DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan. (22nd June 2015)

• Record Type: Journal Article
• Authors: Falvella, Felicia Stefania; Cheli, Stefania; Martinetti, Antonia; Mazzali, Cristina; Iacovelli, Roberto; Maggi, Claudia; Gariboldi, Manuela; Pierotti, Marco Alessandro; Di Bartolomeo, Maria; Sottotetti, Elisa; Mennitto, Roberta; Bossi, Ilaria; de Braud, Filippo; Clementi, Emilio; Pietrantonio, Filippo
• Is Part Of: British journal of clinical pharmacology. Volume 80:Number 3(2015:Sep.)
• Page Start: 581
• Page End: 588
• Publication Date: 2015-06-22
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12631
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12631-sec-0001" sec-type="section"> <title>Aims</title> <p>Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in <italic>DPYD</italic> and <italic>UGT1A1</italic> influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency <italic>DPYD</italic> 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.</p> </sec> <sec id="bcp12631-sec-0002" sec-type="section"> <title>Methods</title> <p>Germline 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 <italic>DPYD</italic> (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 <italic>UGT1A1</italic> (*<italic>28</italic>) genes to assess their association with grade 3–4 AEs.</p> </sec> <sec id="bcp12631-sec-0003" sec-type="section"> <title>Results</title> <p>None of the patients carried rare <italic>DPYD</italic> variants. We found <italic>DPYD</italic> c.496A > G, c.1129‐5923C > G, c.1896 T > C in heterozygosity in 19%, 5% and 8%, respectively, homozygous rs895819 in hsa‐mir‐27a in 9% and homozygous <italic>UGT1A1</italic>*<italic>28</italic> in 8%. Grade 3–4 AEs were observed in 36% patients and were associated with <italic>DPYD</italic> c.496A > G (odds ratio (OR) 4.93, 95% CI 1.29, 18.87; <italic>P</italic> = 0.021) and homozygous rs895819 in hsa‐mir‐27a (OR 11.11, 95% CI 1.21, 102.09; <italic>P</italic> = 0.020). Carriers of <italic>DPYD</italic> c.1896 T > C and homozygous <italic>UGT1A1</italic>*<italic>28</italic> showed an OR of 8.42 (95% CI 0.88, 80.56; <italic>P</italic> = 0.052). Multivariate analysis confirmed an independent value for <italic>DPYD</italic> c.496A > G and c.1896 T > C.</p> </sec> <sec id="bcp12631-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Concomitant assessment of <italic>DPYD</italic> variants and the <italic>UGT1A1</italic>*<italic>28</italic> allele is a promising strategy needing further validation for dose personalization.</p> </sec> </abstract>