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De Mattia et al. Cancer Drug Resist 2019;2:116-30 Cancer
DOI: 10.20517/cdr.2019.04 Drug Resistance

Review Open Access

The use of pharmacogenetics to increase the
safety of colorectal cancer patients treated with
fluoropyrimidines

Elena De Mattia, Rossana Roncato, Chiara Dalle Fratte, Fabrizio Ecca, Giuseppe Toffoli, Erika Cecchin

Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano 33081, Italy.

Correspondence to: Dr. Giuseppe Toffoli and Dr. Erika Cecchin, Experimental and Clinical Pharmacology Unit, Centro di
Riferimento Oncologico di Aviano (CRO) IRCCS, via Franco Gallini 2, Aviano 33081, Italy. E-mail: gtoffoli@cro.it; ececchin@cro.it

How to cite this article: De Mattia E, Roncato R, Dalle Fratte C, Ecca F, Toffoli G, Cecchin E. The use of pharmacogenetics
to increase the safety of colorectal cancer patients treated with fluoropyrimidines. Cancer Drug Resist 2019;2:116-30.
http://dx.doi.org/10.20517/cdr.2019.04

Received: 12 Dec 2018 First Decision: 21 Dec 2018 Revised: 31 Jan 2019 Accepted: 15 Feb 2019 Published: 19 Mar 2019

Science Editor: Enrico Mini Copy Editor: Cai-Hong Wang Production Editor: Huan-Liang Wu

Abstract
Fluoropyrimidines (FP) are given in the combination treatment of the advanced disease or as monotherapy in the neo-
adjuvant and adjuvant treatment of colorectal cancerand other solid tumors including breast, head and neck and gastric
cancer. FP present a narrow therapeutic index with 10 to 26% of patients experiencing acute severe or life-threatening
toxicity. With the high number of patients receiving FP-based therapies, and the significant effects of toxicities on their
quality of life, the prevention of FP-related adverse events is of major clinical interest. Host genetic variants in the rate
limiting enzyme dihydropyrimidine dehydrogenase (DPYD) gene are related to the occurrence of extremely severe, early
onset toxicity in FP treated patients. The pre-treatment diagnostic test of 4 DPYD genetic polymorphisms is suggested by
the currently available pharmacogenetic guidelines. Several prospective implementation projects are ongoing to support
the introduction of up-front genotyping of the patients in clinical practice. Multiple pharmacogenetic studies tried to
assess the predictive role of other polymorphisms in genes involved in the FP pharmacokinetics/pharmacodynamic
pathways, TYMS and MTHFR, but no additional clinically validated genetic markers of toxicity are available to date. The
development of next-generation sequencing platforms opens new possibilities to highlight previously unreported genetic
markers. Moreover, the investigation of the genetic variation in the patients immunological system, a pivotal target in
cancer treatment, could bring notable advances in the field. This review will describe the most recent literature on the
use of pharmacogenetics to increase the safety of a treatment based on FP administration in colorectal cancer patients.

Keywords: Fluoropyrimidines, pharmacogenetics, colorectal cancer, toxicity, DPYD, TYMS, MTHFR

© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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