title: Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker?
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical and Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Botticelli
authors.affiliation: Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), "Sapienza" University of Rome, Rome, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Borro
authors.affiliation: Medical Oncology Unit, Sant'Andrea Hospital, Rome, Italy.
authors.forename: Concetta Elisa
authors.initials: CE
authors.lastname: Onesti
authors.affiliation: Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Strigari
authors.affiliation: Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Gentile
authors.affiliation: Department of Radiological Oncological and Pathological Sciences, "Sapienza" University of Rome, Rome, Italy.
authors.forename: Bruna
authors.initials: B
authors.lastname: Cerbelli
authors.affiliation: Department of Clinical and Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Romiti
authors.affiliation: Medical Oncology Unit, Sant'Andrea Hospital, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Occhipinti
authors.affiliation: Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sebastiani
authors.affiliation: Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Lionetto
authors.affiliation: Department of Medical Oncology, Policlinico Umberto I, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Marchetti
authors.affiliation: Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), "Sapienza" University of Rome, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Simmaco
authors.affiliation: Department of Clinical and Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.|Medical Oncology Unit, Sant'Andrea Hospital, Rome, Italy.|Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: Department of Clinical and Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.|Medical Oncology Unit, Sant'Andrea Hospital, Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Mazzuca