Cascinu S, Berardi R, Salvagni S, Beretta G D, Catalano V, Pucci F, Sobrero A, Tagliaferri P, Labianca R, Scartozzi M, Crocicchio F, Mari E, Ardizzoni A
Department of Medical Oncology, Università Politecnica delle Marche, Ancona, Italy.
Br J Cancer. 2008 Jan 15;98(1):71-6. doi: 10.1038/sj.bjc.6604121. Epub 2007 Dec 4.
Interesting activity has been reported by combining chemotherapy with cetuximab. An alternative approach for blocking EGFR function has been the development of small-molecule inhibitors of tyrosine kinase domain such as gefitinib. We designed a multicentre phase II study in advanced colorectal cancer combining gefitinib+FOLFOX in order to determine the activity and to relate EGFR expression and gene amplification and NF-kB activation to therapeutic results. Patients received FOLFOX-4 regimen plus gefitinib as first-line treatment. Tumour samples were analysed for EGFR protein expression by immunohistochemical analysis and for EGFR gene amplification by fluorescence in situ hybridisation (FISH), chromogenic in situ hybridisation (CISH) and NF-kB activation. Forty-three patients were enrolled into this study; 15 patients experienced a partial response (response rate=34.9%), whereas other 12 (27.9%) had a stable disease. Median progression-free survival (PFS) was 7.8 months and median overall survival (OS) was 13.9 months. We did not find any relationship with EGFR overexpression, gene amplification, while NF-kB activation was associated with a resistance to therapy. Gefitinib does not seem to increase the activity of FOLFOX in advanced colorectal cancer even in patients overexpressing EGFR or with EGFR amplification. Furthermore, while NF-kB activation seems to predict resistance to chemotherapy as demonstrated 'in vitro' models, gefitinib does not overcome this mechanism of resistance, as reported for cetuximab.
已有报道称化疗与西妥昔单抗联合使用具有有趣的活性。阻断表皮生长因子受体（EGFR）功能的另一种方法是开发酪氨酸激酶结构域的小分子抑制剂，如吉非替尼。我们设计了一项针对晚期结直肠癌的多中心II期研究，将吉非替尼与FOLFOX联合使用，以确定其活性，并将EGFR表达、基因扩增和核因子-κB（NF-κB）激活与治疗结果相关联。患者接受FOLFOX-4方案加吉非替尼作为一线治疗。通过免疫组织化学分析对肿瘤样本进行EGFR蛋白表达分析，并通过荧光原位杂交（FISH）、显色原位杂交（CISH）和NF-κB激活分析EGFR基因扩增情况。43例患者入组本研究；15例患者出现部分缓解（缓解率=34.9%），而其他12例（27.9%）病情稳定。无进展生存期（PFS）中位数为7.8个月，总生存期（OS）中位数为13.9个月。我们未发现EGFR过表达、基因扩增与之存在任何关联，而NF-κB激活与治疗耐药相关。即使在EGFR过表达或EGFR扩增的患者中，吉非替尼似乎也不会增加FOLFOX在晚期结直肠癌中的活性。此外，正如体外模型所示，NF-κB激活似乎可预测对化疗的耐药性，而吉非替尼并不能克服这种耐药机制，西妥昔单抗也有类似报道。
