Department of Radiotherapy Campus Mitte, Translational Radiobiology and Radiooncology Research Laboratory, Charite Universit€atsmedizin Berlin, Chariteplatz 1, 10117Berlin, Germany.
Clin Cancer Res. 2011 Aug 1;17(15):5197-204. doi: 10.1158/1078-0432.CCR-10-3338. Epub 2011 Jun 8.
Constitutive activation of epidermal growth factor receptor (EGFR) as a result of gene amplification, mutation, or overexpression of its ligands has been associated with response to EGFR targeting strategies. The role of these molecular mechanisms for the responsiveness of squamous cell carcinoma of the head and neck (SCCHN) to cetuximab-containing regimens remains unknown.
Tumor biopsies from 47 patients, enrolled in a single-arm phase II multicenter study for second-line treatment of recurrent or metastatic SCCHN with cetuximab and docetaxel, were analyzed by immunohistochemistry for expression of EGFR, its deletion variant III (EGFRvIII) and its ligand amphiregulin (AREG). The relation between expression levels and disease control rate (DCR) was evaluated by logistic regression. Association between expression levels, progression-free survival (PFS), and overall survival (OS) was determined by Kaplan-Meier analysis, log-rank test, and uni- and multivariate Cox regression analysis.
High expression of EGFR, EGFRvIII, and AREG was detected in 73%, 17%, and 45% of SCCHN cases, respectively. Expression levels of EGFR had no impact on PFS or OS. High expression levels of EGFRvIII were significantly associated with reduced DCR and shortened PFS (HR: 3.3, P = 0.005) but not with OS. Patients with high AREG expression in tumor cells had significantly shortened OS (HR: 2.2, P = 0.002) and PFS (HR 2.2, P = 0.019) compared with patients with low expression score. Multivariate Cox analysis revealed an independent association of AREG and EGFRvIII with PFS but only AREG was an independent prognosticator of OS.
High EGFRvIII and AREG expression levels identify SCCHN patients who are less likely to benefit from combination treatment with cetuximab and docetaxel.
表皮生长因子受体（EGFR）的基因扩增、突变或配体过表达导致其组成性激活，与 EGFR 靶向策略的反应相关。这些分子机制在头颈部鳞状细胞癌（SCCHN）对含西妥昔单抗方案的反应中的作用尚不清楚。
对 47 例患者的肿瘤活检进行分析，这些患者参加了一项单臂、多中心、Ⅱ期研究，用西妥昔单抗联合多烯紫杉醇治疗复发或转移性 SCCHN。采用免疫组织化学法检测 EGFR、其缺失变异体Ⅲ（EGFRvIII）和配体 Amphiregulin（AREG）的表达。通过逻辑回归评估表达水平与疾病控制率（DCR）之间的关系。通过 Kaplan-Meier 分析、对数秩检验以及单变量和多变量 Cox 回归分析，确定表达水平与无进展生存期（PFS）和总生存期（OS）之间的关系。
73%、17%和 45%的 SCCHN 病例中分别检测到 EGFR、EGFRvIII 和 AREG 的高表达。EGFR 的表达水平对 PFS 或 OS 没有影响。EGFRvIII 的高表达水平与降低的 DCR 和较短的 PFS（HR：3.3，P=0.005）显著相关，但与 OS 无关。肿瘤细胞中 AREG 高表达的患者 OS（HR：2.2，P=0.002）和 PFS（HR 2.2，P=0.019）显著缩短，与低表达评分的患者相比。多变量 Cox 分析显示 AREG 和 EGFRvIII 与 PFS 有独立关联，但只有 AREG 是 OS 的独立预后因素。
高 EGFRvIII 和 AREG 表达水平可识别出不太可能从西妥昔单抗联合多烯紫杉醇联合治疗中获益的 SCCHN 患者。
