Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy
Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy
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DOI：
10.1007/s00280-009-1206-3
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发表时间：
2010-09-01
影响因子：
3
通讯作者：
Park, Young Suk
中科院分区：
文献类型：
--
作者：
Kim, Seung Tae;Lee, Jeeyun;Park, Young Suk
具有DNA错配修复（MMR）缺陷的结肠癌显示出难以区分的临床和病理方面，包括更好的预后和对5-氟尿嘧啶（5-FU）为基础的化疗反应降低。p53作为结直肠癌的预后标志物尚未达成共识。本研究分析了2004年5月至2007年11月间135例结肠腺癌根治性切除术（R 0）后接受含奥沙利铂/5-FU/亚叶酸钙（FOLFOX）辅助化疗的患者，观察MSI-H/MMR-D和p53表达的临床意义。采用免疫组化（IHC）法检测手术切除的肿瘤标本中MMR蛋白MLH 1和MSH 2的表达。通过聚合酶链反应（PCR）扩增，使用荧光染料标记的微卫星位点特异性引物进行MSI分析。具有MMR缺陷的肿瘤定义为表现出MMR蛋白表达缺失（MMR-D）和/或微卫星不稳定性高（MSI-H）基因型的肿瘤。p53的表达模式进行了测定，在半定量的方式通过光学显微镜。有13例（9.6%）患者与II期，108例（80%）与III期，和14例（10.4%）与IV期。14例IV期患者（10.3%）仅转移至肝脏，所有患者均因肝转移而接受了完全切除术。总共对134份肿瘤标本进行了基因分型，对115份标本进行了IHC检测，113例病例的基因分型和IHC结果均可用于分析。基因分型结果显示，12例（9.0%）为MSI-H型，122例（91.0%）为MSI-L/S型。通过IHC，11例（9.6%）患者为MMR-D，104例（90.4%）患者为MMR-I。108例患者（94.7%）的方法一致。我们评估了114例p53表达的免疫染色。在接受辅助FOLFOX的结肠癌患者（n = 135）中，MMR状态与DFS（P = 0.56）或OS（P = 0.61）无显著相关性。根据p53状态，DFS（P = 0.11）和OS（P = 0.94）也无显著差异。对于基因分型/IHC一致的患者（n = 108），MSI-H/MMR-D和MSI-L/S/MMR-I肿瘤患者的DFS（P = 0.57）和OS（P = 0.98）无差异。MMR状态或p53阳性与R 0切除的结肠癌患者接受FOLFOX作为辅助化疗的结局无显著相关性。在辅助化疗中添加奥沙利铂可以克服5-FU对MSI-H/MMR-D结肠癌的负面影响。
Colon cancer with DNA mismatch repair (MMR) defects reveals indistinguishable clinical and pathologic aspects, including better prognosis and reduced response to 5-fluorouracil (5-FU)-based chemotherapy. There has been no consensus for p53 as a prognostic marker in colorectal cancer. This study investigated the clinical implication of MSI-H/MMR-D and p53 expression in R0-resected colon cancer patients who received adjuvant oxaliplatin/5-FU/leucovorin (FOLFOX) therapy.We analyzed 135 patients, who had been treated by adjuvant chemotherapy containing 5-FU and oxaliplatin (FOLFOX) after curative resection (R0) for colon adenocarcinoma between May 2004 and November 2007. Tumor expression of the MMR proteins, MLH1 and MSH2, was detected by immunohistochemistry (IHC) in surgically resected tumor specimens. MSI was analyzed by polymerase chain reaction (PCR) amplification using fluorescent dye-labeled primers specific for microsatellite loci. Tumors with MMR defects were defined as those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Expression patterns of p53 were determined in a semiquantitative manner by light microscopy.There were 13 (9.6%) patients with stage II, 108 (80%) with stage III, and 14 (10.4%) with stage IV. Fourteen patients with stage IV (10.3%) had metastases to liver only, all of whom underwent complete metastasectomy for liver metastases. In total, 134 tumor specimens were genotyped, 115 specimens were tested by IHC and 113 cases had both genotyping and IHC results available for analysis. Genotyping results demonstrated that 12 (9.0%) cases were MSI-H and 122 (91.0%) were MSI-L/S. By IHC, 11 (9.6%) patients were MMR-D and 104 (90.4%) were MMR-I. The methods were in agreement in 108 patients (94.7%). We assessed 114 patients for p53 expression by immunostaining. MMR status was not significantly associated with DFS (P = 0.56) or OS (P = 0.61) in patients with colon cancer (n = 135) receiving adjuvant FOLFOX. According to p53 status, there was also no significant difference for DFS (P = 0.11) and OS (P = 0.94). For patients with genotyping/IHC agreement (n = 108), there was no difference in DFS (P = 0.57) and OS (P = 0.98) between patients with MSI-H/MMR-D and MSI-L/S/MMR-I tumors.The MMR status or p53 positivity was not significantly associated with outcomes to FOLFOX as adjuvant chemotherapy in colon cancer patients with R0 resection. Adding oxaliplatin in adjuvant chemotherapy may overcome negative impact of 5-FU on colon cancers with MSI-H/MMR-D.