Aix-Marseille Université, INSERM CRO2, Marseille, France (E.T., F.B., D.F.-B., L.O., O.C.); Assistance Publique-Hôpitaux de Marseille (AP-HM), CHU Timone, Service de Neuro-Oncologie, Marseille, France (E.T., M.B., M.M., C.B.); Aix-Marseille Université, Public Health Research Unit-EA3279 AP-HM, Marseille, France (A.L.); Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Avicenne, Service de Neurologie, Bobigny, France (A.C.); Université Paris Descartes, Laboratoire de Recherches Biochirurgicales, Hôpital Européen Georges Pompidou, Paris, France (A.C.); INSERM U 975, CNRS UMR 7225, Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moëlle Épinière UMR-S975, Paris, France (M.S.); AP-HP, Service Neurologie 2, Groupe Hospitalier Pitié-Salpêtrière, Paris, France (M.S.); AP-HM, CHU Timone, Service de Neurochirurgie, Marseille, France (P.M.); AP-HM, CHU Timone, Service d'Anatomopathologie, Marseille, France (D.F.-B.); CHU Nord, Laboratoire de Transfert, Marseille (L.O.).
Neuro Oncol. 2014 Mar;16(3):392-9. doi: 10.1093/neuonc/not226. Epub 2013 Dec 9.
A predictive marker of bevacizumab activity is an unmet medical need. We evaluated the predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in recurrent high-grade glioma treated with bevacizumab.
Analyzed in plasma were a set of 11 prebiomakers of interest (vascular endothelial growth factor receptor [VEGF]; VEGF receptor 2; basic fibroblast growth factor; stromal cell derived factor 1; placenta growth factor; urokinase-type plasminogen activator; plasminogen activator inhibitor 1; matrix metalloproteinases 2, 7, and 9; and adrenomedulline), using ELISA, at baseline and 2 weeks after bevacizumab initiation in a prospective cohort of 26 patients (Cohort 1). Correlations were validated in a separate retrospective cohort (Cohort 2; n = 50) and tested in cohort patients treated with cytotoxic agents without bevacizumab (Cohort 3; n = 34). Dosages were correlated to objective response, progression-free survival (PFS), and overall survival (OS).
In Cohort 1, high MMP2 baseline level was associated with a probability of objective response of 83.3% versus 15.4% for low MMP2 level (P = .001). In multivariate analysis, baseline level of MMP2 correlated with PFS (hazard ratio, 3.92; 95% confidence interval [CI]:1.46-10.52; P = .007) and OS (hazard ratio, 4.62; 95% CI: 1.58-13.53; P = .005), as decrease of VEGF (P = .038 for PFS and P = .013 for OS) and MMP9 (P = .016 for PFS and P = .025 for OS). In Cohort 2, MMP2, but not MMP9, confirmed its predictive significance. In Cohort 3, no association was found between MMP2, MMP9, and outcome.
In patients with recurrent high-grade glioma treated with bevacizumab, but not with cytotoxic agent, high MMP2 plasma levels are associated with prolonged tumor control and survival. MMP2 should be tested in randomized clinical trials that evaluate bevacizumab efficacy, and its biological role reassessed.
贝伐单抗活性的预测标志物是未满足的医学需求。我们评估了参与新生血管形成和侵袭的选定循环前生物标志物在接受贝伐单抗治疗的复发性高级别神经胶质瘤患者中的预后预测价值。
使用 ELISA 法分析了 26 例患者（队列 1）基线和贝伐单抗起始后 2 周的一组 11 种前生物标志物（血管内皮生长因子受体 [VEGF]；VEGF 受体 2；碱性成纤维细胞生长因子；基质细胞衍生因子 1；胎盘生长因子；尿激酶型纤溶酶原激活物；纤溶酶原激活物抑制剂 1；基质金属蛋白酶 2、7 和 9；和肾上腺髓质素）。在单独的回顾性队列（队列 2；n = 50）中验证了相关性，并在未接受贝伐单抗治疗的细胞毒性药物的队列患者中进行了测试（队列 3；n = 34）。剂量与客观反应、无进展生存期（PFS）和总生存期（OS）相关。
在队列 1 中，高 MMP2 基线水平与客观反应的概率为 83.3%，而低 MMP2 水平为 15.4%（P =.001）。在多变量分析中，MMP2 的基线水平与 PFS（危险比，3.92；95%置信区间 [CI]：1.46-10.52；P =.007）和 OS（危险比，4.62；95% CI：1.58-13.53；P =.005）相关，VEGF（P =.038 用于 PFS 和 P =.013 用于 OS）和 MMP9（P =.016 用于 PFS 和 P =.025 用于 OS）下降。在队列 2 中，MMP2 但不是 MMP9 证实了其预测意义。在队列 3 中，MMP2 和 MMP9 与结局之间没有关联。
在接受贝伐单抗而非细胞毒性药物治疗的复发性高级别神经胶质瘤患者中，高 MMP2 血浆水平与肿瘤控制和生存时间延长相关。MMP2 应在评估贝伐单抗疗效的随机临床试验中进行测试，并重新评估其生物学作用。
