Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker?
Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker?
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DOI：
10.1371/journal.pone.0163105
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发表时间：
2016-09-22
期刊：
影响因子：
3.7
通讯作者：
Mazzuca, Federica
中科院分区：
文献类型：
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作者：
Botticelli, Andrea;Borro, Marina;Mazzuca, Federica
背景以5-FU为基础的化疗是转移性结直肠癌（mCRC）最常用的一线化疗方案。识别化疗反应的预测标志物是药物选择的一种具有挑战性的方法。本研究分析了5-FU降解率（5-FUDR）和基因多态性（MTHFR、TSER、DPYD）对mCRC患者生存期的预测作用。结果2009年至2014年133例mCRC患者接受以氟尿嘧啶为基础的化疗治疗，其中133例患者的基因型和5-FUDR与临床疗效相关。根据超过1000例患者的5-FUDR正态分布，将患者分为三种代谢类型，如先前发表的：5-FU-DR = 2.2 ng/ml/10（6）个细胞/min（6例患者）的代谢不良者（PM）。PM和UM组的PFS长于正常代谢者组（分别为14.5和11个月vs 8个月; p = 0.029）。相对于正常代谢者，在PM和UM中观察到更高的G3-4毒性率（PM和UM均为50% vs 18%; p = 0.019）。结论5-FUDR基因多态性可能是预测以5-FU为基础的CHT治疗mCRC患者生存率的重要指标。虽然我们的研究结果需要在大型前瞻性研究中得到证实，但它们强化了个体遗传变异可能允许个性化选择化疗以优化临床结果的概念。
Background5-FU based chemotherapy is the most common first line regimen used for metastatic colorectal cancer (mCRC). Identification of predictive markers of response to chemotherapy is a challenging approach for drug selection. The present study analyzes the predictive role of 5-FU degradation rate (5-FUDR) and genetic polymorphisms (MTHFR, TSER, DPYD) on survival.Materials and MethodsGenetic polymorphisms of MTHFR, TSER and DPYD, and the 5-FUDR of homogenous patients with mCRC were retrospectively studied. Genetic markers and the 5-FUDR were correlated with clinical outcome.Results133 patients affected by mCRC, treated with fluoropyrimidine-based chemotherapy from 2009 to 2014, were evaluated. Patients were classified into three metabolic classes, according to normal distribution of 5-FUDR in more than 1000 patients, as previously published: poor-metabolizer (PM) with 5-FU-DR = 2,2 ng/ml/10(6) cells/min (6 pts). PM and UM groups showed a longer PFS respect to normal metabolizer group (14.5 and 11 months respectively vs 8 months; p = 0.029). A higher G3-4 toxicity rate was observed in PM and UM, respect to normal metabolizer (50% in both PM and UM vs 18%; p = 0.019). No significant associations between genes polymorphisms and outcomes or toxicities were observed.Conclusion5-FUDR seems to be significantly involved in predicting survival of patients who underwent 5-FU based CHT for mCRC. Although our findings require confirmation in large prospective studies, they reinforce the concept that individual genetic variation may allow personalized selection of chemotherapy to optimize clinical outcomes.