Cancer Treatment Today

Oncology Guidelines on the UGT1A1*28 Polymorphism

The National Comprehensive Cancer Network Guidelines63 state that irinotecan should be used with caution in patients with Gilbert syndrome or elevated serum bilirubin. There is a commercially available test for UGT1A1. The guideline for its use in clinical practice has not been established. It also includes a caution that UGT1A1 testing on patients who experience irinotecan toxicity is not recommended because they will require a dose reduction regardless of UGT1A1 test result.

ASCO does not provide any guidelines on this matter.

The European Society for Medical Oncology consensus guidelines64 acknowledge the UGT1A1 polymorphism as a predictive biomarker of irinotecan toxicity. It states that UGT1A1 phenotyping remains an option and should be carried out in patients with a suspicion of UGT1A1 deficiency as reflected by low conjugated bilirubin (< 20% of total bilirubin) and in patients where an irinotecan dose of > 180 mg/m2 per administration is planned (recommendation grade C [insufficient evidence]).

The Japanese Society for Cancer of the Colon and Rectum guidelines65 state that because irinotecan toxicity cannot be predicted with certainty on the basis of the presence of a UGT1A1 genetic polymorphism alone, it is essential to monitor patients’ general condition during treatment and to manage adverse drug reactions carefully, irrespective of whether a genetic polymorphism is detected.
Drug Label Information in the United States and Other Countries

According to the Table of Pharmacogenetic Associations from the FDA,66 UGT1A1 *28/*28 results in higher systemic active metabolite concentrations and higher adverse reaction risk (severe neutropenia). Consider reducing the starting dosage by one level and modify the dosage on the basis of individual patient tolerance. Consistent with this, the FDA-approved drug labels for irinotecan and SN-38 (Camptosar, Onivyde, and Trodelvy) state that patients carrying UGT1A1*28/*28 are at increased risk of neutropenia.1,6,7 For these patients, the drug label for Camptosar (irinotecan HCl) recommends at least one level lower starting dose of irinotecan when administered in combination with other agents, or as a single agent1 (Table 3).1 However, the precise dose reduction in this patient population is not known, and subsequent dose modifications should be considered on the basis of individual patient tolerance to treatment. The FDA-approved drug label for Onivyde (irinotecan liposome) recommends a starting dose of 50 mg/m2 (approximately 30% reduction of the standard dose), with an increased dose to 70 mg/m2 as tolerated in subsequent cycles.2 The FDA-approved drug label for Trodelvy (sacituzumab govitecan-hziy) indicates that the dose should be adjusted on the basis of individual patient tolerance because the appropriate dose for these patients is unknown.
Karas S, Innocenti F. All You Need to Know About UGT1A1 Genetic Testing for Patients Treated With Irinotecan: A Practitioner-Friendly Guide. JCO Oncol Pract. 2022 Apr;18(4):270-277. doi: 10.1200/OP.21.00624. Epub 2021 Dec 3. PMID: 34860573; PMCID: PMC9014426.