Defective Mismatch Repair As a Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon Cancer
Defective Mismatch Repair As a Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon Cancer
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DOI：
10.1200/jco.2009.27.1825
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发表时间：
2010-07-10
影响因子：
45.3
通讯作者：
Gallinger, Steven
中科院分区：
文献类型：
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作者：
Sargent, Daniel J.;Marsoni, Silvia;Gallinger, Steven
研究目的：先前的报道表明，与微卫星稳定或错配修复（pMMR）肿瘤患者相比，高水平微卫星不稳定性（MSI-H）或DNA错配修复缺陷（dMMR）的结肠癌患者的生存率有所提高，但氟尿嘧啶（FU）辅助治疗无获益。我们研究了MMR状态作为辅助治疗的预测因子与II期和III期结肠cancer.Methods的患者MMR蛋白MSI检测或免疫组化进行了457例患者谁先前被随机分配到FU为基础的治疗（无论是FU +左旋咪唑或FU + leucovorin; n = 229）与无术后治疗（n = 228）。随后将数据与先前分析的数据合并。主要终点是无病生存期（DFS）。结果457例患者中有70例（15%）表现为dMMR。辅助治疗显著改善pMMR肿瘤患者的DFS（风险比[HR]，0.67; 95% CI，0.48 - 0.93; P = 0.02）。与随机分配接受单纯手术的患者相比，接受FU治疗的dMMR肿瘤患者的DFS没有改善（HR，1.10; 95% CI，0.42 - 2.91; P = 0.85）。在1,027例患者的汇总数据集中，（n = 165例dMMR患者），这些结果得以维持;在II期疾病和dMMR肿瘤患者中，治疗与总生存率降低相关（HR，2.95; 95% CI，1.02 ~ 8.54;结论根据MMR状态对患者进行分层可能为结肠癌辅助治疗提供一种更有针对性的方法。这些数据支持对考虑单独FU治疗的患者进行MMR状态评估，并在治疗决策中考虑MMR状态。
Purpose Prior reports have indicated that patients with colon cancer who demonstrate high-level microsatellite instability (MSI-H) or defective DNA mismatch repair (dMMR) have improved survival and receive no benefit from fluorouracil (FU) -based adjuvant therapy compared with patients who have microsatellite-stable or proficient mismatch repair (pMMR) tumors. We examined MMR status as a predictor of adjuvant therapy benefit in patients with stages II and III colon cancer.Methods MSI assay or immunohistochemistry for MMR proteins were performed on 457 patients who were previously randomly assigned to FU-based therapy (either FU + levamisole or FU + leucovorin; n = 229) versus no postsurgical treatment (n = 228). Data were subsequently pooled with data from a previous analysis. The primary end point was disease-free survival (DFS).Results Overall, 70 (15%) of 457 patients exhibited dMMR. Adjuvant therapy significantly improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.93; P = .02) in patients with pMMR tumors. Patients with dMMR tumors receiving FU had no improvement in DFS (HR, 1.10; 95% CI, 0.42 to 2.91; P = .85) compared with those randomly assigned to surgery alone. In the pooled data set of 1,027 patients (n = 165 with dMMR), these findings were maintained; in patients with stage II disease and with dMMR tumors, treatment was associated with reduced overall survival (HR, 2.95; 95% CI, 1.02 to 8.54; P = .04).Conclusion Patient stratification by MMR status may provide a more tailored approach to colon cancer adjuvant therapy. These data support MMR status assessment for patients being considered for FU therapy alone and consideration of MMR status in treatment decision making.