分析 HER-3、胰岛素样生长因子-1、核因子-kB 和表皮生长因子受体基因拷贝数对接受伊立替康-西妥昔单抗治疗的 K-RAS 野生型结直肠癌患者临床结局的预测价值。
Analysis of HER-3, insulin growth factor-1, nuclear factor-kB and epidermal growth factor receptor gene copy number in the prediction of clinical outcome for K-RAS wild-type colorectal cancer patients receiving irinotecan-cetuximab.
机构信息
Department of Medical Oncology, United Hospitals, and Postgraduate School in Medical Oncology, University of Ancona, Ancona, Italy.
出版信息
Ann Oncol. 2012 Jul;23(7):1706-12. doi: 10.1093/annonc/mdr558. Epub 2011 Nov 23.
BACKGROUND
A large proportion of colorectal cancer patients does not benefit from the use of anti-epidermal growth factor receptor (EGFR) treatment although in the absence of a mutation of the K-RAS gene. Preliminary observations suggested that HER-3, insulin-like growth factor-1 (IGF-1), nuclear factor-kB (NF-kB) and EGFR gene copy number (GCN) might identify patients not likely to benefit from anti-EGFR therapy. We tested the interaction between HER-3, IGF-1, NF-kB, EGFR GCN and K-RAS mutational analysis to verify the relative ability of these variables to identify a subgroup of patients more likely to benefit from EGFR-targeted treatment among those harbouring a K-RAS wild-type status.
PATIENTS AND METHODS
We retrospectively collected tumours from 168 patients with metastatic colorectal cancer treated with irinotecan-cetuximab. K-RAS was assessed with direct sequencing, EGFR amplification was assessed by chromogenic in situ hybridisation (CISH) and HER-3, IGF-1 and NF-kB were assessed by immunohistochemistry.
RESULTS
In patients with K-RAS wild-type tumours, the following molecular factors resulted independently associated with response rate: HER-3 [odds ratio (OR)=4.6, 95% confidence interval (CI) 1.8-13.6, P=0.02], IGF-1 (OR=4.2, 95% CI 2-10.2, P=0.003) and EGFR GCN (OR=4.1, 95% CI 1.9-26.2, P=0.04). These factors also independently correlated with overall survival as follows: HER-3 [hazard ratio (HR)=0.4, 95% CI 0.28-0.85, P=0.008], IGF-1 (HR=0.47, 95% CI 0.24-0.76, P<0.0001) and EGFR GCN (HR=0.59, 95% CI 0.22-0.89, P=0.04).
DISCUSSION
We believe that our data may help further composing the molecular mosaic of EGFR-resistant tumours. The role of HER-3, IGF-1 and CISH EGFR GCN should be prospectively validated in clinical trials investigating anti-EGFR treatment strategies in colorectal cancer patients.
背景
尽管缺乏 K-RAS 基因突变，仍有很大一部分结直肠癌患者不能从抗表皮生长因子受体（EGFR）治疗中获益。初步观察表明，HER-3、胰岛素样生长因子-1（IGF-1）、核因子-kB（NF-kB）和 EGFR 基因拷贝数（GCN）可能可以识别出不太可能从抗 EGFR 治疗中获益的患者。我们测试了 HER-3、IGF-1、NF-kB、EGFR GCN 之间的相互作用，并结合 K-RAS 突变分析，以验证这些变量在识别具有野生型 K-RAS 状态的患者亚组中，相对能够识别更有可能从 EGFR 靶向治疗中获益的患者。
患者和方法
我们回顾性收集了 168 例接受伊立替康-西妥昔单抗治疗的转移性结直肠癌患者的肿瘤样本。通过直接测序评估 K-RAS，通过显色原位杂交（CISH）评估 EGFR 扩增，通过免疫组化评估 HER-3、IGF-1 和 NF-kB。
结果
在 K-RAS 野生型肿瘤患者中，以下分子因素与缓解率独立相关：HER-3[比值比（OR）=4.6，95%置信区间（CI）1.8-13.6，P=0.02]、IGF-1（OR=4.2，95%CI 2-10.2，P=0.003）和 EGFR GCN（OR=4.1，95%CI 1.9-26.2，P=0.04）。这些因素也与总生存期独立相关：HER-3[风险比（HR）=0.4，95%CI 0.28-0.85，P=0.008]、IGF-1[HR=0.47，95%CI 0.24-0.76，P<0.0001]和 EGFR GCN[HR=0.59，95%CI 0.22-0.89，P=0.04]。
讨论
我们认为我们的数据可能有助于进一步构建 EGFR 耐药肿瘤的分子镶嵌图。HER-3、IGF-1 和 CISH EGFR GCN 的作用应在临床试验中进行前瞻性验证，以研究结直肠癌患者的抗 EGFR 治疗策略。
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