Expression of Heat Shock Protein 27 in Melanoma Metastases Is Associated with Overall Response to Bevacizumab Monotherapy: Analyses of Predictive Markers in a Clinical Phase II Study

The aim of this study was to identify potential predictive biomarkers in 35 patients with metastatic melanoma treated with anti-angiogenic bevacizumab monotherapy in a clinical phase II study. The immunohistochemical expression of various angiogenic factors in tissues from primary melanomas and metastases as well as their concentration in blood samples were examined. Strong expression of Heat Shock Protein 27 (HSP27) in metastases correlated significantly with complete or partial response to bevacizumab (p = 0.044). Furthermore, clinical benefit, i.e., complete or partial response or stable disease for at least 6 months, was more frequent in patients with strong expression of HSP27 in primary tumors (p = 0.046). Tissue expression of vascular endothelial growth factor (VEGF-A), its splicing variant VEGF165b or basic fibroblast growth factor (bFGF) did not correlate with response, and the concentration of HSP27, VEGF-A or bFGF measured in blood samples before treatment did not show predictive value. Further, microvessel density, proliferating microvessel density and presence of glomeruloid microvascular proliferations were assessed in sections of primary tumors and metastases. Microvessel density in primary melanomas was significantly higher in patients with clinical benefit than in non-responders (p = 0.042). In conclusion, our findings suggest that strong HSP27 expression in melanoma metastases predicts response to bevacizumab treatment.
Trial Registration
ClinicalTrials.gov NCT00139360

本研究旨在一项II期临床研究中，针对35例接受抗血管生成贝伐珠单抗（bevacizumab）单药治疗的转移性黑色素瘤患者，筛选潜在的预测性生物标志物。研究检测了原发性黑色素瘤及转移灶组织中多种血管生成因子的免疫组化表达水平，以及其在血液样本中的浓度。转移灶中热休克蛋白27（Heat Shock Protein 27, HSP27）的高表达与贝伐珠单抗治疗的完全或部分缓解显著相关（p = 0.044）。此外，原发性肿瘤中HSP27高表达的患者，其临床获益（即完全或部分缓解，或至少6个月的疾病稳定）比例更高（p = 0.046）。血管内皮生长因子（vascular endothelial growth factor, VEGF-A）、其剪接变体VEGF165b以及碱性成纤维细胞生长因子（basic fibroblast growth factor, bFGF）的组织表达均与治疗响应无相关性，且治疗前血液样本中检测到的HSP27、VEGF-A或bFGF浓度也未体现预测价值。本研究同时评估了原发性肿瘤及转移灶切片中的微血管密度、增殖性微血管密度及肾小球样微血管增生情况。原发性黑色素瘤的微血管密度在存在临床获益的患者中显著高于无应答者（p = 0.042）。综上，本研究结果提示，黑色素瘤转移灶中HSP27的高表达可预测患者对贝伐珠单抗治疗的响应。
试验注册：ClinicalTrials.gov 编号NCT00139360