Microsatellite Instability Predicts Improved Response to Adjuvant Therapy With Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803
Microsatellite Instability Predicts Improved Response to Adjuvant Therapy With Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803
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DOI：
10.1200/jco.2008.18.2071
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发表时间：
2009-04-10
影响因子：
45.3
通讯作者：
Redston, Mark
中科院分区：
文献类型：
--
作者：
Bertagnolli, Monica M.;Niedzwiecki, Donna;Redston, Mark
目的表现为DNA错配修复(MMR)缺陷的结肠癌具有不同的临床和病理特征，包括较好的预后和对以氟尿嘧啶(FU)为基础的化疗反应降低。癌症与白血病B组89803例Ⅲ期结肠癌患者随机分为两组，每组1,264例，术后每周静脉推注FU/亚叶酸钙(LV)或每周推注伊立替康、FU和LV(IFL)。主要终点是总存活率；无病生存率(DFS)是次要终点。免疫组织化学方法检测MMR蛋白MLH1和MSH2在肿瘤组织中的表达。DNA微卫星不稳定性也使用一组单核苷酸和二核苷酸标记进行了评估。MMR缺陷的肿瘤是指那些表现为MMR蛋白表达缺失(MMR-D)和/或微卫星不稳定高(MSI-H)的肿瘤。结果在723例经基因分型和IHC检查的肿瘤中，96例(13.3%)为MMR-D/MSI-H。702例(97.1%)基因分型结果与IHC一致。与错配修复完整肿瘤患者相比，接受IFL治疗的MMR-D/MSI-H肿瘤患者的5年DFS有所改善(0.76；95%CI，0.64至0.88 vs 0.59；95%CI，0.53至0.64；P=.03)。在接受FU/LV治疗的患者中未观察到这种关系。与接受FU/LV治疗的MMR-D/MSI-H患者相比，接受IFL治疗的MMR-D/MSI-H患者有延长DFS的趋势(0.57；95%CI，0.42至0.71比0.76；95%CI，0.64至0.88；P=0.07；肿瘤状态与治疗的风险比交互作用，0.51；似然比P=.117)。结论与接受FU/LV治疗的患者相比，肿瘤MMR功能丧失可能预示着预后的改善。临床医学杂志27：1814-1821。(C)2009年美国临床肿瘤学会
PurposeColon cancers exhibiting DNA mismatch repair (MMR) defects demonstrate distinct clinical and pathologic features, including better prognosis and reduced response to fluorouracil (FU) - based chemotherapy. This prospective study investigated adjuvant chemotherapy containing FU and irinotecan in patients with MMR deficient (MMR-D) colon cancers.Patients and MethodsCancer and Leukemia Group B 89803 randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly bolus FU/leucovorin (LV) or weekly bolus irinotecan, FU, and LV (IFL). The primary end point was overall survival; disease-free survival (DFS) was a secondary end point. Tumor expression of the MMR proteins, MLH1 and MSH2, was determined by immunohistochemistry (IHC). DNA microsatellite instability was also assessed using a panel of mono-and dinucleotide markers. Tumors with MMR defects were those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype.ResultsOf 723 tumor cases examined by genotyping and IHC, 96 (13.3%) were MMR-D/MSI-H. Genotyping results were consistent with IHC in 702 cases (97.1%). IFL-treated patients with MMR-D/MSI-H tumors showed improved 5-year DFS as compared with those with mismatch repair intact tumors (0.76; 95% CI, 0.64 to 0.88 v 0.59; 95% CI, 0.53 to 0.64; P = .03). This relationship was not observed among patients treated with FU/LV. A trend toward longer DFS was observed in IFL-treated patients with MMR-D/MSI-H tumors as compared with those receiving FU/LV (0.57; 95% CI, 0.42 to 0.71 v 0.76; 95% CI, 0.64 to 0.88; P = .07; hazard ratio interaction between tumor status and treatment, 0.51; likelihood ratio P = .117).ConclusionLoss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV. J Clin Oncol 27: 1814-1821. (C) 2009 by American Society of Clinical Oncology