Abstract
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 ≤ 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.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.
Highlights
Colorectal cancer (CRC) is the second highest cause of cancer death in Western countries
The aims of this study was to investigate the efficacy of 5-FU degradation rate and genetic polymorphisms (MTHFR, DPYD, and TS enhancing region (TSER)) as prognostic and predictive parameter for progression free survival
Some studies have investigated the methylenetetrahydrofolate reductase (MTHFR), DPYD and TSER genotypes as predictors of toxicity to 5-FU-based chemotherapy. [17, 18, 23,24,25,26,27,28,29,30,31,32,33] The most consistent evidence concerns the DPYD gene, demonstrating an association between severe toxicity and the presence of the polymorphism. [17, 18, 29,30,31,32,33] Interestingly, a case-cohort analysis on the patients enrolled in the phase III CAIRO2 trial showed that DPYD polymorphisms are related to grade 3–4 toxicities, with a trend toward increased overall survival
Summary
Colorectal cancer (CRC) is the second highest cause of cancer death in Western countries. Knowledge of the clinical impact of gene polymorphisms involved in the pharmacokinetics and pharmacodynamics of fluoropyrimidines may provide opportunities for patient-tailored chemotherapy, resulting in decreased incidence of severe side effects, reduced numbers of treatment delays or discontinuations, and possibly increased survival probability. [21] we analysed the effects of the individual 5-FUDR on 5-FU toxicity in a population of 433 CRC patients. We found that both the poor metabolizer (PM) subjects, defined by a 5-FUDR 5th centile, and the ultra-rapid metabolizer (UM) patients, defined by a 5-FUDR ! In the present study the Authors aim is to evaluate the influence of genetic polymorphisms of the genes involved in 5-FU metabolism and the of 5-FUDR on progression free survival in a population of metastatic colorectal cancer patients We found that both the poor metabolizer (PM) subjects, defined by a 5-FUDR 5th centile, and the ultra-rapid metabolizer (UM) patients, defined by a 5-FUDR ! 95th centile, are at higher risk to develop G3-4 toxicity, with an OR of 3.47 and 3.34, respectively, compared to normal metabolizers (5th < 5FUDR < 95th centiles). [22]
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