Andrea Botticelli et al., Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker? PLOS One

Andrea Botticelli1, Marina Borro2, Concetta Elisa Onesti3, Lidia Strigari4, Giovanna Gentile5, Bruna Cerbelli6, Adriana Romiti1, Mario Occhipinti3, Claudia Sebastiani5, Luana Lionetto5, Luca Marchetti7, Maurizio Simmaco2, Paolo Marchetti1,3,5, Federica Mazzuca1,3

1Department of Clinical and Molecular Medicine, “Sapienza” University of Rome, Rome, Italy
2Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), “Sapienza” University of Rome, Rome, Italy
3Medical Oncology Unit, Sant’Andrea Hospital, Rome, Italy
4Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Rome, Italy
5Istituto Dermopatico dell’Immacolata-IRCCS, Rome, Italy
6Department of Radiological Oncological and Pathological Sciences, “Sapienza” University of Rome, Rome, Italy
7Department of Medical Oncology, Policlinico Umberto I, Rome, Italy


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.

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.

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