DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer
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Chiara Cremolini1, Marzia Del Re2, Carlotta Antoniotti1, Sara Lonardi3, Francesca Bergamo3, Fotios Loupakis1, Beatrice Borelli1, Federica Marmorino1, Valentina Citi2, Enrico Cortesi4, Roberto Moretto1, Monica Ronzoni5, Gianluca Tomasello6, Alberto Zaniboni7, Patrizia Racca8, Angela Buonadonna9, Giacomo Allegrini10, Vincenzo Ricci11, Samantha Di Donato12, Vittorina Zagonel3, Luca Boni13, Alfredo Falcone1 and Romano Danesi2
1Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, University of Pisa, Istituto Toscano Tumori, Pisa, Italy
2Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
3Oncologia Medica 1, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padova, Italy
4Department of Medical Oncology, Policlinico Umberto I "Sapienza" University of Rome, Roma, Italy
5Medical Oncology Unit, Ospedale San Raffaele-IRCCS, Milano, Italy
6ASST di Cremona, Ospedale di Cremona, Cremona, Italy
7Fondazione Poliambulanza Hospital, Brescia, Italy
8SSD ColoRectal Unit-Dipartimento di Oncologia, AOU Città della Salute e della Scienza di Torino, Torino, Italy
9Medical Oncology Unit, CRO-National Cancer Institute, Aviano, Italy
10Medical Oncology Unit, Presidio Ospedaliero Felice Lotti, Pontedera, Italy
11Department of Oncology, S.Croce and Carle Teaching Hospital, Cuneo, Italy
12Medical Oncology Department, Nuovo Ospedale-Santo Stefano, Istituto Toscano Tumori, Prato, Italy
13Clinical Trial Coordinating Center, AOU Careggi, Istituto Toscano Tumori, Firenze, Italy
Alfredo Falcone, email: [email protected]
Keywords: DPYD; UGT1A1; 5-fluorouracil; irinotecan; toxicity
Received: September 08, 2017 Accepted: November 13, 2017 Published: December 21, 2017
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.
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