Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Clin Cancer Res. 2009 Dec 1;15(23):7389-97. doi: 10.1158/1078-0432.CCR-09-1149. Epub 2009 Nov 17.
Activation of the epidermal growth factor receptor (EGFR) signaling pathway has been reported to induce resistance to (chemo)radiation in cancers, such as head and neck cancer, whereas EGFR-targeted agents in combination with (chemo)radiation seem to improve treatment efficacy. The aim of this study was to determine the relation between proteins involved in the EGFR pathway and response to (chemo)radiation and survival in a large, well-documented series of cervical cancer patients.
Pretreatment tissue samples of 375 consecutive International Federation of Gynecologists and Obstetricians stage Ib to IVa cervical cancer patients treated with (chemo)radiation between January 1980 and December 2006 were collected. Clinicopathologic and follow-up data were prospectively obtained during standard treatment and follow-up. Protein expression of EGFR, phosphorylated EGFR (pEGFR), PTEN, phosphorylated AKT, and phosphorylated extracellular signal-regulated kinase (pERK) was assessed by immunohistochemistry on tissue microarrays.
EGFR staining was present in 35.3%, pEGFR in 19.7%, PTEN in 34.1%, phosphorylated AKT in 4.1%, and pERK in 29.2% of tumors. pEGFR staining was related to PTEN (P = 0.001) and pERK staining (P = 0.004). EGFR staining was inversely related to PTEN (P = 0.011). In multivariate analysis, membranous staining of EGFR [hazard ratio (HR), 1.84; 95% confidence interval (95% CI), 1.20-2.82; P = 0.005] and cytoplasmic staining of pEGFR (HR, 1.71; 95% CI, 1.11-2.66; P = 0.016) were independent predictors of poor response to (chemo)radiation. Membranous EGFR staining also was an independent prognostic factor for poor disease-specific survival (HR, 1.54; 95% CI, 1.09-2.17; P = 0.014).
EGFR and pEGFR immunostainings are frequently observed and independently associated with poor response to therapy and disease-specific survival in cervical cancer patients primarily treated by (chemo)radiation. Our data present the EGFR pathway as a promising therapeutic target in already ongoing clinical trials.
据报道，表皮生长因子受体（EGFR）信号通路的激活会导致头颈部癌症等癌症对（放）化疗产生耐药性，而 EGFR 靶向药物联合（放）化疗似乎能提高治疗效果。本研究旨在确定在一组大型、记录完备的宫颈癌患者中，EGFR 通路相关蛋白与对（放）化疗的反应和生存之间的关系。
收集了 1980 年 1 月至 2006 年 12 月期间接受（放）化疗的 375 例连续的国际妇产科联合会（FIGO）分期 Ib 至 IVa 期宫颈癌患者的预处理组织样本。在标准治疗和随访期间，前瞻性地获得了临床病理和随访数据。通过组织微阵列免疫组化评估 EGFR、磷酸化 EGFR（pEGFR）、PTEN、磷酸化 AKT 和磷酸化细胞外信号调节激酶（pERK）的蛋白表达。
肿瘤中 EGFR 染色阳性率为 35.3%，pEGFR 染色阳性率为 19.7%，PTEN 染色阳性率为 34.1%，磷酸化 AKT 染色阳性率为 4.1%，pERK 染色阳性率为 29.2%。pEGFR 染色与 PTEN（P=0.001）和 pERK 染色（P=0.004）相关。EGFR 染色与 PTEN 呈负相关（P=0.011）。多变量分析显示，EGFR 的膜染色[风险比（HR），1.84；95%置信区间（95%CI），1.20-2.82；P=0.005]和 pEGFR 的细胞质染色（HR，1.71；95%CI，1.11-2.66；P=0.016）是对（放）化疗反应不良的独立预测因素。膜性 EGFR 染色也是疾病特异性生存不良的独立预后因素（HR，1.54；95%CI，1.09-2.17；P=0.014）。
在主要接受（放）化疗治疗的宫颈癌患者中，EGFR 和 pEGFR 免疫组化染色经常观察到，并与治疗反应不良和疾病特异性生存不良独立相关。我们的数据表明，EGFR 通路是目前正在进行的临床试验中很有前途的治疗靶点。
