University of Texas M. D., Anderson Cancer Center, Houston, TX 77030, USA.
J Clin Oncol. 2010 Jan 10;28(2):193-201. doi: 10.1200/JCO.2009.22.4279. Epub 2009 Nov 30.
There is an unmet need for biomarkers for identifying patients likely to benefit from anticancer treatments, selecting dose, and understanding mechanisms of resistance. Plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptor 2 (sVEGFR-2) are known to be modulated by VEGF pathway inhibitors. It is unknown whether chemotherapy or VEGFR inhibitor/chemotherapy combinations induce changes in these or other cytokines and angiogenic factors (CAFs) and whether such changes could be markers of benefit.
Thirty-five plasma CAFs were analyzed using multiplexed bead arrays and enzyme-linked immunosorbent assays from 123 patients with non-small-cell lung cancer in a randomized phase II study who received vandetanib, a VEGFR and epidermal growth factor receptor inhibitor, monotherapy carboplatin and paclitaxel (CP), or the combination (VCP). Changes in CAFs at days 8, 22, and 43 from baseline were correlated with progression risk.
VEGF increased and sVEGFR-2 decreased by day 43 in the vandetanib arm, whereas a distinct pattern was observed in the CP and VCP arms, with significant decreases in interleukin (IL) -12, IL-1 receptor antagonist, and matrix metalloproteinase 9 (MMP-9) and increased macrophage chemoattractant protein 1. In each treatment arm, changes in different markers were associated with progression risk. For example, increases in IL-8 with VCP, MMP-9 with CP, and VEGF with vandetanib monotherapy were associated with increased progression risk, and increase in intercellular adhesion molecule 1 with vandetanib was associated with decreased risk.
Vandetanib and chemotherapy treatment led to distinct patterns of CAF changes; the combination resembled chemotherapy alone. Changes in specific CAFs correlated with clinical outcome, but markers differed for each treatment arm. CAF profiling may provide insights into the biologic effects of treatment and identify drug-specific markers of activity and clinical benefit.
需要生物标志物来识别可能从抗癌治疗中获益、选择剂量和了解耐药机制的患者。已知血管内皮生长因子（VEGF）和可溶性 VEGF 受体 2（sVEGFR-2）可被 VEGF 通路抑制剂调节。尚不清楚化疗或 VEGFR 抑制剂/化疗联合治疗是否会引起这些或其他细胞因子和血管生成因子（CAFs）的变化，以及这些变化是否可以作为获益的标志物。
对 123 例接受 VEGF 受体和表皮生长因子受体抑制剂凡德他尼、单药卡铂和紫杉醇（CP）或联合治疗（VCP）的非小细胞肺癌患者的 35 种血浆 CAFs 进行了分析。采用多指标 bead 阵列和酶联免疫吸附试验，从随机 II 期研究中检测患者基线时第 8、22 和 43 天的 CAFs 变化与进展风险相关。
凡德他尼组第 43 天 VEGF 增加，sVEGFR-2 减少，而 CP 和 VCP 组则观察到不同的模式，白细胞介素（IL）-12、IL-1 受体拮抗剂和基质金属蛋白酶 9（MMP-9）显著下降，巨噬细胞趋化蛋白 1 增加。在每个治疗组中，不同标志物的变化与进展风险相关。例如，VCP 组中 IL-8 的增加、CP 组中 MMP-9 的增加和凡德他尼单药治疗中 VEGF 的增加与进展风险增加相关，而凡德他尼组中细胞间黏附分子 1 的增加与风险降低相关。
凡德他尼和化疗治疗导致 CAF 变化的不同模式；联合治疗类似于单独化疗。特定 CAFs 的变化与临床结局相关，但每个治疗组的标志物不同。CAF 分析可能提供对治疗生物学效应的深入了解，并确定药物特异性活性和临床获益的标志物。
