Department of Oncology, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, P.O. Box 100, FI-33014, Tampere, Finland.
Department of Oncology, Tampere University Hospital, P.O. Box 2000, FI-33521, Tampere, Finland.
BMC Cancer. 2019 Jul 24;19(1):732. doi: 10.1186/s12885-019-5959-8.
Angiopoietin growth factors (Angs) regulate angiogenesis and lymphangiogenesis by binding to the endothelial Tie2 receptor. Ang2 expression is elevated in tissue hypoxia and inflammation, which also induce cleavage of the extracellular domain of the orphan Tie1 receptor. Here we have examined if the concentrations of Ang2 and the soluble extracellular domain of Tie1 in patient plasma are associated with the prognosis of patients with metastatic breast cancer.
Plasma Tie1 and Ang2 levels were measured in metastatic breast cancer patients treated in a phase II trial with a taxane-bevacizumab combination chemotherapy in the first-line treatment setting. They were analyzed before treatment, after 6 weeks and 6 months of treatment, and at the final study visit. Using the median concentrations as cutoffs, Tie1 and Ang2 data were dichotomized into low and high concentration groups. Additionally, we analyzed Tie1 concentrations in plasma from 10 healthy women participating in a breast cancer primary prevention study.
Plasma samples were available from 58 (89%) of the 65 patients treated in the trial. The baseline Tie1 levels of the healthy controls were significantly lower than those of the metastatic patients (p < 0.001). The overall survival of the patients with a high baseline Tie1 level was significantly shorter (multivariate HR 3.07, 95% CI 1.39-6.79, p = 0.005). Additionally, the progression-free survival was shorter for patients with a high baseline Tie1 level (multivariate HR 3.78, 95% CI 1.57-9.09, p = 0.003). In contrast, the baseline Ang2 levels had no prognostic impact in a multivariate Cox proportional hazard regression analysis. The combined analysis of baseline Tie1 and Ang2 levels revealed that patients with both high Tie1 and high Ang2 baseline levels had a significantly shorter overall survival than the patients with low baseline levels of both markers (multivariate HR for overall survival 4.32, 95% CI 1.44-12.94, p = 0.009).
This is the first study to demonstrate the prognostic value of baseline Tie1 plasma concentration in patients with metastatic breast cancer. Combined with the results of the Ang2 analyses, the patients with both high Tie1 and Ang2 levels before treatment had the poorest survival.
Clinicaltrials.gov: NCT00979641, registration date 19-DEC-2008. The regional Ethics Committee: R08142M, registration date 18-NOV-2008.
血管生成素生长因子（Angs）通过与内皮 Tie2 受体结合来调节血管生成和淋巴管生成。Ang2 的表达在组织缺氧和炎症中升高，这也会诱导孤儿 Tie1 受体的细胞外结构域的裂解。在这里，我们研究了转移性乳腺癌患者血浆中 Ang2 和 Tie1 可溶性细胞外结构域的浓度是否与患者的预后相关。
在一项 II 期试验中，对转移性乳腺癌患者进行紫杉醇联合贝伐单抗的一线治疗，测量转移性乳腺癌患者的血浆 Tie1 和 Ang2 水平。在治疗前、治疗 6 周和 6 个月以及最后一次研究访视时进行分析。使用中位数浓度作为截断值，将 Tie1 和 Ang2 数据分为低浓度组和高浓度组。此外，我们分析了 10 名参加乳腺癌一级预防研究的健康女性的血浆 Tie1 浓度。
试验中 65 例患者中有 58 例（89%）提供了血浆样本。健康对照组的基线 Tie1 水平明显低于转移性患者（p<0.001）。基线 Tie1 水平高的患者总生存期明显缩短（多变量 HR 3.07，95%CI 1.39-6.79，p=0.005）。此外，基线 Tie1 水平高的患者无进展生存期更短（多变量 HR 3.78，95%CI 1.57-9.09，p=0.003）。相比之下，多变量 Cox 比例风险回归分析显示基线 Ang2 水平无预后影响。基线 Tie1 和 Ang2 水平的联合分析显示，基线水平同时高 Tie1 和 Ang2 的患者总生存期明显短于两种标志物基线水平均低的患者（多变量 HR 总生存期 4.32，95%CI 1.44-12.94，p=0.009）。
这是第一项证明转移性乳腺癌患者基线 Tie1 血浆浓度具有预后价值的研究。结合 Ang2 分析结果，治疗前 Tie1 和 Ang2 水平均高的患者生存最差。
Clinicaltrials.gov：NCT00979641，注册日期 2008 年 12 月 19 日。地区伦理委员会：R08142M，注册日期 2008 年 11 月 18 日。
