The Early Safety Signal of Sacituzumab Govitecan-Related Toxicity and the UGT1A1*28 Genotype in Metastatic Breast Cancer: A Real-World Preliminary Report Martínez Pérez, María Nieto-Sánchez, María Teresa Díaz Villamarín, Xando Torres García, Alicia Fernández Varón, Emilio Prados-Carmona, Alvaro Legerén, Marta Cabeza-Barrera, José Blancas López-Barajas, María Isabel Morón Romero, María Rocío sacituzumab-govitecan UGT1A1*28 pharmacogenetics Background/Objectives: Sacituzumab govitecan (SG) releases SN-38, the same active me tabolite as irinotecan, thereby sharing key metabolic pathways and toxicity mechanisms. The clearance of SN-38 is strongly influenced by UGT1A1 polymorphisms, particularly the UGT1A1*28 allele. While UGT1A1*28 genotyping routinely guides irinotecan dosing, no such recommendations exist for SG. This study describes the relationship between UGT1A1*28 and severe SG-related toxicity in real-world practice, identifying early safety signals and exploring the clinical and economic impact. Methods: This retrospective ob servational 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 Ad verse Events version 5.0) and healthcare costs related to hospitalizations were estimated using official institutional tariffs. Results: All nine SG patients with severe toxicity (100%) carried the UGT1A1*28 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). Conclusions: Severe SG-re lated toxicity reveals a consistent UGT1A1*28-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 sup ports implementing preventive UGT1A1 testing to optimize the safety and sustainability of sacituzumab govitecan therapy. 2026-02-25T09:06:35Z 2026-02-25T09:06:35Z 2026-02-24 journal article Martínez-Pérez, M., Nieto-Sánchez, M. T., Díaz-Villamarín, X., Torres-García, A., Fernández-Varón, E., Prados-Carmona, A., Legerén, M., Cabeza-Barrera, J., Blancas, I., & Morón, R. (2026). The Early Safety Signal of Sacituzumab Govitecan-Related Toxicity and the UGT1A1*28 Genotype in Metastatic Breast Cancer: A Real-World Preliminary Report. Journal of Clinical Medicine, 15(5), 1715. https://doi.org/10.3390/jcm15051715 https://hdl.handle.net/10481/111495 10.3390/jcm15051715 eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional MDPI