Meaney Claire L, Zingone Adriana, Brown Derek, Yu Yunkai, Cao Liang, Ryan Bríd M
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Oncotarget. 2017 Jun 20;8(25):40946-40957. doi: 10.18632/oncotarget.16784.
Lung cancer is the leading cause of cancer-related mortality worldwide. Low-dose CT (LDCT) imaging is now recommended to screen high-risk lung cancer individuals in the USA. LDCT has resulted in increased detection of stage I lung cancer for which the current standard of care is surgery alone. However, approximately 30% of these patients develop recurrence and therefore are in need of further treatment upon diagnosis. This study aims to explore blood-based inflammatory biomarkers to identify patients at high-risk of mortality for which additional treatment modalities can be offered at time of diagnosis.
Recent work on a small panel of circulating cytokines identified elevated levels of IL-6, a pro-inflammatory cytokine, as an indicator of poor survival for lung cancer patients. To reflect the broader role of inflammation in lung cancer, we examined a large panel of 33 inflammatory proteins in the sera of 129 lung cancer patients selected from the National Cancer Institute-Maryland case-control study. To reduce heterogeneity, we specifically focused our study on stage I lung adenocarcinoma patients.
We replicated the previous observations that IL-6 is associated with prognosis of lung cancer and extended its utility to prognosis in this highly-selected population of stage I lung adenocarcinoma patients. In addition, we developed a multi-marker, combined prognostic classifier that includes the pro-inflammatory Th-17 cell effector cytokine, IL-17. Patients with high levels of IL-6 and IL-17A had a significantly adverse survival compared with patients with low levels (P for trend <0.0001). Patients in the high risk group, with high levels of both proteins had a 5-year survival rate of 46% in comparison to 93% for those with low levels of both markers. Furthermore, we validated the same trends for the IL-6 and IL-17A prognostic signature in an independent data set.
The results identified here justify further investigation of this novel, combined cytokine prognostic classifier for the identification of high-risk stage I lung adenocarcinoma patients. This classifier has the much-needed potential to identify patients at high risk of recurrence and thus prospectively identify the subset of patients requiring more aggressive treatment regimens at the time of diagnosis.
肺癌是全球癌症相关死亡的主要原因。在美国，现在推荐使用低剂量CT（LDCT）成像来筛查高危肺癌个体。LDCT已导致I期肺癌的检出率增加，目前其治疗标准是单纯手术。然而，这些患者中约有30%会出现复发，因此在诊断时需要进一步治疗。本研究旨在探索基于血液的炎症生物标志物，以识别具有高死亡风险的患者，以便在诊断时提供额外的治疗方式。
最近对一小部分循环细胞因子的研究发现，促炎细胞因子白细胞介素-6（IL-6）水平升高是肺癌患者生存不良的一个指标。为了反映炎症在肺癌中的更广泛作用，我们检测了从美国国立癌症研究所-马里兰病例对照研究中选取的129例肺癌患者血清中的一大组33种炎症蛋白。为了减少异质性，我们的研究特别聚焦于I期肺腺癌患者。
我们重复了之前的观察结果，即IL-6与肺癌预后相关，并将其应用扩展到这个高度选择的I期肺腺癌患者群体的预后评估中。此外，我们开发了一种多标志物联合预后分类器，其中包括促炎的Th-17细胞效应细胞因子IL-17。与低水平患者相比，IL-6和IL-17A水平高的患者生存情况明显较差（趋势P<0.0001）。两种蛋白水平都高的高危组患者5年生存率为46%，而两种标志物水平都低的患者为93%。此外，我们在一个独立数据集中验证了IL-6和IL-17A预后特征的相同趋势。
此处得到的结果证明有必要进一步研究这种新型的联合细胞因子预后分类器，以识别高危I期肺腺癌患者。这种分类器有很大潜力识别出复发风险高的患者，从而在诊断时前瞻性地识别出需要更积极治疗方案的患者亚组。
