Etienne-Grimaldi Marie-Christine, Formento Jean-Louis, Francoual Mireille, François Eric, Formento Patricia, Renée Nicole, Laurent-Puig Pierre, Chazal Maurice, Benchimol Daniel, Delpero Jean-Robert, Letoublon Christian, Pezet Denis, Seitz Jean-François, Milano Gérard
Oncopharmacology Department, Centre Antoine Lacassagne, Université René Descartes, Paris, France.
Clin Cancer Res. 2008 Aug 1;14(15):4830-5. doi: 10.1158/1078-0432.CCR-07-4906.
K-Ras mutations predict resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies. Because combinations of anti-EGFR with 5-fluorouracil (5-FU)-based chemotherapy are promising treatments, we analyzed the effect of K-Ras mutations in patients having received exclusive 5-FU therapy.
This study was conducted on 93 stage IV colorectal cancer patients with unresectable measurable liver metastasis receiving 5-FU-leucovorin (56 men and 37 women; 77 cancer deaths). Liver metastases (n = 93) along with primary tumors (n = 48) were analyzed for K-Ras mutations (codons 12 and 13), p53 mutations (exons 4-9), p53 polymorphism (codon 72), thymidylate synthase (TS) polymorphism (28-bp repeats including G>C mutation), methylenetetrahydrofolate reductase polymorphism (677C>T, 1298A>C), thymidylate synthase (TS) activity, dihydropyrimidine dehydrogenase activity, folylpolyglutamate synthase activity, and p53 protein expression.
Thirty-six of 93 (38.7%) metastases were K-Ras mutated (30 at codon 12 and 6 at codon 13). Mutated primary tumors (16 of 48) matched perfectly with mutated metastases. The additional analyzed tumor markers were not different between K-Ras mutated and wild-type tumors. The objective response rate was 37%: 44.4% in K-Ras mutated versus 32.1% in wild-type K-Ras metastasis (P = 0.27). Low TS activity in metastasis was the only significant predictor of tumor response (P = 0.047). K-Ras status did not influence specific survival.
The present data indicate a perfect concordance of K-Ras mutations between primary and liver metastasis and suggest that any predictive and/or prognostic value of K-Ras mutations in treatments combining anti-EGFR monoclonal antibodies with 5-FU should be exclusively linked to the anti-EGFR agent.
K-Ras突变可预测对抗表皮生长因子受体（EGFR）单克隆抗体的耐药性。由于抗EGFR与基于5-氟尿嘧啶（5-FU）的化疗联合使用是很有前景的治疗方法，我们分析了K-Ras突变对接受单纯5-FU治疗患者的影响。
本研究针对93例IV期不可切除的可测量肝转移结直肠癌患者进行（56例男性和37例女性；77例癌症死亡）。分析肝转移灶（n = 93）以及原发肿瘤（n = 48）的K-Ras突变（密码子12和13）、p53突变（外显子4-9）、p53多态性（密码子72）、胸苷酸合成酶（TS）多态性（28 bp重复序列，包括G>C突变）、亚甲基四氢叶酸还原酶多态性（677C>T、1298A>C）、胸苷酸合成酶（TS）活性、二氢嘧啶脱氢酶活性、叶酰聚谷氨酸合成酶活性以及p53蛋白表达。
93个转移灶中有36个（38.7%）发生K-Ras突变（密码子12处30个，密码子13处6个）。突变的原发肿瘤（48个中的16个）与突变的转移灶完全匹配。K-Ras突变型和野生型肿瘤之间的其他分析肿瘤标志物无差异。客观缓解率为37%：K-Ras突变型转移灶为44.4%，野生型K-Ras转移灶为32.1%（P = 0.27）。转移灶中低TS活性是肿瘤反应的唯一显著预测指标（P = 0.047）。K-Ras状态不影响特定生存期。
目前的数据表明原发肿瘤和肝转移灶之间K-Ras突变完全一致，并提示在抗EGFR单克隆抗体与5-FU联合治疗中，K-Ras突变的任何预测和/或预后价值都应仅与抗EGFR药物相关。
