study suggest that VCAM-1 may be a predictive biomarker for regorafenib benefit, while multiple protein markers may be prognostic of outcome in patients with mCRC.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:2146–54

  • Received March 30, 2020.
  • Revision received June 8, 2020.
  • Accepted July 20, 2020.
  • Published first August 3, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (10)
October 2020
Volume 19, Issue 10
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Prognostic and Predictive Biomarkers in Patients with Metastatic Colorectal Cancer Receiving Regorafenib
Yingmiao Liu, Jing Lyu, Kirsten Bell Burdett, Alexander B. Sibley, Ace J. Hatch, Mark D. Starr, John C. Brady, Kelli Hammond, Federica Marmorino, Daniele Rossini, Richard M. Goldberg, Alfredo Falcone, Chiara Cremolini, Kouros Owzar, Anastasia Ivanova, Dominic T. Moore, Michael S. Lee, Hanna K. Sanoff, Federico Innocenti and Andrew B. Nixon
Mol Cancer Ther October 1 2020 (19) (10) 2146-2154; DOI: 10.1158/1535-7163.MCT-20-0249

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Prognostic and Predictive Biomarkers in Patients with Metastatic Colorectal Cancer Receiving Regorafenib
Yingmiao Liu, Jing Lyu, Kirsten Bell Burdett, Alexander B. Sibley, Ace J. Hatch, Mark D. Starr, John C. Brady, Kelli Hammond, Federica Marmorino, Daniele Rossini, Richard M. Goldberg, Alfredo Falcone, Chiara Cremolini, Kouros Owzar, Anastasia Ivanova, Dominic T. Moore, Michael S. Lee, Hanna K. Sanoff, Federico Innocenti and Andrew B. Nixon
Mol Cancer Ther October 1 2020 (19) (10) 2146-2154; DOI: 10.1158/1535-7163.MCT-20-0249
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Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

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