DNA Mismatch Repair Status and Colon Cancer Recurrence and Survival in Clinical Trials of 5-Fluorouracil-Based Adjuvant Therapy
DNA Mismatch Repair Status and Colon Cancer Recurrence and Survival in Clinical Trials of 5-Fluorouracil-Based Adjuvant Therapy
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DOI：
10.1093/jnci/djr153
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发表时间：
2011-06-01
影响因子：
10.3
通讯作者：
Sargent, Daniel J.
中科院分区：
文献类型：
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作者：
Sinicrope, Frank A.;Foster, Nathan R.;Sargent, Daniel J.
大约15%的结直肠癌的发生是由于DNA错配修复（MMR）系统的功能缺陷。我们确定了MMR状态与结肠癌复发的关联，并研究了5-氟尿嘧啶（FU）为基础的辅助治疗对复发variables.Methods的影响，我们纳入了II期和III期结肠癌患者（n = 2141）谁在5-FU为基础的辅助治疗的随机试验治疗。通过聚合酶链反应分析肿瘤的微卫星不稳定性和/或通过免疫组织化学分析MMR蛋白表达，以确定缺陷型MMR（dMMR）或有效型MMR（pMMR）状态。使用卡方检验（2）或Fisher精确检验或Wilcoxon秩和检验确定MMR状态和/或5-FU治疗与临床病理学和复发协变量的相关性。使用单变量和多变量考克斯模型分析复发时间（TTR）、无病生存期（DFS）和总生存期（OS），后者校正了协变量。显示dMMR的肿瘤按假定的生殖系起源与散发起源分类，并评估其预后和预测影响。结果在本研究人群中，2141例肿瘤中有344例（16.1%）检测到dMMR。与pMMR肿瘤相比，dMMR与5年复发率降低（33% vs 22%; P <0.001）、TTR延迟（P <0.001）和远端复发率减少（22% vs 12%; P <0.001）相关。在多变量模型中，dMMR与TTR延迟（风险比= 0.72，95%置信区间= 0.56 - 0.91，P = 0.005）、DFS（P = 0.035）和OS（P = 0.031）改善独立相关。在III期癌症中，基于5-FU的治疗与单独手术或不使用5-FU相比，dMMR肿瘤的远端复发减少（11% vs 29%; P = 0.011），pMMR肿瘤的所有部位复发减少（P <0.001）。与未观察到获益的散发性肿瘤相比，怀疑有种系突变的dMMR肿瘤在5-FU治疗后与DFS改善相关（P = 0.006）。结论与pMMR结肠癌相比，dMMR结肠癌患者的肿瘤复发率降低，TTR延迟，生存率提高。在dMMR III期肿瘤中，以5-FU为基础的辅助治疗减少了远处复发，亚组分析表明，任何治疗获益仅限于疑似生殖系肿瘤与散发性肿瘤。
Background Approximately 15% of colorectal cancers develop because of defective function of the DNA mismatch repair (MMR) system. We determined the association of MMR status with colon cancer recurrence and examined the impact of 5-fluorouracil (FU)-based adjuvant therapy on recurrence variables.Methods We included stage II and III colon carcinoma patients (n = 2141) who were treated in randomized trials of 5-FU-based adjuvant therapy. Tumors were analyzed for microsatellite instability by polymerase chain reaction and/or for MMR protein expression by immunohistochemistry to determine deficient MMR (dMMR) or proficient MMR (pMMR) status. Associations of MMR status and/or 5-FU-based treatment with clinicopathologic and recurrence covariates were determined using chi(2) or Fisher Exact or Wilcoxon rank-sum tests. Time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) were analyzed using univariate and multivariable Cox models, with the latter adjusted for covariates. Tumors showing dMMR were categorized by presumed germline vs sporadic origin and were assessed for their prognostic and predictive impact. All statistical tests were two-sided.Results In this study population, dMMR was detected in 344 of 2141 (16.1%) tumors. Compared with pMMR tumors, dMMR was associated with reduced 5-year recurrence rates (33% vs 22%; P < .001), delayed TTR (P < .001), and fewer distant recurrences (22% vs 12%; P < .001). In multivariable models, dMMR was independently associated with delayed TTR (hazard ratio = 0.72, 95% confidence interval = 0.56 to 0.91, P = .005) and improved DFS (P = .035) and OS (P = .031). In stage III cancers, 5-FU-based treatment vs surgery alone or no 5-FU was associated with reduced distant recurrence for dMMR tumors (11% vs 29%; P = .011) and reduced recurrence to all sites for pMMR tumors (P < .001). The dMMR tumors with suspected germline mutations were associated with improved DFS after 5-FU-based treatment compared with sporadic tumors where no benefit was observed (P = .006).Conclusions Patients with dMMR colon cancers have reduced rates of tumor recurrence, delayed TTR, and improved survival rates, compared with pMMR colon cancers. Distant recurrences were reduced by 5-FU-based adjuvant treatment in dMMR stage III tumors, and a subset analysis suggested that any treatment benefit was restricted to suspected germline vs sporadic tumors.