DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer

// Chiara Cremolini 1 , Marzia Del Re 2 , Carlotta Antoniotti 1 , Sara Lonardi 3 , Francesca Bergamo 3 , Fotios Loupakis 1 , Beatrice Borelli 1 , Federica Marmorino 1 , Valentina Citi 2 , Enrico Cortesi 4 , Roberto Moretto 1 , Monica Ronzoni 5 , Gianluca Tomasello 6 , Alberto Zaniboni 7 , Patrizia Racca 8 , Angela Buonadonna 9 , Giacomo Allegrini 10 , Vincenzo Ricci 11 , Samantha Di Donato 12 , Vittorina Zagonel 3 , Luca Boni 13 , Alfredo Falcone 1 and Romano Danesi 2 1 Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, University of Pisa, Istituto Toscano Tumori, Pisa, Italy 2 Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy 3 Oncologia Medica 1, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padova, Italy 4 Department of Medical Oncology, Policlinico Umberto I "Sapienza" University of Rome, Roma, Italy 5 Medical Oncology Unit, Ospedale San Raffaele-IRCCS, Milano, Italy 6 ASST di Cremona, Ospedale di Cremona, Cremona, Italy 7 Fondazione Poliambulanza Hospital, Brescia, Italy 8 SSD ColoRectal Unit-Dipartimento di Oncologia, AOU Città della Salute e della Scienza di Torino, Torino, Italy 9 Medical Oncology Unit, CRO-National Cancer Institute, Aviano, Italy 10 Medical Oncology Unit, Presidio Ospedaliero Felice Lotti, Pontedera, Italy 11 Department of Oncology, S.Croce and Carle Teaching Hospital, Cuneo, Italy 12 Medical Oncology Department, Nuovo Ospedale-Santo Stefano, Istituto Toscano Tumori, Prato, Italy 13 Clinical Trial Coordinating Center, AOU Careggi, Istituto Toscano Tumori, Firenze, Italy Correspondence to: Alfredo Falcone, email: alfredo.falcone@med.unipi.it Keywords: DPYD; UGT1A1; 5-fluorouracil; irinotecan; toxicity Received: September 08, 2017 Accepted: November 13, 2017 Published: December 21, 2017 ABSTRACT Our study addresses the issue of the clinical reliability of three candidate DPYD and one UGT single nucleotide polymorphisms in predicting 5-fluorouracil- and irinotecan-related adverse events. To this purpose, we took advantage of a large cohort of metastatic colorectal cancer patients treated with first-line 5-fluorouracil- and irinotecan-based chemotherapy regimens (i.e., FOLFIRI or FOLFOXIRI) plus bevacizumab in the randomized clinical trial TRIBE by GONO (clinicaltrials.gov: NCT00719797), in which adverse events were carefully and prospectively collected at each treatment cycle. Here we show that patients bearing DPYD c.1905+1G/A and c.2846A/T genotypes, together with UGT1A1*28 variant carriers, have an increased risk of experiencing clinically relevant toxicities, including hematological AEs and stomatitis. No carrier of the DPYD c.1679T>G minor allele was identified. Present results support the preemptive screening of mentioned DPYD and UGT1A1 variants to identify patients at risk of clinically relevant 5-fluoruracil- and irinotecan-related AEs, in order to improve treatments’ safety through a “genotype-guided” approach.