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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Research Article

Expression of genes involved in vascular morphogenesis and maturation predicts efficacy of bevacizumab-based chemotherapy in patients undergoing liver resection

Stefan Stremitzer, Wu Zhang, Dongyun Yang, Yan Ning, Yu Sunakawa, Satoshi Matsusaka, Anish Parekh, Satoshi Okazaki, Diana Hanna, Stephanie H. Astrow, Miriana Moran, Jose Hernandez, Craig Stephens, Stefan J. Scherer, Judith Stift, Friedrich Wrba, Thomas Gruenberger and Heinz-Josef Lenz
Stefan Stremitzer
Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California
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Wu Zhang
Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California
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Dongyun Yang
Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California
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Yan Ning
Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California
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Yu Sunakawa
Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California
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Satoshi Matsusaka
Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California
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Anish Parekh
Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California
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Satoshi Okazaki
Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California
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Diana Hanna
Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California
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Stephanie H. Astrow
Cancer Genetics, Inc.
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Miriana Moran
Cancer Genetics, Inc.
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Jose Hernandez
Cancer Genetics, Inc.
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Craig Stephens
Cancer Genetics, Inc.
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Stefan J. Scherer
Biocenter, University of Wuerzburg
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Judith Stift
Clinical Institute of Pathology, Medical University Vienna
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Friedrich Wrba
Clinical Institute of Pathology, Medical University Vienna
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Thomas Gruenberger
Department of Surgery I, Rudolfstiftung Hospital
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Heinz-Josef Lenz
Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California
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  • For correspondence: lenz@usc.edu
DOI: 10.1158/1535-7163.MCT-16-0275
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Abstract

Angiogenesis-related gene expression is associated with the efficacy of anti-VEGF therapy. We tested whether intratumoral mRNA expression levels of genes involved in vascular morphogenesis and early vessel maturation predict response, recurrence-free survival (RFS), and overall survival (OS) in a unique cohort of patients with colorectal liver metastases (CLM) treated with bevacizumab-based chemotherapy followed by curative liver resection. Intratumoral mRNA was isolated from resected bevacizumab-pretreated CLM from 125 patients. In 42 patients, a matching primary tumor sample collected prior to bevacizumab treatment was available. Relative mRNA levels of 9 genes (ACVRL1, EGFL7, EPHB4, HIF1A, VEGFA, VEGFB, VEGFC, FLT1, KDR) were analyzed by RT-PCR and evaluated for associations with response, RFS, and OS. P values for the associations between the individual dichotomized expression level and RFS were adjusted for choosing the optimal cut-off value. In CLM, high expression of VEGFB, VEGFC, HIF1A, and KDR and low expression of EGFL7 were associated with favorable RFS in multivariable analysis (P<0.05). High ACVRL1 levels predicted favorable 3-year OS (P=0.041) and radiologic response (PR 1.093, SD 0.539, P=0.002). In primary tumors, low VEGFA and high EGFL7 were associated with radiologic and histologic response (P<0.05). High VEGFA expression predicted shorter RFS (10.1 vs. 22.6 mo; HR 2.83, P=0.038). High VEGFB (46% vs. 85%; HR 5.75, P=0.009) and low FLT1 (55% vs. 100%; P=0.031) predicted lower 3-year OS rates. Our data suggest that intratumoral mRNA expression of genes involved in vascular morphogenesis and early vessel maturation may be promising predictive and/or prognostic biomarkers.

  • Received May 4, 2016.
  • Revision received July 19, 2016.
  • Accepted August 2, 2016.
  • Copyright {copyright, serif}2016, American Association for Cancer Research.
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Published OnlineFirst August 17, 2016
doi: 10.1158/1535-7163.MCT-16-0275

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Expression of genes involved in vascular morphogenesis and maturation predicts efficacy of bevacizumab-based chemotherapy in patients undergoing liver resection
Stefan Stremitzer, Wu Zhang, Dongyun Yang, Yan Ning, Yu Sunakawa, Satoshi Matsusaka, Anish Parekh, Satoshi Okazaki, Diana Hanna, Stephanie H. Astrow, Miriana Moran, Jose Hernandez, Craig Stephens, Stefan J. Scherer, Judith Stift, Friedrich Wrba, Thomas Gruenberger and Heinz-Josef Lenz
Mol Cancer Ther August 17 2016 DOI: 10.1158/1535-7163.MCT-16-0275

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Expression of genes involved in vascular morphogenesis and maturation predicts efficacy of bevacizumab-based chemotherapy in patients undergoing liver resection
Stefan Stremitzer, Wu Zhang, Dongyun Yang, Yan Ning, Yu Sunakawa, Satoshi Matsusaka, Anish Parekh, Satoshi Okazaki, Diana Hanna, Stephanie H. Astrow, Miriana Moran, Jose Hernandez, Craig Stephens, Stefan J. Scherer, Judith Stift, Friedrich Wrba, Thomas Gruenberger and Heinz-Josef Lenz
Mol Cancer Ther August 17 2016 DOI: 10.1158/1535-7163.MCT-16-0275
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Copyright 2016 by the American Association for Cancer Research.

Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

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