Management of stage II colon cancer - the use of molecular biomarkers for adjuvant therapy decision.
Management of stage II colon cancer - the use of molecular biomarkers for adjuvant therapy decision.
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DOI：
10.1186/1471-230x-13-36
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发表时间：
2013-02-27
影响因子：
2.4
通讯作者：
Stanta G
中科院分区：
文献类型：
--
作者：
Donada M;Bonin S;Barbazza R;Pettirosso D;Stanta G
辅助化疗对II期结直肠癌患者的益处尚不确定。本研究的目的是探讨临床、病理和分子参数的联合作用，以确定哪些II期患者更能从辅助治疗中获益。我们检查了120例II期结肠癌患者。其中，60例患者术后接受了5-FU辅助化疗，另外60例未接受治疗。免疫组化（IHC）检测胸腺苷酸合成酶（TYMS）、TP53 （p53）、β-连环蛋白（CTNNB1）和CD8的表达。对于TYMS，采用实时qRT-PCR检测其mRNA表达水平。整个案例研究的特点是MMR（错配修复）系统中存在缺陷，CpG岛甲基化表型（CIMP或CIMP- high）的存在以及BRAF基因中的V600E突变。组织病理水平记录肿瘤浸润深度、淋巴血管浸润、大静脉浸润、宿主淋巴细胞反应及肿瘤边界形态。BRAF基因中V600E突变的存在是无病生存和总生存的不良预后因素（DFS; 95% CI: 1.03 -6.37; p = 0.04和OS； HR, 3.68; 95% CI: 1.43-9.47; p < 0.01），与5-FU治疗无关。辅助治疗显著提高了TYMS高水平患者的生存率（p = 0.04），而TYMS低水平患者单独手术治疗的预后更好（DFS； HR, 6.07; 95% CI, 0.82 ~ 44.89; p = 0.04）。在MMR系统（dMMR）缺陷的患者中，5-FU治疗与生存率降低相关（DFS； HR, 37.98; 95% CI， 1.04至1381.31;p = 0.04），而对CIMP-High相关肿瘤（DFS； HR, 0.17; 95% CI， 0.02至1.13;p = 0.05）有益。根据MMR状态、CIMP表型和TYMS mRNA表达对患者进行表征，可能为II期结肠癌的辅助治疗提供更有针对性的方法。
There is uncertainty on the benefit of adjuvant chemotherapy in patients with stage II colorectal cancers. The aim of this study is to investigate the combined role of clinical, pathological and molecular parameters to identify those stage II patients who better benefit from adjuvant therapy. We examined 120 stage II colon cancer patients. Of these, 60 patients received adjuvant 5-FU chemotherapy after surgery and the other 60 did not receive therapy. Immunohistochemical (IHC) analyses were performed to evaluate the expressions of Thymidylate synthetase (TYMS), TP53 (p53), β-catenin (CTNNB1) and CD8. For TYMS, its mRNA expression levels were also investigated by real time qRT-PCR. The entire case study was characterized by the presence of a defect in the MMR (mismatch repair) system, the presence of the CpG island methylator phenotype (CIMP or CIMP-High) and for the V600E mutation in the BRAF gene. At the histo-pathological level, the depth of tumour invasion, lymphovascular invasion, invasion of large veins, host lymphocytic response and tumour border configuration were recorded. The presence of the V600E mutation in the BRAF gene was a poor prognostic factor for disease free and overall survival (DFS; hazard ratio [HR], 2.57; 95% CI: 1.03 -6.37; p = 0.04 and OS; HR, 3.68; 95% CI: 1.43-9.47; p < 0.01 respectively), independently of 5-FU treatment. Adjuvant therapy significantly improved survival in patients with high TYMS levels (p = 0.04), while patients with low TYMS had a better outcome if treated by surgery alone (DFS; HR, 6.07; 95% CI, 0.82 to 44.89; p = 0.04). In patients with a defect in the MMR system (dMMR), 5-FU therapy was associated to reduced survival (DFS; HR, 37.98; 95% CI, 1.04 to 1381.31; p = 0.04), while it was beneficial for CIMP-High associated tumours (DFS; HR, 0.17; 95% CI, 0.02 to 1.13; p = 0.05). Patients’ characterization according to MMR status, CIMP phenotype and TYMS mRNA expression may provide a more tailored approach for adjuvant therapy in stage II colon cancer.