University of Regensburg, Regensburg, Germany.
Oncology. 2011;81(1):3-8. doi: 10.1159/000330194. Epub 2011 Sep 2.
Genetic alterations within the epidermal growth factor receptor (EGFR) pathway, including KRAS mutations, have been demonstrated to be associated with response to EGFR inhibitors like cetuximab in colorectal cancers. Mutations in the KRAS gene have been found in 70-90% of pancreatic cancers. Unfortunately, the addition of cetuximab to chemotherapy did not increase response or survival in patients with advanced pancreatic cancer in phase II and phase III studies. The aim of this study was to evaluate the relationship between KRAS mutations and response or survival in patients with metastatic pancreatic cancer treated with cetuximab plus chemotherapy.
Within a multicenter phase II trial, 64 patients with metastatic pancreatic cancer were treated with cetuximab in combination with gemcitabine and oxaliplatin until disease progression. Analyses of the EGFR pathway, including KRAS mutations, could be performed in 25 patients. Analyses were carried out following microdissection of the tumor.
Fourteen (56%) of the 25 patients examined harbored a point mutation in codon 12 of the KRAS gene. No differences between the groups were noted in median progression-free survival (104 days in KRAS wild-type patients vs. 118 days in patients with KRAS mutations). Overall survival was longer in wild-type patients compared to patients with KRAS mutations (263 vs. 162 days), but the difference did not reach statistical significance. A further analysis of our clinical phase II trial showed that the presence of a rash was significantly correlated with overall survival.
KRAS mutation in codon 12 may be associated with reduced survival compared to KRAS wild type. The role of KRAS mutations for cetuximab therapy in pancreatic cancer warrants further investigation in larger trials to exclude an epiphenomenon. Furthermore, the development of a rash is indicative of clinical benefit.
表皮生长因子受体（EGFR）通路中的基因改变，包括 KRAS 突变，已被证明与 EGFR 抑制剂（如西妥昔单抗）在结直肠癌中的反应有关。在 70-90%的胰腺癌中发现 KRAS 基因突变。不幸的是，在 II 期和 III 期研究中，西妥昔单抗联合化疗并未增加晚期胰腺癌患者的反应率或生存率。本研究旨在评估 KRAS 突变与接受西妥昔单抗联合化疗的转移性胰腺癌患者的反应或生存之间的关系。
在一项多中心 II 期试验中，64 例转移性胰腺癌患者接受西妥昔单抗联合吉西他滨和奥沙利铂治疗，直至疾病进展。在 25 例患者中可进行 EGFR 通路分析，包括 KRAS 突变。通过肿瘤的微切割进行分析。
在 25 例接受检查的患者中，有 14 例（56%）存在 KRAS 基因 12 密码子点突变。在无进展生存期方面，KRAS 野生型患者的中位无进展生存期为 104 天，KRAS 突变患者为 118 天，两组之间无差异。野生型患者的总生存期长于 KRAS 突变患者（263 天 vs. 162 天），但差异无统计学意义。对我们的 II 期临床试验的进一步分析表明，皮疹的存在与总生存期显著相关。
与 KRAS 野生型相比，12 密码子 KRAS 突变可能与生存时间缩短相关。KRAS 突变在胰腺癌中对西妥昔单抗治疗的作用需要在更大的试验中进一步研究，以排除偶发事件。此外，皮疹的发生提示临床获益。
