Hematology-Oncology Unit, 4 Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, "ATTIKON" University Hospital, 12462 Athens, Greece.
Department of Cytopathology, National and Kapodistrian University of Athens, Medical School, "ATTIKON" University Hospital, 12462 Athens, Greece.
World J Gastroenterol. 2017 Aug 28;23(32):5913-5924. doi: 10.3748/wjg.v23.i32.5913.
To investigate the impact of thymidylate synthase (), and in the survival of metastatic colorectal cancer (mCRC) patients treated with chemotherapy.
Clinical data were collected retrospectively from records of consecutive patients with mCRC treated with fluoropyrimidine-based chemotherapy from 1/2005 to 1/2007. Formalin-fixed paraffin-embedded tissues were retrieved for analysis. genotypes were identified with restriction fragment analysis PCR, while and mutation status was evaluated using real-time PCR assays. gene polymorphisms of each of the 3' untranslated region (UTR) and 5'UTR were classified into three groups according to the probability they have for high, medium and low expression (and similar levels of risk) based on evidence from previous studies. Univariate and multivariate survival analyses were performed.
The analysis recovered 89 patients with mCRC (46.1% metastatic disease and 53.9% relapsed). Of these, 46 patients (51.7%) had colon cancer and 43 (48.3%) rectal cancer as primary. All patients were treated with fluoropyrimidine-based chemotherapy (5FU or capecitabine) as single-agent or in combination with irinotecan or/and oxaliplatin or/and bevacizumab. With a median follow-up time of 14.8 mo (range 0-119.8), 85 patients (95.5%) experienced disease progression, and 63 deaths (70.8%) were recorded. The 3-year and 5-year OS rate was 25.4% and 7.7% while the 3-year progression-free survival rate was 7.1%. Multivariate analysis of polymorphisms, and with clinicopathological parameters indicated that 3'UTR polymorphisms are associated with risk for disease progression and death ( < 0.05 and < 0.03 respectively). When compared to tumors without any del allele (genotypes ins/ins and ins/loss of heterozygosity (LOH) linked with high expression) tumors with del/del genotype (low expression group) and tumors with ins/del or del/LOH (intermediate expression group) have lower risk for disease progression (HR = 0.432, 95%CI: 0.198-0.946, < 0.04 and HR = 0.513, 95%CI: 0.287-0.919, < 0.03 respectively) and death (HR = 0.366, 95%CI: 0.162-0.827, < 0.02 and HR = 0.559, 95%CI: 0.309-1.113, < 0.06 respectively). Additionally, mutation was associated independently with the risk of disease progression (HR = 1.600, 95%CI: 1.011-2.531, < 0.05). The addition of irinotecan in 1 line chemotherapy was associated independently with lower risk for disease progression and death (HR = 0.600, 95%CI: 0.372-0.969, < 0.04 and HR = 0.352, 95%CI: 0.164-0.757, < 0.01 respectively).
The genotypes ins/ins and ins/LOH associate with worst prognosis in mCRC patients under fluoropyrimidine-based chemotherapy. Large prospective studies are needed for validation of our findings.
研究胸苷酸合成酶（）和（）对接受氟嘧啶类化疗的转移性结直肠癌（mCRC）患者生存的影响。
回顾性收集了 2005 年 1 月至 2007 年 1 月期间接受氟嘧啶类化疗的 mCRC 连续患者的临床资料。从存档的福尔马林固定石蜡包埋组织中提取标本进行分析。采用限制性片段分析 PCR 鉴定基因型，实时 PCR 检测和突变状态。根据之前研究的证据，将每个 3'非翻译区（UTR）和 5'UTR 的基因多态性分为高、中、低表达（和相似风险水平）的三种可能性，并对其进行分类。进行单因素和多因素生存分析。
该分析共纳入 89 例 mCRC 患者（46.1%转移性疾病和 53.9%复发）。其中，46 例（51.7%）为结肠癌，43 例（48.3%）为直肠癌。所有患者均接受氟嘧啶类化疗（5FU 或卡培他滨）单药或联合伊立替康或/和奥沙利铂或/和贝伐珠单抗治疗。中位随访时间为 14.8 个月（范围 0-119.8），85 例（95.5%）患者出现疾病进展，63 例（70.8%）死亡。3 年和 5 年 OS 率分别为 25.4%和 7.7%，3 年无进展生存率为 7.1%。多因素分析表明，与临床病理参数相关的和突变与疾病进展和死亡风险有关（均<0.05和<0.03）。与无任何缺失等位基因（基因型 ins/ins 和缺失杂合性（LOH）与高表达相关）的肿瘤相比，缺失/缺失基因型（低表达组）和缺失/插入或缺失/LOH（中表达组）的肿瘤疾病进展风险较低（HR=0.432，95%CI：0.198-0.946，<0.04 和 HR=0.513，95%CI：0.287-0.919，<0.03），死亡风险较低（HR=0.366，95%CI：0.162-0.827，<0.02 和 HR=0.559，95%CI：0.309-1.113，<0.06）。此外，突变与疾病进展风险独立相关（HR=1.600，95%CI：1.011-2.531，<0.05）。一线化疗中添加伊立替康与疾病进展和死亡风险降低独立相关（HR=0.600，95%CI：0.372-0.969，<0.04 和 HR=0.352，95%CI：0.164-0.757，<0.01）。
在接受氟嘧啶类化疗的 mCRC 患者中，基因型 ins/ins 和 ins/LOH 与最差的预后相关。需要进行大型前瞻性研究来验证我们的发现。
