Manders Peggy, Tjan-Heijnen Vivianne C G, Span Paul N, Grebenchtchikov Nicolai, Foekens John A, Beex Louk V A M, Sweep C G J Fred
Department of Chemical Endocrinology, University Medical Centre Nijmegen, Nijmegen, The Netherlands.
Cancer Res. 2004 Jan 15;64(2):659-64. doi: 10.1158/0008-5472.can-03-1820.
One of the most thoroughly studied systems in relation to its prognostic relevance in patients with breast cancer, is the plasminogen activation system. This system comprises of, among others, the urokinase-type plasminogen activator (uPA) and its main inhibitor (PAI-1). In this study we investigated whether the uPA:PAI-1 complex is associated with the responsiveness of patients with primary breast cancer to adjuvant systemic therapy. Quantitative enzyme-linked immunosorbent assays were used to assess the levels of uPA, PAI-1, and uPA:PAI-1 complex in 1119 tumors of patients with primary invasive breast cancer. These patients were followed for a median follow-up time of 59 months (range, 2-267 months) after the primary diagnosis. Correlations with well-known clinicopathological factors, and univariate and multivariate survival analyses were performed. High uPA:PAI-1 complex levels were correlated with an adverse histological grade, and inversely associated with negative estrogen and progesterone receptor status. High tumor levels of uPA:PAI-1 complex predicted an early relapse in the univariate relapse-free survival analysis (P < 0.001). The multivariate analysis showed that high uPA:PAI-1 complex levels were associated with a decreased relapse-free survival time (P = 0.033), independently of age, tumor size, number of lymph nodes affected, progesterone receptor status, uPA, adjuvant endocrine, and chemotherapy. More important, it was demonstrated that there is a larger benefit from adjuvant chemotherapy for patients with higher versus lower tumor levels of uPA:PAI-1 complex. The results of this study imply that the expression of uPA:PAI-1 complex independently predicts the efficacy of adjuvant chemotherapy in patients with primary breast cancer.
在乳腺癌患者中，与预后相关性研究最为深入的系统之一是纤溶酶原激活系统。该系统尤其包括尿激酶型纤溶酶原激活剂（uPA）及其主要抑制剂（PAI-1）。在本研究中，我们调查了uPA:PAI-1复合物是否与原发性乳腺癌患者对辅助全身治疗的反应性相关。采用定量酶联免疫吸附测定法评估1119例原发性浸润性乳腺癌患者肿瘤中的uPA、PAI-1和uPA:PAI-1复合物水平。这些患者在初次诊断后中位随访时间为59个月（范围2 - 267个月）。进行了与已知临床病理因素的相关性分析以及单变量和多变量生存分析。高uPA:PAI-1复合物水平与不良组织学分级相关，与雌激素和孕激素受体阴性状态呈负相关。在单变量无复发生存分析中，肿瘤中高uPA:PAI-1复合物水平预示着早期复发（P < 0.001）。多变量分析显示，高uPA:PAI-1复合物水平与无复发生存时间缩短相关（P = 0.033），独立于年龄、肿瘤大小、受累淋巴结数量、孕激素受体状态、uPA、辅助内分泌治疗和化疗。更重要的是，结果表明，对于uPA:PAI-1复合物肿瘤水平较高与较低的患者，辅助化疗带来的益处更大。本研究结果表明，uPA:PAI-1复合物的表达独立预测原发性乳腺癌患者辅助化疗的疗效。
