Elucidating the role of pharmacogenetics in irinotecan efficacy and adverse events in metastatic colorectal cancer patients

ABSTRACT

Introduction

Irinotecan is a cytotoxic agent that is widely used in the treatment of several types of solid tumors. However, although it is generally well tolerated, approximately 20% to 35% of patients develop severe toxicity, particularly delayed-type diarrhea and neutropenia. As the incidence of such toxicities is often associated with the UGT1A1 *28/*28, *6/*28 and *6/*6 genotypes, individualized dosing could reduce these adverse events. Furthermore, prospective trials have shown that patients harboring the UGT1A1 *1/*1 and *1/*28 genotypes can tolerate higher doses of irinotecan, which may in turn impact on a better outcome. Upfront UGT1A1 genotyping could therefore be a usefulness strategy in order to individualize irinotecan dosing, but consensus on the recommended dose based on the UGT1A1 genotype is still lacking.

Areas covered

This review summarizes the results of the main pharmacogenetic studies focused on irinotecan. We provide an overview of current evidence and recommendations for individualized dosing of irinotecan in metastatic colorectal cancer patients.

Expert opinion

Implementation of UGT1A1*28 and UGT1A1*6 genotyping in clinical practice is a first step toward personalizing irinotecan therapy. This approach is likely to improve patient care and reduce healthcare costs. Future large and prospective studies will help to clarify the clinical value of other genetic markers in irinotecan treatment personalization.

KEYWORDS:

• Irinotecan
• dose-individualization
• genotyping
• ugt1a1
• pharmacogenetics
• biomarkers

Article highlights

• Several enzymes are involved in irinotecan transport and metabolism, highlighting UGT1A1, ABCB1, ABCC2, ABCG2 and CYP3A4, among others.

• UGT1A1*28 and UGT1A1*6 are currently the most reliable pharmacogenetic markers of irinotecan toxicity.

• Patients harbouring the UGT1A1*28/*28, UGT1A1*6/*28 or UGT1A1*6/*6 genotypes are at higher risk of irinotecan-induced severe toxicity.

• Irinotecan dosing should be determined considering UGT1A1 genotype.

• Patients with a favorable UGT1A1 genotype could tolerate higher doses of irinotecan in the FOLFIRI regimen.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank Carolyn Newey for English language editing.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Declaration of interest

David Páez has received honoraria from the Speakers Bureau of Merck Serono and F. Hoffmann-La Roche Ltd., and declares a scientific advisory role for Amgen and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was supported by the Instituto de Salud Carlos III (JR20/00008 for Pau Riera).