Botticelli Andrea, Borro Marina, Onesti Concetta Elisa, Strigari Lidia, Gentile Giovanna, Cerbelli Bruna, Romiti Adriana, Occhipinti Mario, Sebastiani Claudia, Lionetto Luana, Marchetti Luca, Simmaco Maurizio, Marchetti Paolo, Mazzuca Federica
Department of Clinical and Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.
Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), "Sapienza" University of Rome, Rome, Italy.
PLoS One. 2016 Sep 22;11(9):e0163105. doi: 10.1371/journal.pone.0163105. eCollection 2016.
5-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.
Genetic 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.
133 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 ≤ 0,85 ng/ml/106 cells/min (8 pts); normal metabolizer with 0,85 < 5-FU-DR < 2,2 ng/ml/106 cells/min (119 pts); ultra-rapid metabolizer (UM) with 5-FU-DR ≥ 2,2 ng/ml/106 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.
5-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.
基于5-氟尿嘧啶（5-FU）的化疗是转移性结直肠癌（mCRC）最常用的一线治疗方案。识别化疗反应的预测标志物是药物选择的一项具有挑战性的工作。本研究分析了5-FU降解率（5-FUDR）和基因多态性（MTHFR、TSER、DPYD）对生存的预测作用。
回顾性研究mCRC同质患者的MTHFR、TSER和DPYD基因多态性以及5-FUDR。将基因标志物和5-FUDR与临床结局进行关联分析。
评估了2009年至2014年接受氟嘧啶类化疗的133例mCRC患者。根据之前发表的1000多例患者中5-FUDR的正态分布，将患者分为三个代谢类别：慢代谢者（PM），5-FU-DR≤0.85 ng/ml/10⁶细胞/分钟（8例）；正常代谢者，0.85＜5-FU-DR＜2.2 ng/ml/10⁶细胞/分钟（119例）；超快代谢者（UM），5-FU-DR≥2.2 ng/ml/10⁶细胞/分钟（6例）。与正常代谢者组相比，PM组和UM组的无进展生存期更长（分别为14.5个月和11个月，而正常代谢者组为8个月；p = 0.029）。与正常代谢者相比，PM组和UM组观察到更高的3-4级毒性发生率（PM组和UM组均为50%，而正常代谢者组为18%；p = 0.019）。未观察到基因多态性与结局或毒性之间存在显著关联。
5-FUDR似乎在预测接受基于5-FU的化疗治疗mCRC患者的生存方面具有重要作用。尽管我们的研究结果需要在大型前瞻性研究中得到证实，但它们强化了个体基因变异可能允许个性化选择化疗以优化临床结局的概念。
