Unidad de Gastroenterología, Hospital General Universitario de Alicante, Alicante, Spain.
Gastroenterology. 2011 Apr;140(4):1174-81. doi: 10.1053/j.gastro.2010.12.035. Epub 2010 Dec 24.
BACKGROUND & AIMS: 5-Fluorouracil (5-FU)-based adjuvant chemotherapy does not increase survival times of patients with colorectal tumors with microsatellite instability. We determined the response of patients with colorectal tumors with the CpG island methylator phenotype (CIMP) to 5-FU-based therapy.
We analyzed a population-based cohort of 302 patients with colorectal cancer (CRC) for a median follow-up time of 50.7 months. CIMP status was determined by analysis of the CACNAG1, SOCS1, RUNX3, NEUROG1, and MLH1 promoters; tumors were considered to be CIMP positive if at least 3 promoters were methylated.
Tumors from 29.5% of patients (89/302) were CIMP positive; CIMP status did not influence disease-free survival (DFS; log-rank = 0.3). Of tumors of TNM stages II-III (n = 196), 32.7% were CIMP positive. Among patients with stages II-III CRC who did not receive adjuvant 5-FU chemotherapy, those with CIMP-positive tumors had longest times of DFS (log-rank = 0.04); In patients who received chemotherapy, those with CIMP-positive tumors had shorter times of DFS (log-rank = 0.02). In patients with CIMP-negative tumors, adjuvant 5-FU chemotherapy significantly increased time of DFS (log-rank = 0.00001). However, in patients with CIMP-positive tumors, adjuvant 5-FU chemotherapy did not affect time of DFS (log-rank = 0.7). Multivariate analysis showed a significant, independent interaction between 5-FU treatment and CIMP status (hazard ratio [HR], 0.6; 95% confidence interval [CI], 0.5-0.8). Among patients with CIMP-positive tumors, adjuvant chemotherapy was not an independent predictor of outcome (HR, 0.8; 95% CI, 0.3-2.0). In patients who did not receive adjuvant 5-FU chemotherapy, CIMP status was the only independent predictor of survival (HR, 2.0; 95% CI, 1.1-3.8).
Patients with CIMP-positive colorectal tumors do not benefit from 5-FU-based adjuvant chemotherapy.
基于 5-氟尿嘧啶（5-FU）的辅助化疗并不能提高具有微卫星不稳定性的结直肠肿瘤患者的生存时间。我们确定了具有 CpG 岛甲基化表型（CIMP）的结直肠肿瘤患者对基于 5-FU 治疗的反应。
我们分析了一个基于人群的 302 例结直肠癌（CRC）患者队列，中位随访时间为 50.7 个月。CIMP 状态通过分析 CACNAG1、SOCS1、RUNX3、NEUROG1 和 MLH1 启动子来确定；如果至少 3 个启动子发生甲基化，则认为肿瘤为 CIMP 阳性。
29.5%的患者（89/302）的肿瘤为 CIMP 阳性；CIMP 状态不影响无病生存期（DFS；log-rank = 0.3）。在 TNM 分期为 II-III 期的肿瘤（n = 196）中，32.7%为 CIMP 阳性。在未接受辅助 5-FU 化疗的 II-III 期 CRC 患者中，CIMP 阳性肿瘤的 DFS 时间最长（log-rank = 0.04）；在接受化疗的患者中，CIMP 阳性肿瘤的 DFS 时间较短（log-rank = 0.02）。在 CIMP 阴性肿瘤患者中，辅助 5-FU 化疗显著增加了 DFS 时间（log-rank = 0.00001）。然而，在 CIMP 阳性肿瘤患者中，辅助 5-FU 化疗并未影响 DFS 时间（log-rank = 0.7）。多变量分析显示，5-FU 治疗与 CIMP 状态之间存在显著的独立相互作用（风险比[HR]，0.6；95%置信区间[CI]，0.5-0.8）。在 CIMP 阳性肿瘤患者中，辅助化疗不是结局的独立预测因素（HR，0.8；95%CI，0.3-2.0）。在未接受辅助 5-FU 化疗的患者中，CIMP 状态是唯一独立的生存预测因素（HR，2.0；95%CI，1.1-3.8）。
CIMP 阳性结直肠肿瘤患者不能从基于 5-FU 的辅助化疗中获益。
