title: VEGFA SNP rs2010963 is associated with vascular toxicity in recurrent glioblastomas and longer response to bevacizumab.
abstract: Although anti-VEGF therapy is widely used in high-grade gliomas, no predictor of response or toxicity has been reported yet. We investigated here the association of the functional single nucleotide polymorphism (SNP) rs2010963, located in the 5' untranslated terminal region of the VEGFA gene, with survival, response to bevacizumab (BVZ) and vascular toxicity. The rs2010963 was genotyped by Taqman assay in blood DNA from 954 glioma patients with available survival data, including 225 glioblastoma (GBM) patients treated with BVZ. VEGFA plasma levels were assessed by ELISA in 87 patients before treatment. Thrombo-hemorragic adverse events were recorded during BVZ treatment or not, and in an independent population of 92 GBM patients treated with temozolomide. The CC genotype was associated with the occurrence of thrombo-hemorragic events (CC 25 versus CG 13.5 and GG 5.2 %; P = 0.0044) during BVZ. A similar but weaker and non significant trend was observed in patients not receiving BVZ. A CC genotype was associated with higher levels of plasma VEGFA at baseline (107.6 versus 57.50 pg/mL in heterozygotes (CG) and 52.75 pg/mL in GG patients, P = 0.035 and P = 0.028 respectively). The CC genotype tended to be associated to longer PFS when treated with BVZ (P = 0.05), but not when treated with the temozolomide treatment. Our data suggest that the rs2010963 genotype is associated with longer PFS, higher risk of vascular events in recurrent GBM especially treated with BVZ, and higher plasma VEGFA concentration. It may help to identify patients at risk of vascular adverse events during BVZ treatment.
authors.affiliation: UMPC Univ Paris VI, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, INSERM U 1127, CNRS, UMR 7225; GH Pitié-Salpêtrièr, Sorbonne Universités, 75013, Paris, France.
authors.forename: Anna Luisa
authors.initials: AL
authors.lastname: Di Stefano
authors.forename: Marianne
authors.initials: M
authors.lastname: Labussiere
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lombardi
authors.forename: Marica
authors.initials: M
authors.lastname: Eoli
authors.forename: Donata
authors.initials: D
authors.lastname: Bianchessi
authors.forename: Francesco
authors.initials: F
authors.lastname: Pasqualetti
authors.forename: Patrizia
authors.initials: P
authors.lastname: Farina
authors.forename: Stefania
authors.initials: S
authors.lastname: Cuzzubbo
authors.forename: Jaime
authors.initials: J
authors.lastname: Gallego-Perez-Larraya
authors.forename: Blandine
authors.initials: B
authors.lastname: Boisselier
authors.forename: Francois
authors.initials: F
authors.lastname: Ducray
authors.forename: Caroline
authors.initials: C
authors.lastname: Cheneau
authors.forename: Arrigo
authors.initials: A
authors.lastname: Moglia
authors.forename: Gaetano
authors.initials: G
authors.lastname: Finocchiaro
authors.forename: Yannick
authors.initials: Y
authors.lastname: Marie
authors.forename: Amithys
authors.initials: A
authors.lastname: Rahimian
authors.forename: Khe
authors.initials: K
authors.lastname: Hoang-Xuan
authors.forename: Jean Yves
authors.initials: JY
authors.lastname: Delattre
authors.forename: Karima
authors.initials: K
authors.lastname: Mokhtari
authors.forename: Marc
authors.initials: M
authors.lastname: Sanson
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005838:Genotype; D005909:Glioblastoma / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D006470:Hemorrhage / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D013927:Thrombosis / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab