K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy
K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy
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DOI：
10.1158/1078-0432.ccr-07-4906
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发表时间：
2008-08-01
影响因子：
11.5
通讯作者：
Milano, Gerard
中科院分区：
文献类型：
--
作者：
Etienne-Grimaldi, Marie-Christine;Formento, Jean-Louis;Milano, Gerard
目的：K-Ras突变可预测抗表皮生长因子受体（EGFR）单克隆抗体的耐药性。由于抗EGFR与5-氟尿嘧啶（5-FU）为基础的化疗组合是有前途的治疗方法，我们分析了K-Ras突变的影响，在接受独家5-FU therapy.Experimental设计：本研究进行了93个IV期结直肠癌患者不可切除的可测量的肝转移接受5-FU-leucovorin（56名男性和37名女性，77例癌症死亡）。分析肝转移瘤（n = 93）沿着原发肿瘤（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（677 C> T 1298 A> 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和p53蛋白表达。93例转移瘤中36例（38.7%）为K-Ras突变（30例位于密码子12，6例位于密码子13）。突变的原发性肿瘤（48例中的16例）与突变的转移瘤完全匹配。额外分析的肿瘤标志物在K-Ras突变和野生型肿瘤之间没有差异。客观缓解率为37%：K-Ras突变组为44.4%，野生型K-Ras转移组为32.1%（P = 0.27）。转移灶中TS活性低是肿瘤缓解的唯一显著预测因子（P = 0.047）。K-Ras状态并没有影响特定survival.Conclusions：目前的数据表明一个完美的一致性K-Ras突变之间的原发性和肝转移，并建议任何预测和/或预后价值的K-Ras突变的治疗结合抗EGFR单克隆抗体与5-FIJ应专门链接到抗EGFR药物。
Purpose: 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.Experimental Design: 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.Results: 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.Conclusions: 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-FIJ should be exclusively linked to the anti-EGFR agent.