Department of Neurosurgery, Stanford University, Stanford, California; Department of Radiology, Stanford University, Stanford, California; Stanford Center for Biomedical Informatics Research and Biomedical Informatics Training Program, Stanford, California; School of Medicine, Stanford University, Stanford, California; Department of Biomolecular Engineering, University of California, Santa Cruz, California.
Neuro Oncol. 2017 Jul 1;19(7):997-1007. doi: 10.1093/neuonc/now270.
In previous clinical trials, antiangiogenic therapies such as bevacizumab did not show efficacy in patients with newly diagnosed glioblastoma (GBM). This may be a result of the heterogeneity of GBM, which has a variety of imaging-based phenotypes and gene expression patterns. In this study, we sought to identify a phenotypic subtype of GBM patients who have distinct tumor-image features and molecular activities and who may benefit from antiangiogenic therapies.
Quantitative image features characterizing subregions of tumors and the whole tumor were extracted from preoperative and pretherapy perfusion magnetic resonance (MR) images of 117 GBM patients in 2 independent cohorts. Unsupervised consensus clustering was performed to identify robust clusters of GBM in each cohort. Cox survival and gene set enrichment analyses were conducted to characterize the clinical significance and molecular pathway activities of the clusters. The differential treatment efficacy of antiangiogenic therapy between the clusters was evaluated.
A subgroup of patients with elevated perfusion features was identified and was significantly associated with poor patient survival after accounting for other clinical covariates (P values <.01; hazard ratios > 3) consistently found in both cohorts. Angiogenesis and hypoxia pathways were enriched in this subgroup of patients, suggesting the potential efficacy of antiangiogenic therapy. Patients of the angiogenic subgroups pooled from both cohorts, who had chemotherapy information available, had significantly longer survival when treated with antiangiogenic therapy (log-rank P=.022).
Our findings suggest that an angiogenic subtype of GBM patients may benefit from antiangiogenic therapy with improved overall survival.
在之前的临床试验中，抗血管生成疗法（如贝伐单抗）在新诊断的胶质母细胞瘤（GBM）患者中并未显示出疗效。这可能是由于 GBM 的异质性，它具有多种基于成像的表型和基因表达模式。在这项研究中，我们试图确定一种 GBM 患者的表型亚型，这些患者具有不同的肿瘤成像特征和分子活性，可能受益于抗血管生成疗法。
从 117 例 GBM 患者的术前和治疗前灌注磁共振（MR）图像中提取了定量图像特征，这些特征可表征肿瘤的亚区和整个肿瘤。在两个独立的队列中，进行了无监督共识聚类以确定 GBM 的稳健聚类。进行 Cox 生存和基因集富集分析以表征聚类的临床意义和分子通路活性。评估了聚类之间抗血管生成治疗的差异治疗效果。
确定了一个具有升高的灌注特征的亚组，该亚组与患者的生存不良显著相关，在考虑了其他临床协变量后（P 值<.01；危险比>3），在两个队列中均一致发现。在该患者亚组中，血管生成和缺氧途径得到了富集，这表明抗血管生成治疗具有潜在的疗效。对来自两个队列的具有化疗信息的血管生成亚组的患者进行汇总分析发现，接受抗血管生成治疗的患者的生存时间明显延长（对数秩 P=.022）。
我们的研究结果表明，GBM 患者的血管生成亚型可能受益于抗血管生成治疗，从而提高总体生存率。
