Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Clin Cancer Res. 2009 Dec 1;15(23):7322-9. doi: 10.1158/1078-0432.CCR-09-1570. Epub 2009 Nov 24.
Alterations in the RAS and RAF pathway relate to epigenetic and epigenomic aberrations, and are important in colorectal carcinogenesis. KRAS mutation in metastatic colorectal cancer predicts resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy (cetuximab or panitumumab). It remains uncertain, however, whether KRAS mutation predicts prognosis or clinical outcome of colon cancer patients independent of anti-EGFR therapy.
We conducted a study of 508 cases identified among 1,264 patients with stage III colon cancer who enrolled in a randomized adjuvant chemotherapy trial (5-fluorouracil, leucovorin with or without irinotecan) in 1999-2001 (CALGB 89803). KRAS mutations were detected in 178 tumors (35%) by pyrosequencing. Kaplan-Meier and Cox proportional hazard models assessed the prognostic significance of KRAS mutation and adjusted for potential confounders including age, sex, tumor location, tumor/node stage, performance status, adjuvant chemotherapy arm, and microsatellite instability status.
Compared with patients with KRAS-wild-type tumors, patients with KRAS-mutated tumors did not experience any difference in disease-free, recurrence-free, or overall survival. The 5-year disease-free, recurrence-free, and overall survival rates (KRAS-mutated versus KRAS-wild-type patients) were 62% versus 63% (log-rank P = 0.89), 64% versus 66% (P = 0.84), and 75% versus 73% (P = 0.56), respectively. The effect of KRAS mutation on patient survival did not significantly differ according to clinical features, chemotherapy arm, or microsatellite instability status, and the effect of adjuvant chemotherapy assignment on outcome did not differ according to KRAS status.
In this large trial of chemotherapy in stage III colon cancer patients, KRAS mutational status was not associated with any significant influence on disease-free or overall survival.
RAS 和 RAF 通路的改变与表观遗传和表观基因组异常有关，在结直肠癌的发生中很重要。转移性结直肠癌中 KRAS 突变预测对表皮生长因子受体 (EGFR) 靶向治疗（西妥昔单抗或帕尼单抗）的耐药性。然而，KRAS 突变是否独立于抗 EGFR 治疗预测结肠癌患者的预后或临床结局仍不确定。
我们对 1999 年至 2001 年期间参加随机辅助化疗试验（5-氟尿嘧啶、亚叶酸联合或不联合伊立替康）的 1264 例 III 期结肠癌患者中的 508 例进行了一项研究。通过焦磷酸测序检测 178 例肿瘤中的 KRAS 突变。Kaplan-Meier 和 Cox 比例风险模型评估了 KRAS 突变的预后意义，并针对年龄、性别、肿瘤部位、肿瘤/淋巴结分期、表现状态、辅助化疗臂和微卫星不稳定性状态等潜在混杂因素进行了调整。
与 KRAS 野生型肿瘤患者相比，KRAS 突变型肿瘤患者在无病、无复发和总生存方面均无差异。5 年无病、无复发和总生存率（KRAS 突变型与 KRAS 野生型患者）分别为 62%与 63%（对数秩 P = 0.89）、64%与 66%（P = 0.84）和 75%与 73%（P = 0.56）。KRAS 突变对患者生存的影响与临床特征、化疗臂或微卫星不稳定性状态无关，辅助化疗方案对结局的影响也与 KRAS 状态无关。
在这项 III 期结肠癌患者化疗的大型试验中，KRAS 突变状态与无病或总生存无显著影响。
