Service d'anatomie et cytologie pathologiques, CHU Rangueil, Toulouse, France 50032.
Hum Pathol. 2013 Oct;44(10):2149-58. doi: 10.1016/j.humpath.2013.03.020. Epub 2013 Jul 8.
To date, chemosensitivity to neoadjuvant chemotherapy of patients with high-grade osteosarcoma is evaluated on surgical resection by evaluation of the percentage of necrotic cells. As yet, no predictive profile of response to chemotherapy has been used in clinical practice. Because we have previously shown that the integrin pathway controls genotoxic-induced cell death and hypoxia, we hypothesized that in primary biopsies, expression of proteins involved in this pathway could be associated with sensitivity to neoadjuvant chemotherapy in high-grade osteosarcoma. We studied β1, β3, and β5 integrin expression and integrin-linked kinase, focal adhesion kinase (FAK), glycogen synthase kinase 3β (GSK3β), Rho B, angiopoietin-2, β-catenin, and ezrin expression by immunohistochemistry in 36 biopsies of osteosarcomas obtained before treatment. All patients received a chemotherapy regimen in the neoadjuvant setting. An immunoreactive score was assessed, combining the percentage of positive tumor cells and staining intensity. We evaluated the correlation of the biomarkers with response to chemotherapy, metastasis-free survival, and overall survival. A combination of 3 biomarkers (β5 integrin, FAK, and GSK3β) discriminated good and poor responders to chemotherapy, with the highest area under the curve (89.9%; 95% confidence interval, 77.4-1.00) and a diagnostic accuracy of 90.3%. Moreover, high expression of ezrin was associated with an increased risk of metastasis (hazard ratio, 3.93; 95% confidence interval, 1.19-12.9; P = .024). We report a protein expression profile in high-grade osteosarcoma associating β5 integrin, FAK, and GSK3β that significantly correlates with poor response to neoadjuvant chemotherapy. This biomarker profile could help select patients for whom an alternative protocol using inhibitors of this pathway can be proposed.
迄今为止，高等级骨肉瘤患者对新辅助化疗的化疗敏感性是通过评估坏死细胞的百分比在手术切除时进行评估的。到目前为止，还没有用于临床实践的化疗反应预测特征。因为我们之前已经表明整合素途径控制遗传毒性诱导的细胞死亡和缺氧，所以我们假设在原发性活检中，参与该途径的蛋白质的表达可能与高等级骨肉瘤对新辅助化疗的敏感性相关。我们通过免疫组织化学研究了 36 例骨肉瘤治疗前活检标本中β1、β3 和β5 整合素表达以及整合素连接激酶、粘着斑激酶（FAK）、糖原合成酶激酶 3β（GSK3β）、Rho B、血管生成素-2、β-连环蛋白和 ezrin 的表达。所有患者在新辅助治疗中均接受了化疗方案。通过评估阳性肿瘤细胞的百分比和染色强度来评估免疫反应评分。我们评估了生物标志物与化疗反应、无转移生存和总生存的相关性。3 种生物标志物（β5 整合素、FAK 和 GSK3β）的组合可区分对化疗反应良好和反应不佳的患者，曲线下面积最高（89.9%；95%置信区间，77.4-1.00），诊断准确性为 90.3%。此外，ezrin 的高表达与转移风险增加相关（危险比，3.93；95%置信区间，1.19-12.9；P=.024）。我们报告了高等级骨肉瘤中的一种蛋白质表达谱，该谱与β5 整合素、FAK 和 GSK3β相关，与新辅助化疗反应不佳显著相关。这种生物标志物谱可以帮助选择可以提出使用该途径抑制剂的替代方案的患者。
