The PROCURE Project, a translational study involving 26 Spanish institutions, has found that germline variants of the UGT1A1 gene — including the *28/*28 genotype — do not predict the adverse effects of trastuzumab-deruxtecan (T-DXd) in patients with advanced breast cancer. The result pushes the search towards other biomarkers to guide toxicity risk stratification.
What was known
T-DXd has shown remarkable efficacy in advanced breast cancer, but about 20% of patients stop treatment because of adverse events. Pharmacogenetic variants in uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) increase the toxicity risk of other antibody-drug conjugates that use topoisomerase I inhibitors, but they had not been studied for T-DXd.
What this work adds
This is a translational study investigating the association between germline pharmacogenomic variants and T-DXd toxicity in patients with HER2-positive or HER2-low advanced breast cancer. UGT1A1*28 genotypes were determined in blood samples, and analyses used clinical data and adverse events extracted from patients’ medical records. Stratified Cox models were used to quantify the risk of treatment discontinuation by genotype.
Main results
Between July 2022 and March 2024, 292 patients with genetic and clinical information were enrolled. Median T-DXd treatment duration was 12.0 months (95% CI 10.5-14.1). UGT1A1 genotype distribution was 43.2% wild-type (*1/*1), 46.2% heterozygous (*1/*28) and 10.3% homozygous (*28/*28). No association was seen between UGT1A1 genotypes and the most common T-DXd adverse events. Poor metabolisers (*28/*28), compared with extensive and intermediate metabolisers, showed a trend towards a higher incidence of neutropenia (13.3%).
What it means
The authors conclude that UGT1A1 variants were not predictive of T-DXd-related adverse events in advanced breast cancer. The study highlights the need to identify alternative biomarkers to optimise toxicity risk stratification and guide personalised treatment strategies. In practical terms, UGT1A1 genotyping should not currently be used as a tool to decide on or adjust T-DXd.
Spanish context
The PROCURE Project is a cooperative research initiative bringing together 26 Spanish institutions and relying on real-world clinical data, a model that allows pharmacogenomic questions the pivotal trials do not address to be answered. Its design reflects the growing weight of Spanish cooperative groups in breast oncology.
Reference: Sánchez-Bayona R, de Nicolás-Hernández J, Saura C, Gion M, Cejalvo JM, Llabrés E, et al. Analysis of UGT1A1 germline variants in patients with advanced breast cancer treated with trastuzumab-deruxtecan: results from the PROCURE Project. ESMO Open, 2026. https://doi.org/10.1016/j.esmoop.2026.107695
