The Early Safety Signal of Sacituzumab Govitecan-Related Toxicity and the UGT1A1*28 Genotype in Metastatic Breast Cancer: A Real-World Preliminary Report

<b>Background/Objectives:</b> Sacituzumab govitecan (SG) releases SN-38, the same active metabolite as irinotecan, thereby sharing key metabolic pathways and toxicity mechanisms. The clearance of SN-38 is strongly influenced by <i>UGT1A1</i> polymorphisms, particularly the <i>UGT1A1*28</i> allele. While <i>UGT1A1*28</i> genotyping routinely guides irinotecan dosing, no such recommendations exist for SG. This study describes the relationship between <i>UGT1A1*28</i> and severe SG-related toxicity in real-world practice, identifying early safety signals and exploring the clinical and economic impact. <b>Methods:</b> This retrospective observational study (2021-2025) included patients with metastatic breast cancer treated with SG and patients with advanced gastrointestinal malignancies treated with irinotecan at a tertiary hospital. In the SG cohort, genotyping followed grade ≥3 toxicity; in the irinotecan cohort, it was performed prospectively. Toxicity (Common Terminology Criteria for Adverse Events version 5.0) and healthcare costs related to hospitalizations were estimated using official institutional tariffs. <b>Results:</b> All nine SG patients with severe toxicity (100%) carried the <i>UGT1A1*28</i> allele. In the irinotecan cohort (n = 74), which was managed with genotype-guided dosing, severe toxicity and hospitalization were less frequent. SG was associated with higher mean costs per treated patient (€2817.01 vs. €1233.63), driven by toxicity-related admissions (33.3% vs. 10.8%). Genotyping costs (€10.51) were negligible compared to daily hospitalization expenses (up to €1984.90). <b>Conclusions:</b> Severe SG-related toxicity reveals a consistent <i>UGT1A1*28</i>-associated vulnerability. Given the drug's recent approval in Spain, these data represent an urgent real-world safety signal. The marked disparity between low genotyping costs and high hospitalization expenses supports implementing preventive <i>UGT1A1</i> testing to optimize the safety and sustainability of sacituzumab govitecan therapy.