DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan

Abstract

AIMSTriplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated but more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not. rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations. METHODSGermline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G, c.1129-5923C > G, c.1896 T > C), hsa-mir-27a (rs895819) and UGT1A1 (*28) genes to assess their association with grade 3-4 AEs. RESULTSNone of the patients carried rare DPYD variants. We found DPYD c.496A > G, c.1129-5923C > G, c.1896 T > C in heterozygosity in 19%, 5% and 8%, WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Pharmacogenetic testing of DPYD and UGT1A1 is recommended in clinical practice prior to administration of fluoropyrimidines and irinotecan, respectively. respectively, homozygous rs895819 in hsa-mir-27a in 9% and homozygous UGT1A1*28 in 8%. Grade 3-4 AEs were observed in 36% patients and were associated with DPYD c.496A > G (odds ratio (OR) 4.93, 95% CI 1.29, 18.87; P = 0.021) and homozygous rs895819 in hsa-mir-27a (OR 11.11, 95% CI 1.21, 102.09; P = 0.020). Carriers of DPYD c.1896 T > C and homozygous UGT1A1*28 showed an OR of 8.42 (95% CI 0.88, 80.56; P = 0.052). Multivariate analysis confirmed an independent value for DPYD c

Cost Evaluation of Irinotecan‐Related Toxicities Associated With the UGT1A1*28 Patient Genotype

“…Every year, about 16,000 patients in Italy undergo treatment with an irinotecan‐containing regimen based on the epidemiological data on the incidence of mCRC in Italy in 2012 . The results of the current analysis can be used to provide an estimate of the impact of the incremental cost of toxicity management associated with UGT1A1*28 at a national level, based on the prevalence of the UGT1A1*28 allele in populations residing in Italy . Based on the results of this study, an approximate calculation of the total incremental cost spent by the Italian Public Health System to manage the chemotherapy‐related toxicity for mCRC patients carrying at least one *28 allele and being treated with irinotecan would be around €8 million, every year.…”

“…17 The results of the current analysis can be used to provide an estimate of the impact of the incremental cost of toxicity management associated with UGT1A1*28 at a national level, based on the prevalence of the UGT1A1*28 allele in populations residing in Italy. 18,19 Based on the results of this study, an approximate calculation of the total incremental cost spent by the Italian Public Health System to manage the chemotherapy-related toxicity for mCRC patients carrying at least one *28 allele and being treated with irinotecan would be around e8 million, every year. The cost for genotyping all the 16,000 irinotecan-candidate patients, based on a genotyping cost of e163 per patient (according to the Regional Health System, Supplementary Table 2), would be around e2.6 million.…”

Toxicity Syndromes, Patient-Related Clinical Indicator of Toxicity Burden Induced by Intensive Triplet Chemotherapy-Based Regimens in Gastrointestinal Cancers With Metastatic Disease

“…The rates of LTS-ms and LTS-ss were compared by Chi-square test (23). More, in FIr-C/FOx-C study, exploratory analysis of 5-FU/CPT-11 pharmacogenomic biomarkers, specifically 5-FU degradation rate (5-FUDR), defining reduced metabolizers if <1.2 ng/mL/10 6 cells/min, and Single Nucleotide Polimorphisms (SNPs) ABCB1 (C3435T, C1236T), CYP3A4 (1B, 53), DYPD1 (IVS14+1, A166G), UGT1A1 (28) were preliminarily related with the occurrence of LTS (4,24,25).…”

Vaccine–Drug Interactions: Cytokines, Cytochromes, and Molecular Mechanisms

“…However, inter-individual variability as a result of SNPs in several key metabolic genes has already been employed in a number of clinical setting, including oncology [51,52], infectivology [53], and other diseases [54][55][56]. As a number of genes and SNPs are known to potentially influence the risk of vaccine-drug interactions by interfering with both immune response [44][45][46][47][48][49][50] and CYP activity [41][42][43], further studies are required to fully explore this topic.…”