Sørensen Nanna M, Byström Per, Christensen Ib J, Berglund Ake, Nielsen Hans Jørgen, Brünner Nils, Glimelius Bengt
Section of Biomedicine, Department of Veterinary Pathobiology, Faculty of Life Sciences, University of Copenhagen, Copenhagen, Denmark.
Clin Cancer Res. 2007 Jul 15;13(14):4117-22. doi: 10.1158/1078-0432.CCR-07-0186.
Tissue inhibitor of metalloproteinase-1 (TIMP-1) is known to protect cells against apoptosis. We raised the hypothesis that elevated tumor tissue levels and thereby plasma levels of TIMP-1 would predict resistance to apoptosis-inducing chemotherapy.
Ninety patients with metastatic colorectal cancer were included in the study. Plasma TIMP-1 and serum carcinoembryonic antigen (CEA) were measured in samples obtained before the first cycle of chemotherapy.
Analysis of best objective response (complete or partial response versus stable or progressive disease) showed that patients with low plasma TIMP-1 had higher probability of obtaining an objective response [odds ratio (OR), 3.5; 95% confidence interval (95% CI), 1.4-8.5, P=0.007]. CEA treated as a continuous variable was also a statistically significant predictor of no response (OR, 1.3; 95% CI, 1.0-1.7, P=0.02, area under the curve 0.66) but much less so. Plasma TIMP-1 was the only significant covariate in a multivariable analysis of best objective response (OR, 3.6; 95% CI, 1.4-9.5; P=0.001). Plasma TIMP-1 scored as a continuous variable on the log scale (log(e)) was significantly associated with overall survival [OS; hazard ratio (HR), 3.8; 95% CI, 2.4-5.9; P<0.0001] and with time to progression (TTP; HR, 1.5; 95% CI, 1.0-2.3; P=0.048). Multivariable analysis showed that plasma TIMP-1 was significant for OS when including routine clinical baseline covariates (HR, 3.5; 95% CI, 2.1-5.8; P<0.0001). A multivariable analysis including TTP instead of OS showed that only plasma TIMP-1 was retained in the model (HR, 1.5). CEA was not significantly associated with TTP or OS when TIMP-1 was included in the model.
This study shows that plasma TIMP-1 levels are significantly and independently associated with objective response, TTP, and OS in patients with metastatic colorectal cancer receiving combination chemotherapy.
已知金属蛋白酶组织抑制剂-1（TIMP-1）可保护细胞免受凋亡。我们提出假说，即肿瘤组织中TIMP-1水平升高进而血浆中TIMP-1水平升高可预测对诱导凋亡化疗的耐药性。
90例转移性结直肠癌患者纳入本研究。在化疗第一周期前采集的样本中检测血浆TIMP-1和血清癌胚抗原（CEA）。
对最佳客观反应（完全或部分缓解与稳定或疾病进展）的分析表明，血浆TIMP-1水平低的患者获得客观反应的概率更高[比值比（OR），3.5；95%置信区间（95%CI），1.4 - 8.5，P = 0.007]。将CEA作为连续变量处理时，它也是无反应的统计学显著预测因子（OR，1.3；95%CI，1.0 - 1.7，P = 0.02，曲线下面积0.66），但预测能力要弱得多。在最佳客观反应的多变量分析中，血浆TIMP-1是唯一显著的协变量（OR，3.6；95%CI，1.4 - 9.5；P = 0.001）。以对数尺度（log(e)）作为连续变量评分的血浆TIMP-1与总生存期[OS；风险比（HR），3.8；95%CI，2.4 - 5.9；P < 0.0001]以及疾病进展时间（TTP；HR，1.5；95%CI，1.0 - 2.3；P = 0.048）显著相关。多变量分析表明，当纳入常规临床基线协变量时，血浆TIMP-1对OS有显著意义（HR，3.5；95%CI，2.1 - 5.8；P < 0.0001）。一项包含TTP而非OS的多变量分析表明，模型中仅保留了血浆TIMP-1（HR，1.5）。当模型中纳入TIMP-1时，CEA与TTP或OS无显著相关性。
本研究表明，在接受联合化疗的转移性结直肠癌患者中，血浆TIMP-1水平与客观反应、TTP和OS显著且独立相关。
