title: Genetic variants in VEGF pathway genes in neoadjuvant breast cancer patients receiving bevacizumab: Results from the randomized phase III GeparQuinto study.
abstract: Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression-free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2-negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre-planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF-A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49-3.75), 1.20 (95% CI, 0.88-1.64) and 0.61 (95% CI, 0.34-1.12). Notably, some SNPs in VEGF-A exhibited a more pronounced effect in the triple-negative subgroup. Several SNPs in VEGF-A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.
authors.affiliation: Department of Gynecology and Obstetrics, University Breast Center for Franconia, Erlangen University Hospital, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen-EMN Comprehensive Cancer Center, Erlangen, Germany.
authors.forename: Alexander
authors.identifier: http://orcid.org/0000-0003-2601-3398
authors.initials: A
authors.lastname: Hein
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: GBG Forschungs GmbH, Neu-Isenburg, Germany.|Department of Gynecology and Obstetrics, Frankfurt University Hospital, Goethe University of Frankfurt, Frankfurt Am Main, Germany.
authors.forename: Gunter
authors.initials: G
authors.lastname: von Minckwitz
authors.affiliation: Department of Gynecology and Obstetrics, University Breast Center for Franconia, Erlangen University Hospital, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen-EMN Comprehensive Cancer Center, Erlangen, Germany.|Biostatistics Unit, Department of Gynecology and Obstetrics, Erlangen University Hospital, Erlangen, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Häberle
authors.affiliation: Department of Obstetrics and Gynecology, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Eidtmann
authors.affiliation: CHOP Onkologie Bethanien, Frankfurt, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Tesch
authors.affiliation: Helios-Klinikum, Berlin-Buch, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Untch
authors.affiliation: Eilenriede-Klinik, Hannover, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Hilfrich
authors.affiliation: Department of Obstetrics and Gynecology, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schem
authors.affiliation: Breast Center of Düsseldorf, Luisenkrankenhaus, Düsseldorf, Germany.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Rezai
authors.affiliation: Department of Gynecology, University of Rostock, Rostock, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Gerber
authors.affiliation: Department of Obstetrics and Gynecology, Magdeburg University Hospital, Magdeburg, Germany.
authors.forename: Serban
authors.initials: S
authors.lastname: Dan Costa
authors.affiliation: St. Getrauden Breast Center, St. Gertrauden Krankenhaus, Berlin, Germany.
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Blohmer
authors.affiliation: Department of Gynecology and Obstetrics, Frankfurt University Hospital, Goethe University of Frankfurt, Frankfurt Am Main, Germany.|Neue Frauenklinik, Lucerne Cantonal Hospital, Lucerne, Switzerland.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schwedler
authors.affiliation: Praxisklinik, Krebsheilkunde Für Frauen, Brustzentrum, Berlin, Germany.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Kittel
authors.affiliation: Department of Gynecology, University of Tübingen, Tübingen, Germany.|Department of Gynecology and Obstetrics, Düsseldorf University Hospital, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Fehm
authors.affiliation: St. Johannes Hospital, Dortmund, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Kunz
authors.affiliation: Department of Gynecology and Obstetrics, University Breast Center for Franconia, Erlangen University Hospital, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen-EMN Comprehensive Cancer Center, Erlangen, Germany.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.affiliation: Institute of Human Genetics, Erlangen University Hospital, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.affiliation: Department of Gynecology, Klinikum Zum Roten Kreuz, Munich, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Hanusch
authors.affiliation: Department of Gynecology, University of Ulm, Ulm, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Huober
authors.affiliation: Department of Gynecology and Obstetrics, Lübeck University Hospital, Lübeck, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Liedtke
authors.affiliation: Helios-Klinikum, Berlin-Buch, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Mau
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Moisse
authors.affiliation: Department of Gynecology and Obstetrics, Hamburg University Hospital, Hamburg, Germany.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Müller
authors.affiliation: GBG Forschungs GmbH, Neu-Isenburg, Germany.
authors.forename: Valentina
authors.initials: V
authors.lastname: Nekljudova
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Gilian
authors.initials: G
authors.lastname: Peuteman
authors.affiliation: Department of Gynecology and Obstetrics, Ludwig Maximilian University, Munich, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Rack
authors.affiliation: Department of Gynecology and Obstetrics, University Breast Center for Franconia, Erlangen University Hospital, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen-EMN Comprehensive Cancer Center, Erlangen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rübner
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Van Brussel
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Medical School-Mayo Foundation, Rochester, MN.
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Medical School-Mayo Foundation, Rochester, MN.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Weinshilboum
authors.affiliation: GBG Forschungs GmbH, Neu-Isenburg, Germany.|Department of Gynecology and Obstetrics, Frankfurt University Hospital, Goethe University of Frankfurt, Frankfurt Am Main, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.affiliation: Department of Gynecology and Obstetrics, University Breast Center for Franconia, Erlangen University Hospital, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen-EMN Comprehensive Cancer Center, Erlangen, Germany.|Division of Hematology/Oncology, Department of Medicine, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, CA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics; D017024:Chemotherapy, Adjuvant; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000517:prevention & control; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab
keywords: SNP; VEGF; anti-angiogenesis; bevacizumab; biomarker; breast cancer; genetic variant; prognosis