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. 2016 Sep 22;11(9):e0163105.
doi: 10.1371/journal.pone.0163105. eCollection 2016.

Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker?

Andrea Botticelli  1 , Marina Borro  2 , Concetta Elisa Onesti  3 , Lidia Strigari  4 , Giovanna Gentile  5 , Bruna Cerbelli  6 , Adriana Romiti  1 , Mario Occhipinti  3 , Claudia Sebastiani  5 , Luana Lionetto  5 , Luca Marchetti  7 , Maurizio Simmaco  2 , Paolo Marchetti  1   3   5 , Federica Mazzuca  1   3
Affiliations

Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker?

Andrea Botticelli et al. PLoS One. .

Abstract

Background: 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.

Materials and methods: 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.

Results: 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.

Conclusion: 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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. PFS according to the metabolic classes (p = 0.0029).
Fig 2
Fig 2. PFS of patients with normal and altered 5-FU-DR (p = 0.03).
Fig 3
Fig 3. The boxplot of time to progression according to the 5FUDR-based metabolic classes.
Fig 4
Fig 4. 5-fluorouracil metabolism.
See this image and copyright information in PMC

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