STAT3 磷酸化对转移性结直肠癌患者基于抗 EGFR 治疗的临床疗效的影响。

Impact of STAT3 phosphorylation on the clinical effectiveness of anti-EGFR-based therapy in patients with metastatic colorectal cancer.

机构信息

Department of Medical Oncology, University Hospital of Besançon, Besançon, France.

出版信息

Clin Colorectal Cancer. 2013 Mar;12(1):28-36. doi: 10.1016/j.clcc.2012.09.002. Epub 2012 Oct 17.

DOI:10.1016/j.clcc.2012.09.002

PMID:23083634

Abstract

UNLABELLED

Half of patients with KRAS wild-type colorectal cancer do not benefit from adding anti-epithelial growth factor receptor (EGFR) to standard chemotherapy regimens. This retrospective study was performed in 94 patients with metastatic colorectal cancer (mCRC) treated in the second line with cetuximab and chemotherapy. Signal transducer and activator of transcription 3 (STAT3) phosphorylation in tumor cells was correlated with decreased median progression-free survival and overall survival (OS). These results highlight the potential role of STAT3 as a molecular target to optimize anti-EGFR therapies.

BACKGROUND

Signal transducer and activator of transcription 3 (STAT3) is involved in epithelial growth factor receptor (EGFR) signaling in a KRAS-independent manner. Phosphorylated STAT3 (pSTAT3) expression in patients with metastatic colorectal cancer (mCRC) treated with anti-EGFR-containing salvage chemotherapy has never been investigated.

PATIENTS AND METHODS

: The first endpoint of this retrospective study was to evaluate the impact of pSTAT3 on the time to progression (TTP) in 94 patients with mCRC treated with anti-EGFR-based therapies in the second- or third-line setting between July 2004 and November 2009. The influence of pSTAT3 on objective response rate and overall survival (OS) was also reported. Nuclear expression of pSTAT3 status was evaluated by immunohistochemical tests on formalin-fixed and paraffin-embedded tumor samples obtained before therapy.

RESULTS

Positive expression of pSTAT3 was observed in 24.5% of the tumor samples. The probability of achieving an objective response was 13% among patients with positive nuclear expression of pSTAT3 compared with 41% for patients displaying pSTAT3-negative tumors (P = .02). In a multivariate logistic regression model, high-grade skin rash, wild-type KRAS status, and negative pSTAT3 status significantly improved TTP and OS.

CONCLUSION

These results underscore an impact of pSTAT3 on the clinical efficacy of anti-EGFR-containing chemotherapy regimens and support the prospective assessment of this biomarker.

摘要

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KRAS 野生型结直肠癌患者中有一半不能从标准化疗方案中添加抗表皮生长因子受体 (EGFR) 中获益。这项回顾性研究共纳入 94 名转移性结直肠癌（mCRC）患者，这些患者二线接受西妥昔单抗和化疗治疗。肿瘤细胞中信号转导和转录激活因子 3（STAT3）的磷酸化与中位无进展生存期和总生存期（OS）缩短相关。这些结果突出了 STAT3 作为优化抗 EGFR 治疗的潜在分子靶点的作用。

背景

信号转导和转录激活因子 3（STAT3）以 KRAS 非依赖性方式参与表皮生长因子受体（EGFR）信号转导。从未研究过接受含抗 EGFR 挽救性化疗的转移性结直肠癌（mCRC）患者中磷酸化 STAT3（pSTAT3）的表达。

患者和方法

这项回顾性研究的首要终点是评估 94 例 mCRC 患者二线或三线接受抗 EGFR 治疗时 pSTAT3 对无进展生存期（TTP）的影响，这些患者于 2004 年 7 月至 2009 年 11 月接受治疗。还报告了 pSTAT3 对客观缓解率和总生存期（OS）的影响。采用免疫组织化学试验检测福尔马林固定和石蜡包埋的肿瘤样本中 pSTAT3 的核表达，这些样本是在治疗前获得的。

结果

在 24.5%的肿瘤样本中观察到 pSTAT3 的阳性表达。pSTAT3 核表达阳性患者的客观缓解率为 13%，而 pSTAT3 阴性肿瘤患者的客观缓解率为 41%（P =.02）。在多变量逻辑回归模型中，高级别皮肤不良反应、野生型 KRAS 状态和 pSTAT3 阴性状态显著改善了 TTP 和 OS。