Division of Molecular Biology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
J Thorac Oncol. 2010 Dec;5(12):1939-48. doi: 10.1097/JTO.0b013e3181f77a39.
The selection of patients with non-small cell lung cancer (NSCLC) for epidermal growth factor receptor (EGFR) inhibitor (EGFR-tyrosine kinase inhibitors [TKIs]) therapy is suboptimal as tumor tissue is often unavailable. Ligands of EGFR, transforming growth factor-alpha (TGFa) and amphiregulin (ARG), and the insulin-like growth factor (IGF) family have been associated with resistance to EGFR-TKIs. The aim of our study was to explore whether concentrations of these factors measured in serum were predictive of response to EGFR-TKIs.
We assessed serum levels of marker candidates using enzyme-linked immunosorbent (TGFa and ARG) and chemiluminescent (IGF1 and IGF-binding protein-3) assays in 61 patients with advanced NSCLC treated with EGFR-TKIs and 63 matched advanced NSCLC control patients without EGFR-TKIs treatment. We dichotomized marker levels at the 20th, 50th, or 80th percentile and evaluated whether the effect of EGFR-TKIs treatment on disease-specific survival (DSS) differed by marker level based on multivariate proportional hazards regression with an interaction term.
The effect of EGFR-TKIs treatment on DSS showed a significant difference by TGFa and ARG (interaction p = 0.046 and p = 0.004, respectively). Low concentrations of TGFa and high concentrations of ARG were associated with a better DSS in EGFR-TKIs patients compared with control patients. Patients with high concentrations of IGF-binding protein-3 had significantly longer DSS, independent of treatment (hazard ratio: 0.60 per 1 mg/liter, 95% confidence interval: 0.46-0.79).
Our results suggest that concentrations of TGFa and ARG measured in serum are predictive of EGFR-TKI response. The combination of these two biomarkers could be of value in the process of selecting patients for treatment with EGFR-TKIs.
由于通常无法获得肿瘤组织，因此选择非小细胞肺癌（NSCLC）患者进行表皮生长因子受体（EGFR）抑制剂（EGFR-酪氨酸激酶抑制剂[TKIs]）治疗并不理想。EGFR 的配体转化生长因子-α（TGFa）和 Amphiregulin（ARG）以及胰岛素样生长因子（IGF）家族与 EGFR-TKIs 的耐药性有关。我们研究的目的是探讨测量血清中这些因素的浓度是否可预测对 EGFR-TKIs 的反应。
我们使用酶联免疫吸附（TGFa 和 ARG）和化学发光（IGF1 和 IGF 结合蛋白-3）测定法评估了 61 名接受 EGFR-TKIs 治疗的晚期 NSCLC 患者和 63 名匹配的未接受 EGFR-TKIs 治疗的晚期 NSCLC 对照患者的血清中候选标志物的浓度。我们将标志物水平在第 20、50 或 80 百分位处进行二分，并根据多变量比例风险回归评估 EGFR-TKIs 治疗对疾病特异性生存率（DSS）的影响是否因标志物水平而异，该回归中包含交互项。
EGFR-TKIs 治疗对 DSS 的影响因 TGFa 和 ARG 而存在显著差异（交互 p = 0.046 和 p = 0.004）。与对照患者相比，EGFR-TKI 患者中 TGFa 浓度较低且 ARG 浓度较高与更好的 DSS 相关。与治疗无关，IGF 结合蛋白-3 浓度较高的患者 DSS 显著延长（风险比：每 1 毫克/升 0.60，95%置信区间：0.46-0.79）。
我们的结果表明，血清中测量的 TGFa 和 ARG 浓度可预测 EGFR-TKI 反应。这两种生物标志物的组合可能在选择接受 EGFR-TKIs 治疗的患者过程中具有价值。
