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Oncotarget. 2017 Dec 21;9(8):7859-7866. doi: 10.18632/oncotarget.23559. eCollection 2018 Jan 30.

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

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Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, University of Pisa, Istituto Toscano Tumori, Pisa, Italy.
Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Oncologia Medica 1, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padova, Italy.
Department of Medical Oncology, Policlinico Umberto I "Sapienza" University of Rome, Roma, Italy.
Medical Oncology Unit, Ospedale San Raffaele-IRCCS, Milano, Italy.
ASST di Cremona, Ospedale di Cremona, Cremona, Italy.
Fondazione Poliambulanza Hospital, Brescia, Italy.
SSD ColoRectal Unit-Dipartimento di Oncologia, AOU Città della Salute e della Scienza di Torino, Torino, Italy.
Medical Oncology Unit, CRO-National Cancer Institute, Aviano, Italy.
Medical Oncology Unit, Presidio Ospedaliero Felice Lotti, Pontedera, Italy.
Department of Oncology, S. Croce and Carle Teaching Hospital, Cuneo, Italy.
Medical Oncology Department, Nuovo Ospedale-Santo Stefano, Istituto Toscano Tumori, Prato, Italy.
Clinical Trial Coordinating Center, AOU Careggi, Istituto Toscano Tumori, Firenze, Italy.


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 ( 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.


5-fluorouracil; DPYD; UGT1A1; irinotecan; toxicity

Conflict of interest statement

CONFLICTS OF INTEREST All authors declare no potential competing interests.

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