Division of Oncology , Mayo Clinic, Rochester, MN 55905, USA.
J Natl Cancer Inst. 2011 Jun 8;103(11):863-75. doi: 10.1093/jnci/djr153. Epub 2011 May 19.
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.
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 χ(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.
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).
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.
约 15%的结直肠癌是由于 DNA 错配修复（MMR）系统功能缺陷引起的。我们确定了 MMR 状态与结肠癌复发的关系，并研究了 5-氟尿嘧啶（FU）为基础的辅助治疗对复发变量的影响。
我们纳入了接受 5-FU 为基础的辅助治疗的随机试验中治疗的 II 期和 III 期结肠癌患者（n=2141）。通过聚合酶链反应检测微卫星不稳定性和/或免疫组织化学检测 MMR 蛋白表达来分析肿瘤，以确定缺陷型 MMR（dMMR）或功能型 MMR（pMMR）状态。使用 χ(2)、Fisher 确切检验或 Wilcoxon 秩和检验确定 MMR 状态和/或基于 FU 的治疗与临床病理和复发协变量的关联。使用单变量和多变量 Cox 模型分析复发时间（TTR）、无病生存（DFS）和总生存（OS），后者调整了协变量。通过假定的种系与散发性起源对显示 dMMR 的肿瘤进行分类，并评估其预后和预测影响。所有统计检验均为双侧。
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%比 22%；P<.001）、TTR 延迟（P<.001）和远处复发减少（22%比 12%；P<.001）相关。在多变量模型中，dMMR 与 TTR 延迟独立相关（风险比=0.72，95%置信区间=0.56 至 0.91，P=0.005），DFS 和 OS 改善（P=0.035 和 P=0.031）。在 III 期癌症中，与单独手术或不接受 5-FU 相比，5-FU 为基础的治疗与 dMMR 肿瘤的远处复发减少（11%比 29%；P=0.011）和 pMMR 肿瘤的所有部位复发减少相关（P<.001）。与未观察到获益的散发性肿瘤相比，具有疑似种系突变的 dMMR 肿瘤在接受 5-FU 为基础的治疗后 DFS 改善（P=0.006）。
与 pMMR 结肠癌相比，dMMR 结肠癌患者的肿瘤复发率、TTR 延迟和生存率均降低。dMMR III 期肿瘤的 5-FU 为基础的辅助治疗可降低远处复发率，亚组分析表明，任何治疗获益均限于疑似种系与散发性肿瘤。
