Oden-Gangloff A, Di Fiore F, Bibeau F, Lamy A, Bougeard G, Charbonnier F, Blanchard F, Tougeron D, Ychou M, Boissière F, Le Pessot F, Sabourin J-C, Tuech J-J, Michel P, Frebourg T
Inserm U614, Faculty of Medicine, Institute for Biomedical Research, University of Rouen, Rouen, France.
Br J Cancer. 2009 Apr 21;100(8):1330-5. doi: 10.1038/sj.bjc.6605008.
Recent studies have suggested that activation of the EGFR pathway leads to malignant transformation only if the p53 protein is inactivated. Therefore, we evaluated the impact of TP53 mutations on cetuximab-based chemotherapy (CT) sensitivity in combination with KRAS mutations that have been associated with cetuximab resistance. KRAS and TP53 status were assessed in tumours from 64 metastatic colorectal cancer patients treated with cetuximab-based CT and correlated to clinical response using the Fisher's exact test. Times to progression (TTPs) according to gene status were calculated using the Kaplan-Meier method and compared with log-rank test. TP53 mutations were found in 41 patients and were significantly associated with controlled disease (CD), as defined as complete response, partial response or stable disease (P=0.037) and higher TTP (20 vs 12 weeks, P=0.004). Remarkably, in the subgroup of 46 patients without KRAS mutation, but not in patients with KRAS mutation, TP53 mutations were also associated with CD (P=0.008) and higher TTP (24 vs 12 weeks, P=0.0007). This study suggests that TP53 mutations are predictive of cetuximab sensitivity, particularly in patients without KRAS mutation, and that TP53 genotyping could have a clinical interest to select patients who should benefit from cetuximab-based CT.
近期研究表明，只有当p53蛋白失活时，表皮生长因子受体（EGFR）信号通路的激活才会导致恶性转化。因此，我们评估了TP53突变对基于西妥昔单抗的化疗（CT）敏感性的影响，并结合了与西妥昔单抗耐药相关的KRAS突变进行研究。对64例接受基于西妥昔单抗的CT治疗的转移性结直肠癌患者的肿瘤进行KRAS和TP53状态评估，并使用Fisher精确检验将其与临床反应相关联。根据基因状态，采用Kaplan-Meier方法计算疾病进展时间（TTP），并通过对数秩检验进行比较。41例患者发现有TP53突变，且与疾病控制（CD）显著相关，疾病控制定义为完全缓解、部分缓解或疾病稳定（P = 0.037）以及更高的TTP（20周对12周，P = 0.004）。值得注意的是，在46例无KRAS突变的患者亚组中，而非有KRAS突变的患者中，TP53突变也与疾病控制（P = 0.008）和更高的TTP（24周对12周，P = 0.0007）相关。本研究表明，TP53突变可预测西妥昔单抗的敏感性，尤其是在无KRAS突变的患者中，并且TP53基因分型对于选择可能从基于西妥昔单抗的CT中获益的患者可能具有临床意义。
