title: Expression of Genes Involved in Vascular Morphogenesis and Maturation Predicts Efficacy of Bevacizumab-Based Chemotherapy in Patients Undergoing Liver Resection.
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 before bevacizumab treatment was available. Relative mRNA levels of 9 genes (ACVRL1, EGFL7, EPHB4, HIF1A, VEGFA, VEGFB, VEGFC, FLT1, and 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 months; 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. Mol Cancer Ther; 15(11); 2814-21. ©2016 AACR.
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.|Department of Surgery, Medical University Vienna, Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stremitzer
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ning
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sunakawa
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsusaka
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Anish
authors.initials: A
authors.lastname: Parekh
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okazaki
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Diana
authors.initials: D
authors.lastname: Hanna
authors.affiliation: Cancer Genetics, Inc., Los Angeles, California.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Astrow
authors.affiliation: Cancer Genetics, Inc., Los Angeles, California.
authors.forename: Miriana
authors.initials: M
authors.lastname: Moran
authors.affiliation: Cancer Genetics, Inc., Los Angeles, California.
authors.forename: Jose
authors.initials: J
authors.lastname: Hernandez
authors.affiliation: Cancer Genetics, Inc., Los Angeles, California.
authors.forename: Craig
authors.initials: C
authors.lastname: Stephens
authors.affiliation: Biocenter, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Scherer
authors.affiliation: Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria.
authors.forename: Judith
authors.initials: J
authors.lastname: Stift
authors.affiliation: Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Wrba
authors.affiliation: Department of Surgery I, Rudolfstiftung Hospital, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gruenberger
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California. lenz@usc.edu.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab / Q000494:pharmacology / Q000627:therapeutic use*; D001808:Blood Vessels / Q000196:embryology* / Q000378:metabolism*; D003131:Combined Modality Therapy; D005260:Female; D015870:Gene Expression; D006498:Hepatectomy; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009024:Morphogenesis / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics*; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab