Di Stefano Anna Luisa, Labussiere Marianne, Lombardi Giuseppe, Eoli Marica, Bianchessi Donata, Pasqualetti Francesco, Farina Patrizia, Cuzzubbo Stefania, Gallego-Perez-Larraya Jaime, Boisselier Blandine, Ducray Francois, Cheneau Caroline, Moglia Arrigo, Finocchiaro Gaetano, Marie Yannick, Rahimian Amithys, Hoang-Xuan Khe, Delattre Jean Yves, Mokhtari Karima, Sanson Marc
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.
J Neurooncol. 2015 Feb;121(3):499-504. doi: 10.1007/s11060-014-1677-x. Epub 2014 Dec 7.
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.
尽管抗血管内皮生长因子（VEGF）疗法在高级别胶质瘤中广泛应用，但尚未有关于反应或毒性预测指标的报道。我们在此研究位于VEGFA基因5'非翻译末端区域的功能性单核苷酸多态性（SNP）rs2010963与生存、对贝伐单抗（BVZ）的反应及血管毒性之间的关联。通过Taqman分析法对954例有生存数据的胶质瘤患者血液DNA中的rs2010963进行基因分型，其中包括225例接受BVZ治疗的胶质母细胞瘤（GBM）患者。在87例患者治疗前通过酶联免疫吸附测定（ELISA）评估VEGFA血浆水平。记录BVZ治疗期间或未治疗时的血栓 - 出血不良事件，以及在一个独立的92例接受替莫唑胺治疗的GBM患者群体中的情况。CC基因型与BVZ治疗期间血栓 - 出血事件的发生相关（CC为25%，CG为13.5%，GG为5.2%；P = 0.0044）。在未接受BVZ治疗的患者中观察到类似但较弱且无统计学意义的趋势。CC基因型与基线时较高的血浆VEGFA水平相关（杂合子（CG）为107.6 pg/mL，GG患者为52.75 pg/mL，分别为P = 0.035和P = 0.028）。CC基因型在用BVZ治疗时倾向于与更长的无进展生存期（PFS）相关（P = 0.05），但在用替莫唑胺治疗时则不然。我们的数据表明，rs2010963基因型与更长的PFS、复发性GBM尤其是接受BVZ治疗时血管事件的较高风险以及较高的血浆VEGFA浓度相关。它可能有助于识别BVZ治疗期间有血管不良事件风险的患者。
