Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab
Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab
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DOI：
10.1093/jnci/dji174
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发表时间：
2005-07-06
影响因子：
10.3
通讯作者：
Koeppen, H
中科院分区：
文献类型：
--
作者：
Ince, WL;Jubb, AM;Koeppen, H
背景最近的一项III期临床试验显示，在一线伊立替康、5-氟尿嘧啶和亚叶酸（IFL）的基础上，加入贝伐单抗（一种抗血管内皮生长因子-A的单克隆抗体）可延长转移性结直肠癌患者的中位生存期。我们对试验中的患者进行了回顾性分析，以评估k-ras、b-raf或p53或P53表达的突变状态是否可以预测哪些患者更可能对贝伐单抗有反应。研究方法：对295例患者（274例原发性肿瘤，21例转移瘤）的显微切割肿瘤进行DNA序列分析，以确定k-ras，b-raf和p53的突变。免疫组化法检测细胞核P53蛋白表达。使用考克斯回归分析估计总生存期的风险比和95%置信区间（CI）。结果如下：在所有生物标志物亚组中，与安慰剂治疗患者相比，贝伐珠单抗治疗患者的死亡风险估计风险比小于1。213例患者中有88例（41%）观察到k-ras和/或b-raf突变。与一个或两个基因突变的患者相比，野生型k-ras[b-raf]状态肿瘤患者死亡的风险比在IFL+贝伐单抗治疗组为0.51（95%CI = 0.28 - 0.95），在IFL+安慰剂治疗组为0.66（95%CI = 0.37 - 1.19）。205例患者中有139例（68%）发现p53突变，266例患者中有191例（72%）P53过度表达; p53突变和P53过度表达与生存率无统计学显著相关性。结论：我们没有发现k-ras、b-raf或p53突变与在转移性结直肠癌IFL基础上加用贝伐单抗增加中位生存期之间存在统计学显著相关性。
Background. A recent phase III trial showed that the addition of bevacizumab, a monoclonal antibody to vascular endothelial growth factor-A, to first-line irinotecan, 5-fluorouracil, and leucovorin (IFL) prolonged median survival in patients with metastatic colorectal cancer. We carried out a retrospective analysis of patients in the trial to evaluate whether mutation status of k-ras, b-raf, or p53 or P53 expression could predict which patients were more likely to respond to bevacizumab. Methods: Microdissected tumors from 295 patients (274 primary tumors, 21 metastases) were subject to DNA sequence analysis to identify mutations in k-ras, b-raf, and p53. Nuclear P53 expression was determined by immunohistochemistry. Hazard ratios and 95% confidence intervals (CI) for overall survival were estimated using Cox regression analysis. Results: In all biomarker subgroups, estimated hazard ratios for risk of death were less than 1 for bevacizumab-treated patients as compared with those for placebo-treated patients. Mutations in k-ras and/or b-raf were observed in 88 of 213 patients (41%). Hazard ratios for death among patients with tumors with wild-type k-ras[b-raf status, as compared with those of patients with mutations in one or both genes, were 0.51 (95% Cl = 0.28 to 0.95) among those treated with IFL plus bevacizumab and 0.66 (95% CI = 0.37 to 1.19) among those treated with IFL plus placebo. Mutations in p53 were found in 139 of 205 patients (68%), and P53 was over-expressed in 191 of 266 patients (72%); neither p53 mutation nor P53 overexpression was statistically significantly associated with survival. Conclusions: We did not find a statistically significant relationship between mutations of k-ras, b-raf, or p53 and the increase in median survival associated with the addition of bevacizumab to IFL in metastatic colorectal cancer.