Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study
Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study
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DOI：
10.1016/s1470-2045(05)70102-9
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发表时间：
2005-05-01
期刊：
影响因子：
51.1
通讯作者：
Bardelli, A
中科院分区：
文献类型：
--
作者：
Moroni, M;Veronese, S;Bardelli, A
背景抗表皮生长因子受体（antiEGFR）单克隆抗体西妥昔单抗和帕尼单抗在约10%的转移性结直肠患者中具有良好的临床活性。对化疗有抵抗力的癌症。这些药物的临床反应或耐药性的分子机制尚不清楚。 方法 对 31 名转移性结直肠癌患者的肿瘤进行筛查，以检测 EGFR 或其直接细胞内效应物的遗传变化，这些患者在接受西妥昔单抗或帕尼单抗治疗后出现客观缓解 (n=10) 或疾病稳定或疾病进展 (n=21)。具体来说，我们评估了 EGFR 拷贝数以及 EGFR 催化结构域和 KRAS、BRAF 和 PIK3CA 中选定外显子的突变谱。 结果 通过荧光原位杂交 (FISH) 评估的 9 名具有客观反应的患者中，有 8 名的 EGFR 拷贝数增加。相比之下，通过 FISH 评估的 21 名无反应者中的 1 名 EGFR 拷贝数增加（反应者与无反应者的 p < 0.0001，Fisher 精确检验）。 EGFR 催化结构域及其直接下游效应器 PIK3CA、KRAS 和 BRAF 的突变状态与疾病反应无关。在结直肠癌细胞系中，完全抑制 EGFR 拷贝数扩增的细胞增殖的西妥昔单抗浓度，并不影响 EGFR 未扩增的细胞的增殖。 解释 我们认为，对抗 EGFR 治疗的反应具有遗传基础，并建议可以根据 EGFR 拷贝数选择患者进行治疗。
Background The antiepidermal growth factor receptor (antiEGFR) monoclonal antibodies cetuximab and panitumumab have good clinical activity in about 10% of patients with metastatic colorectal. cancer that is resistant to chemotherapy. The molecular mechanisms underlying clinical response or resistance to these agents are unknown.Methods Tumours from 31 patients with metastatic colorectal cancer who had either an objective response (n=10) or stable disease or progressive disease (n=21) after treatment with cetuximab or panitumumab were screened for genetic changes in EGFR or its immediate intracellular effectors. Specifically, we assessed the EGFR copy number and the mutation profile of the EGFR catalytic domain and of selected exons in KRAS, BRAF, and PIK3CA.Results Eight of nine of patients with objective responses who were assessable by fluorescence in-situ hybridisation (FISH) had an increased EGFR copy number. By contrast, one of 21 non-responders assessable by FISH had an increased EGFR copy number (p < 0.0001 for responders vs non-responders, Fisher's exact test). The mutation status of the EGFR catalytic domain and its immediate downstream effectors PIK3CA, KRAS, and BRAF did not correlate with disease response. In colorectal-cancer cell lines, the concentration of cetuximab that completely inhibited proliferation of cells with amplified EGFR copy number did not affect proliferation of cells with unamplified EGFR.Interpretation We propose that the response to antiEGFR treatment has a genetic basis and suggest that patients might be selected for treatment on the basis of EGFR copy number.