In Vivo Detection of EGFRvIII in Glioblastoma via Perfusion Magnetic Resonance Imaging Signature Consistent with Deep Peritumoral Infiltration: The φ-Index.
In Vivo Detection of EGFRvIII in Glioblastoma via Perfusion Magnetic Resonance Imaging Signature Consistent with Deep Peritumoral Infiltration: The φ-Index.
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DOI：
10.1158/1078-0432.ccr-16-1871
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发表时间：
2017-08-15
期刊：
影响因子：
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通讯作者：
Davatzikos C
中科院分区：
文献类型：
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作者：
Bakas S;Akbari H;Pisapia J;Martinez-Lage M;Rozycki M;Rathore S;Dahmane N;O'Rourke DM;Davatzikos C
表皮生长因子受体变体III（EGFRvIII）突变被认为是胶质母细胞瘤（最常见和最具侵袭性的脑癌）的驱动突变和治疗靶点。目前，检测EGFRvIII需要术后组织分析，这是离体的，无法捕捉肿瘤的空间异质性。考虑到越来越多的证据表明，在体内成像签名捕捉癌症的分子特征，本研究的目的是检测EGFRvIII在原发性胶质母细胞瘤的非侵入性，使用常规临床获得的成像。我们发现肿瘤周围浸润和血管形成模式与EGFRvIII状态相关。因此，我们构建了一个定量的患者内瘤周异质性指数（PHI/φ指数），通过对比即时和远端瘤周水肿的灌注模式。在独立发现（n = 64）和验证（n = 78）队列的术前灌注扫描中应用φ指数，揭示了该EGFRvIII成像特征的普遍性。两个队列的分析表明，获得的特征具有高度准确性（89.92%）、特异性（92.35%）和敏感性（83.77%），具有显著的区分能力（p = 4.0033 × 10 − 10，AUC = 0.8869）。结果表明，EGFRvIII+肿瘤具有高度浸润-迁移表型，在整个瘤周水肿中显示出相似的灌注模式。相反，EGFRvIII-肿瘤显示出与瘤周局限性血管化一致的灌注动力学，这表明广泛的瘤周切除/放射可能有益。该EGFRvIII签名潜在地适合于临床翻译，因为从临床获得的图像的分析获得。使用患者内异质性测量，而不是基于人群的关联，使得φ指数可能抵抗扫描仪间的变化。总的来说，我们的研究结果使EGFRvIII的非侵入性评估，为患者选择靶向治疗，分层到临床试验，个性化的治疗计划，并可能治疗反应评估。
The epidermal growth factor receptor variant III (EGFRvIII) mutation has been considered a driver mutation and therapeutic target in glioblastoma, the most common and aggressive brain cancer. Currently, detecting EGFRvIII requires postoperative tissue analyses, which are ex vivo and unable to capture the tumor’s spatial heterogeneity. Considering the increasing evidence of in vivo imaging signatures capturing molecular characteristics of cancer, this study aims to detect EGFRvIII in primary glioblastoma non-invasively, using routine clinically-acquired imaging. We found peritumoral infiltration and vascularization patterns being related to EGFRvIII status. We therefore constructed a quantitative within-patient peritumoral heterogeneity index (PHI/φ-index), by contrasting perfusion patterns of immediate and distant peritumoral edema. Application of φ-index in preoperative perfusion scans of independent discovery (n=64) and validation (n=78) cohorts, revealed the generalizability of this EGFRvIII imaging signature. Analysis in both cohorts demonstrated that the obtained signature is highly accurate (89.92%), specific (92.35%) and sensitive (83.77%), with significantly distinctive ability (p=4.0033×10−10, AUC=0.8869). Findings indicated a highly infiltrative-migratory phenotype for EGFRvIII+ tumors, which displayed similar perfusion patterns throughout peritumoral edema. Contrarily, EGFRvIII− tumors displayed perfusion dynamics consistent with peritumorally-confined vascularization, suggesting potential benefit from extensive peritumoral resection/radiation. This EGFRvIII signature is potentially suitable for clinical translation, since obtained from analysis of clinically-acquired images. Use of within-patient heterogeneity measures, rather than population-based associations, renders φ-index potentially resistant to inter-scanner variations. Overall, our findings enable non-invasive evaluation of EGFRvIII for patient selection for targeted therapy, stratification into clinical trials, personalized treatment planning, and potentially treatment-response evaluation.