Thoracic Oncology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
J Thorac Oncol. 2011 Nov;6(11):1889-94. doi: 10.1097/JTO.0b013e3182286d41.
The epidermal growth factor receptor (EGFR) mutation status is a validated biomarker for the stratification of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) treatment in patients with non-small cell lung cancer (NSCLC); however, its use is limited in patients with wild-type EGFR, and new biomarkers are needed. We hypothesized that the serum concentration of heparan sulfate (HS), which activates oncogenic growth factor receptor signaling through EGFR and non-EGFR signaling pathways, may be a novel glycobiological biomarker for EGFR-TKIs treatment in NSCLC.
The pretreatment serum HS concentrations were determined using enzyme-linked immunosorbent assay in 83 patients with stage IV non-small cell lung adenocarcinoma who received EGFR-TKIs treatment. The relationship between the serum HS concentrations and patient characteristics, tumor response, progression-free survival (PFS), and overall survival (OS) were analyzed.
Patient sex, performance status, smoking history, and EGFR mutation status were associated with tumor response. The serum HS concentrations were significantly higher among patients with progressive disease than among those without progressive disease (p = 0.003). Furthermore, the serum HS concentrations were strongly associated with a poor PFS and OS in a univariate Cox analysis (p = 0.0022 and p = 0.0003, respectively). A stratified multivariate Cox model according to the EGFR mutation status showed that higher HS concentrations were significantly associated with a shorter PFS and OS (p = 0.0012 and p = 0.0003).
We concluded that a high-serum HS concentration was strongly related to a poor treatment outcome of EGFR-TKIs and may be a promising noninvasive and repeatable glycobiological biomarker in cancer treatment.
表皮生长因子受体（EGFR）突变状态是一种经证实的生物标志物，可用于非小细胞肺癌（NSCLC）患者中 EGFR 酪氨酸激酶抑制剂（EGFR-TKIs）治疗的分层；然而，其在 EGFR 野生型患者中的应用受到限制，需要新的生物标志物。我们假设，通过 EGFR 和非 EGFR 信号通路激活致癌生长因子受体信号的硫酸乙酰肝素（HS）的血清浓度可能是 NSCLC 中 EGFR-TKIs 治疗的新型糖生物学生物标志物。
我们采用酶联免疫吸附试验（ELISA）检测了 83 例接受 EGFR-TKIs 治疗的 IV 期非小细胞肺腺癌患者的预处理血清 HS 浓度。分析了血清 HS 浓度与患者特征、肿瘤反应、无进展生存期（PFS）和总生存期（OS）之间的关系。
患者性别、表现状态、吸烟史和 EGFR 突变状态与肿瘤反应有关。进展性疾病患者的血清 HS 浓度明显高于非进展性疾病患者（p = 0.003）。此外，单因素 Cox 分析显示，血清 HS 浓度与较差的 PFS 和 OS 显著相关（p = 0.0022 和 p = 0.0003）。根据 EGFR 突变状态分层的多变量 Cox 模型显示，较高的 HS 浓度与较短的 PFS 和 OS 显著相关（p = 0.0012 和 p = 0.0003）。
我们得出结论，高血清 HS 浓度与 EGFR-TKIs 治疗效果差密切相关，可能是癌症治疗中一种有前途的非侵入性和可重复的糖生物学生物标志物。
