背景:循环细胞因子可以代表非侵入性生物标志物,以改善对癌症患者临床结局的预测。这里,血浆IL-8,CCL4,骨桥蛋白,LIF和BDNF在基线(T0)测定,治疗2个月后(T2)和,在可行的情况下,进展时(TP),在接受BRAF和MEK抑制剂治疗的70例黑色素瘤患者中。基线细胞因子水平与临床反应的关系,评估了无进展生存期(PFS)和总生存期(OS).
方法:使用xMAP技术测量细胞因子浓度。他们区分应答(Rs)和非应答(NRs)患者的能力通过接受者操作特性分析来评估。用Kaplan-Meier方法估计PFS和OS。Cox比例风险模型用于单变量和多变量分析,以95%置信区间估计粗略和调整后的风险比。
结果:在大多数样品中无法检测到CCL4和LIF。NRs在T0和T2时的中位骨桥蛋白浓度明显高于Rs。NRs中IL-8的T0和T2值也高于Rs,虽然没有达到统计学意义。对于BDNF没有检测到差异。在具有匹配的T0、T2和TP样本的39个Rs中,骨桥蛋白和IL-8从T0到T2显着降低,并在TP时再次升高,BDNF水平保持不变。在NR中,在T2时无一细胞因子显示显著降低。只有骨桥蛋白表现出良好的区分Rs和NRs的能力。高IL-8T0水平与显著较短的PFS和OS以及较高的进展和死亡风险相关。在多变量分析中仍然是OS的独立阴性预后因素。骨桥蛋白T0浓度升高也与OS恶化和死亡风险增加显著相关。高IL-8和高骨桥蛋白的患者显示最低的PFS和OS,在多变量分析中,这种细胞因子组合仍然与死亡风险增加3-6倍独立相关。
结论:循环IL-8和骨桥蛋白是改善靶向治疗患者预后评估的有用生物标志物,作为提高其临床疗效的潜在靶点值得关注。
BACKGROUND: Circulating cytokines can represent non-invasive biomarkers to improve prediction of clinical outcomes of cancer patients. Here, plasma levels of IL-8, CCL4,
osteopontin, LIF and BDNF were determined at baseline (T0), after 2 months of therapy (T2) and, when feasible, at progression (TP), in 70 melanoma patients treated with BRAF and MEK inhibitors. The association of baseline cytokine levels with clinical response, progression-free survival (PFS) and overall survival (OS) was evaluated.
METHODS: Cytokine concentrations were measured using the xMAP technology. Their ability to discriminate between responding (Rs) and non-responding (NRs) patients was assessed by Receiver Operating Characteristics analysis. PFS and OS were estimated with the Kaplan-Meier method. The Cox proportional hazard model was used in the univariate and multivariate analyses to estimate crude and adjusted hazard ratios with 95% confidence intervals.
RESULTS: CCL4 and LIF were undetectable in the majority of samples. The median
osteopontin concentration at T0 and T2 was significantly higher in NRs than in Rs. The median T0 and T2 values of IL-8 were also higher in NRs than in Rs, although the statistical significance was not reached. No differences were detected for BDNF. In 39 Rs with matched T0, T2, and TP samples,
osteopontin and IL-8 significantly decreased from T0 to T2 and rose again at TP, while BDNF levels remained unchanged. In NRs, none of the cytokines showed a significant decrease at T2. Only
osteopontin demonstrated a good ability to discriminate between Rs and NRs. A high IL-8 T0 level was associated with significantly shorter PFS and OS and higher risk of progression and mortality, and remained an independent negative prognostic factor for OS in multivariate analysis. An elevated osteopontin T0 concentration was also significantly associated with worse OS and increased risk of death. Patients with high IL-8 and high osteopontin showed the lowest PFS and OS, and in multivariate analysis this cytokine combination remained independently associated with a three- to six-fold increased risk of mortality.
CONCLUSIONS: Circulating IL-8 and
osteopontin appear useful biomarkers to refine prognosis evaluation of patients undergoing targeted therapy, and deserve attention as potential targets to improve its clinical efficacy.