Influencia de los polimorfismos del gen UGT1A1 en el tratamiento con sacituzumab govitecan. Revisión narrativa

Abstract

Objective

Sacituzumab govitecan is an antineoplastic therapy composed of a monoclonal antibody directed to the Trop2 antigen, conjugated to SN-38, an active metabolite of irinotecan that inhibits topoisomerase I. It is indicated for the treatment of metastatic triple-negative breast cancer in patients who have received at least two prior lines of treatment, with at least one in the metastatic context. SN-38 is eliminated by glucuronidation mediated by uridine diphosphate-glucuronosyltransferase-1A1 (UGT1A1) enzymes, present in the liver. Mutations in the UGT1A1 gene decrease the expression of these enzymes, which increases the concentration of SN-38 and, consequently, increases the toxicity of the drug, especially in the form of neutropenia and diarrhea. This study aims to analyze the relationship between UGT1A1 gene polymorphisms and toxicity associated with treatment with sacituzumab govitecan, in addition to reviewing the usefulness of genetic screening prior to starting therapy.

Methods

A non-systematic literature review was conducted on the impact of UGT1A1 gene polymorphisms on the safety of sacituzumab govitecan treatment in patients with triple-negative breast cancer. The search included primary and secondary literature sources and communications from oncology conferences.

Results

Patients treated with sacituzumab govitecan with the UGT1A1*28/*28 mutated genotype are more likely to experience grade more than 3 hematologic adverse events: neutropenia (approximate incidence of 60% compared to 40% for 1/*1 and 1/*28 genotypes), febrile neutropenia (18% homozygotes vs. 5% heterozygotes and 3% wild-type), grade more than 3 anemia (15% vs. 6% and 4%, respectively); as well as grade more than 3 diarrhea (24% vs. 13% and 6%, respectively). Additionally, treatment discontinuation rates are higher in *28/*28 individuals (6% compared to 1% heterozygotes and 2% wild-type).

Conclusions

Patients homozygous for the UGT1A1*28 allele are at significantly increased risk of developing serious adverse events. Despite the clear relationship between UGT1A1 polymorphisms and sacituzumab-govitecan toxicity, the review suggests that there is insufficient consensus on the need for systematic genetic screening. However, the findings indicate that such screening could be useful for identifying patients at risk and personalizing sacituzumab govitecan therapy.