Analysis of UGT1A1 germline variants in patients with advanced breast cancer treated with trastuzumab-deruxtecan: results from the PROCURE Project.

BACKGROUND: Although trastuzumab-deruxtecan (T-DXd) has demonstrated significant efficacy in advanced breast cancer, treatment discontinuation due to adverse events occurs in ∼20% of patients. Pharmacogenetic variants in uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) increase the toxicity risk for other antibody-drug conjugates using topoisomerase I inhibitors, but they remain unexplored for T-DXd. MATERIAL AND METHODS: The PROCURE Project is a translational study involving 26 Spanish institutions, investigating the association of germline pharmacogenomic variants with T-DXd toxicity for patients with HER2-positive or HER2-low advanced breast cancer. UGT1A1∗28 genotypes were determined in blood samples, and pharmacogenomic analyses were performed using the clinical data and adverse events extracted from the medical records of the patients. Additionally, stratified Cox models were used to quantify the risk of treatment discontinuation in the different UGT1A1 genotypes. RESULTS: Between July 2022 and March 2024, a total of 292 patients with genetic and clinical information were enrolled in the study. At data cutoff, the median treatment duration with T-DXd was 12.0 months 95% confidence interval (CI) 10.5-14.1. UGT1A1 genotype distribution among patients was 43.2% wild-type (∗1/∗1), 46.2% heterozygous (∗1/∗28), and 10.3% homozygous (∗28/∗28). No association was observed between UGT1A1 genotypes and the most common T-DXd adverse events. However, poor metabolizers (∗28/∗28) compared with extensive and intermediate metabolizers (∗1/∗1 and ∗1/∗28, respectively) showed a trend toward higher incidence of neutropenia (13.3% versus <6%), as well as a higher incidence of grade ≥3 gastrointestinal toxicity (diarrhea and vomiting). The incidence of drug-induced pneumonitis/interstitial lung disease (ILD) was 11.0% (32/292). No association was observed between UGT1A1 variants and the incidence of pneumonitis/ILD. Patients carrying UGT1A1∗28/∗28 genotype showed a longer treatment duration (HR 0.47, 95% CI 0.23-0.93, P = 0.03) compared with UGT1A1 wild-type patients. CONCLUSIONS: In the PROCURE Project, UGT1A1 variants, including the ∗28/∗28 genotype, were not predictive of T-DXd-related adverse events in advanced breast cancer. The project highlights the need to identify alternative biomarkers to optimize toxicity risk stratification and guide personalized treatment strategies.