Polymorphisms in Cyclooxygenase-2 and Epidermal Growth Factor Receptor Are Associated with Progression-Free Survival Independent of K-ras in Metastatic Colorectal Cancer Patients Treated with Single-Agent Cetuximab
Polymorphisms in Cyclooxygenase-2 and Epidermal Growth Factor Receptor Are Associated with Progression-Free Survival Independent of K-ras in Metastatic Colorectal Cancer Patients Treated with Single-Agent Cetuximab
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DOI：
10.1158/1078-0432.ccr-07-5165
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发表时间：
2008-12-01
影响因子：
11.5
通讯作者：
Lenz, Heinz-Josef
中科院分区：
文献类型：
--
作者：
Lurje, Georg;Nagashima, Fumio;Lenz, Heinz-Josef
目的：最近，在一项西妥昔单抗治疗对氟尿嘧啶、奥沙利铂和伊立替康化疗难治的表皮生长因子受体（EGFR）表达转移性结直肠癌（mCRC）患者的11期研究中报告了12%的客观缓解率（IMC-0144）。在这项大规模的分子相关性研究中，我们检测了参与EGFR信号通路的K-ras突变状态和基因多态性是否与IMC-0144的临床结局相关。实验设计：我们分析了西妥昔单抗IMC-0144 II期临床试验中346例mCRC患者中130例的所有可用组织样本。结果：COX-2（考克斯-2）-765 G > C [C/C; RR，0.31; 95%可信区间（95% CI），0.12-0.84; P = 0.032]，考克斯-2 +8473 T > C（C/C; RR，0.67; 95%CI，0.40-1.13; P = 0.003），EGF+61 A> G EGFR +497 G > A（A/G; RR，0.82; 95% CI，0.56-1.20; P = 0.017）基因型与其他基因型比较，差异有统计学意义（P < 0.05）。此外，肿瘤没有K-ras突变的患者比K-ras突变的患者表现出更好的RR，PFS和总生存期。多因素分析中，考克斯-2 +8473 T > C（调整后P = 0.013）和EGFR +497 G）A（校正P = 0.010）与无进展生存期显著相关，与皮疹毒性、K-ras突变状态和东部协作组体能状态无关。考克斯-2和EGFR的多态性可能是预测西妥昔单抗单药治疗的mCRC患者的临床结局的有用的独立分子标志物，与皮疹毒性、K-ras突变、和东部肿瘤协作组体能状态。
Purpose: Recently, an objective response rate of 12% was reported in a phase 11 study of cetuximab in patients with epidermal growth factor receptor (EGFR) -expressing metastatic colorectal cancer (mCRC) refractory to fluoropyrimicline-, oxaliplatin-, and irinotecan-based chemotherapy (IMC-0144). In this large molecular correlates study, we tested whether K-ras mutation status and polymorphisms in genes involved in the EGFR-signaling pathway were associated with clinical outcome in IMC-0144.Experimental Design: We analyzed all available tissue samples from 130 of 346 mCRC patients enrolled in the IMC-0144 phase II clinical trial of cetuximab. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissues, and K-ras mutation status and the genotypes were analyzed using PCR-RFLP, direct DNA-sequencing, and 5'-end [gamma-P-33] ATP-labeled PCR-protocols.Results: The PFS of patients with cyclooxygenase-2 (COX-2) -765 G > C [C/C; risk ratio (RR), 0.31; 95% confidence interval (95% CI), 0.12-0.84; P = 0.032], COX-2 +8473 T > C (C/C; RR, 0.67; 95% CI, 0.40-1.13; P = 0.003), EGF+61A > G (G/G; RR, 0.57; 95% CI, 0.34-0.95; P = 0.042), and EGFR +497 G > A (A/G; RR, 0.82; 95% CI, 0.56-1.20; P = 0.017) genotypes was significantly longer compared with those with other genotypes. In addition, patients whose tumors did not have K-ras mutations showed better RR, PFS, and overall survival than patients with K-ras mutations. In multivariable analysis, COX-2 +8473 T > C (adjusted P = 0.013) and EGFR +497 G)A (adjusted P = 0.010) remained significantly associated with progression-free survival, independent of skin rash toxicity, K-ras mutation status, and Eastern Cooperative Group performance status.Conclusions: Polymorphisms in COX-2 and EGFR may be useful independent molecular markers to predict clinical outcome in patients with mCRC treated with single-agent cetuximab, independent of skin rash toxicity, K-ras mutation, and Eastern Cooperative Oncology Group performance status.