{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T02:55:45Z","timestamp":1789181745064,"version":"build-2803163510"},"reference-count":29,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2015,6,22]],"date-time":"2015-06-22T00:00:00Z","timestamp":1434931200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2015,9]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in <jats:italic>DPYD<\/jats:italic> and <jats:italic>UGT1A1<\/jats:italic> influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency <jats:italic>DPYD<\/jats:italic> variants (c.1905 + 1G &gt; A, c.1679 T &gt; G, c.2846A &gt; T) are validated but more frequent ones (c.496A &gt; G, c.1129\u20105923C &gt; G and c.1896 T &gt; C) are not. rs895819 T &gt; C polymorphism in hsa\u2010mir\u201027a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats: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\u2010Time PCR. We evaluated the functional variants in <jats:italic>DPYD<\/jats:italic> (rare: c.1905 + 1G &gt; A, c.1679 T &gt; G, c.2846A &gt; T; most common: c.496A &gt; G, c.1129\u20105923C &gt; G, c.1896 T &gt; C), hsa\u2010mir\u201027a (rs895819) and <jats:italic>UGT1A1<\/jats:italic> (*<jats:italic>28<\/jats:italic>) genes to assess their association with grade 3\u20134 AEs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>None of the patients carried rare <jats:italic>DPYD<\/jats:italic> variants. We found <jats:italic>DPYD<\/jats:italic> c.496A &gt; G, c.1129\u20105923C &gt; G, c.1896 T &gt; C in heterozygosity in 19%, 5% and 8%, respectively, homozygous rs895819 in hsa\u2010mir\u201027a in 9% and homozygous <jats:italic>UGT1A1<\/jats:italic>*<jats:italic>28<\/jats:italic> in 8%. Grade 3\u20134 AEs were observed in 36% patients and were associated with <jats:italic>DPYD<\/jats:italic> c.496A &gt; G (odds ratio (OR) 4.93, 95% CI 1.29, 18.87; <jats:italic>P<\/jats:italic> = 0.021) and homozygous rs895819 in hsa\u2010mir\u201027a (OR 11.11, 95% CI 1.21, 102.09; <jats:italic>P<\/jats:italic> = 0.020). Carriers of <jats:italic>DPYD<\/jats:italic> c.1896 T &gt; C and homozygous <jats:italic>UGT1A1<\/jats:italic>*<jats:italic>28<\/jats:italic> showed an OR of 8.42 (95% CI 0.88, 80.56; <jats:italic>P<\/jats:italic> = 0.052). Multivariate analysis confirmed an independent value for <jats:italic>DPYD<\/jats:italic> c.496A &gt; G and c.1896 T &gt; C.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Concomitant assessment of <jats:italic>DPYD<\/jats:italic> variants and the <jats:italic>UGT1A1<\/jats:italic>*<jats:italic>28<\/jats:italic> allele is a promising strategy needing further validation for dose personalization.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.12631","type":"journal-article","created":{"date-parts":[[2015,3,17]],"date-time":"2015-03-17T20:11:28Z","timestamp":1426623088000},"page":"581-588","source":"Crossref","is-referenced-by-count":57,"title":["DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan"],"prefix":"10.1111","volume":"80","author":[{"given":"Felicia Stefania","family":"Falvella","sequence":"first","affiliation":[{"name":"Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences University Hospital \u2018Luigi Sacco\u2019, Universit\u00e0 di Milano  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Cheli","sequence":"additional","affiliation":[{"name":"Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences University Hospital \u2018Luigi Sacco\u2019, Universit\u00e0 di Milano  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Martinetti","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Mazzali","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences University Hospital \u2018Luigi Sacco\u2019, Universit\u00e0 di Milano  Milan Italy"},{"name":"Department of Management Economics and Industrial Engineering, Politecnico di Milano  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Iacovelli","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Maggi","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Gariboldi","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology and Molecular Medicine Fondazione IRCCS Istituto Nazionale dei Tumori  Milan Italy"},{"name":"FIRC Institute of Molecular Oncology Foundation  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco Alessandro","family":"Pierotti","sequence":"additional","affiliation":[{"name":"Scientific Directorate Fondazione IRCCS Istituto Nazionale dei Tumori  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Di Bartolomeo","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Sottotetti","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Mennitto","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Bossi","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"de Braud","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Clementi","sequence":"additional","affiliation":[{"name":"Scientific Institute, IRCCS E. 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