Background/Objectives: Irinotecan is used in monotherapy or combined with other drugs for treating different cancer streams. SN-38, the active metabolite of irinotecan, is 70% inactivated by the uridine diphosphate (UDP) glucuronosyltransferase family 1 member A1 (UGT1A1) enzyme. The UGT1A1*6 (rs4148323) and *28 (rs3064744) alleles in the gene encoding the enzyme lead to decreased enzyme expression and increased severe irinotecan toxicity. Carrying one or two copies of these alleles results in a UGT1A1 intermediate or poor metabolizer status (IM, PM). The Food and Drug Administration (FDA)-approved drug labels and European Medicines Agency (EMA) European Public Assessment Report (EPAR) for irinotecan recommend dose adjustments based on UGT1A1 genotypes, but only for UGT1A1 PM patients. However, available pharmacogenetic (PGx) dosing guidelines for the UGT1A1–irinotecan interaction lack a consensus about considered genetic variants, genotype-translated phenotypes, and therapeutic recommendations. We aimed to describe evidence regarding the impact of the UGT1A1 genotype in irinotecan toxicity to inform irinotecan-dosing recommendations based on possible UGT1A1 genotypes. Methods: A systematic review was performed to find all the Phase I clinical trials looking for the maximum tolerated dose (MTD) or dose-limiting toxicities (DLTs) of irinotecan depending on the UGT1A1 genotype. Results: Toxicity-related events and the MTD of irinotecan differ among UGT1A1 normal metabolizers (NM), IM, and PM patients considering the UGT1A1*28 and/or *6 variants. Conclusions: Dose adjustments might also be recommended for UGT1A1 IM patients (*1/*28 or *1/*6 genotypes), with a 15% dose reduction considered.

Background/Objectives: The clinical implementation of pharmacogenetics (PGx) remains limited, even for well-established drug–gene interactions. In addition to insufficient infrastructure and PGx education among healthcare professionals, there is currently no consensus regarding which genetic variants should be tested, the most appropriate testing approach (e.g., single-gene vs. multi-gene panels), or how to translate genotypes into actionable therapeutic recommendations. Methods: We describe the implementation of PGx in real daily clinical routine at a single institution to guide other centers. We analyze the drug–gene interactions and genetic variants included in our program based on allelic, genotypic, and phenotypic frequencies, resulting therapeutic recommendations. Linkage disequilibrium and haplotype analyses are also performed. Results and Conclusions: PGx testing was primarily requested by the oncology department. Not all variants included in typical panels had clinical utility in our setting. We do not recommend testing CYP2C19*17 prior to clopidogrel prescription, as it does not translate into a dosing recommendation. TPMT*3B may be considered just to confirm TPMT*3A due to its linkage with TPMT*3C. Similarly, we do not recommend the routine testing of CYP2C9*2 prior to siponimod prescription, as it does not inform therapeutic decisions according to the current drug label.

Background/Objectives: Cetuximab, formulated in Erbitux^® (5 mg/mL), is a therapeutic monoclonal antibody (mAb) widely used in several cancer treatments. Currently, there is insufficient knowledge about the behavior of cetuximab with regard to the risk associated with its routine handling or unintentional mishandling in hospitals. Forced degradation studies can simulate these conditions and provide insights into the biophysical and biochemical properties of mAbs. Methods: In this study, we conducted a deep physicochemical and functional characterization of the critical quality attributes of cetuximab in control samples and under controlled degraded conditions, including freeze–thaw cycles, heat, agitation, and light exposure. To achieve this purpose, we used a set of proper analytical techniques, including CD, IT-FS, DLS, SE/UHPLC-UV, UHPLC-MS/MS, and ELISA, to check functionality based on antigen–antibody binding. Results: The results revealed that light exposure was the stress stimuli with the greatest impact on the drug product, leading to the formation of non-natural oligomers, fragmentation, and oxidation of methionine residues. Additionally, cetuximab (Erbitux^®, 5 mg/mL) showed a tendency to aggregate when submitted to 60 °C for 1 h. In terms of functionality, cetuximab (Erbitux^®, 5 mg/mL) samples were found to be affected when subjected to freeze–thaw cycles, 60 °C (1 h), and when exposed to light (daylight with room temperature excursion and accelerated light exposure). Conclusions: Thus, we suggest that Erbitux^® (5 mg/mL) should be shielded from these environmental conditions, as they compromise both the safety and efficacy of the drug product.

Background/Objectives: 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 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 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. 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-related 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 supports implementing preventive UGT1A1 testing to optimize the safety and sustainability of sacituzumab govitecan therapy.

Fluoropyrimidines (FPs) are commonly prescribed in many cancer streams. The EMA and FDA-approved drug labels for FPs recommend genotyping the DPYD*2A (rs3918290), *13 (rs55886062), *HapB3 (rs56038477), alleles, and DPYD rs67376798 before treatment starts. We implemented the DPYD genotyping in our daily clinical routine, but we still found patients showing severe adverse drug events (ADEs) to FPs. We studied among these patients the DPYD rs1801265, rs17376848, rs1801159, rs1801160, rs1801158, and rs2297595 as explanatory candidates of the interindividual differences for FP-related toxicities, examining the association with the response to FPs . We also studied the impact of DPYD testing for FP dose tailoring in our clinical practice and characterized the DPYD gene in our population. We found a total acceptance among physicians of therapeutic recommendations translated from the DPYD test, and this dose tailoring does not affect the treatment efficacy. We also found that the DPYD*4 (defined by rs1801158) allele is associated with a higher risk of ADEs (severity grade ≥ 3) in both the univariate (O.R. = 5.66; 95% C.I. = 1.35–23.67; p = 0.014) and multivariate analyses (O.R. = 5.73; 95% C.I. = 1.41–28.77; p = 0.019) among FP-treated patients based on the DPYD genotype. This makes it a candidate variant for implementation in clinical practice.

Fluoropyrimidines (FPs) are commonly prescribed in many cancer streams. The DPYD*2A (rs3918290), *13 (rs55886062), *HapB3 (rs56038477), alleles, and DPYD rs67376798, had shown the highest level of evidence about their association with FPs response. The EMA and FDA-approved drug labels for FPs, recommend genotyping these variants before treatment starts. We implemented the DPYD genotyping in our daily clinical routine, but we still find patients showing severe adverse drug events (ADEs) to FPs. We studied among these patients the association with the response to FPs of DPYD rs1801265, rs17376848, rs1801159, rs1801160, rs1801158, and rs2297595; as explanatory candidates of the interindividual differences for the FP-related toxicities. We also studied the impact of DPYD*2A, *13, *HapB3, and rs67376798 genotype for FP dose tailoring in our clinical practice and characterized the DPYD gene in our population. We found that FP dose lowering based on DPYD genotype does not affect the treatment efficacy. Also, the DPYD*4 (defined by rs1801158) allele was associated with a higher risk of ADEs (severity grade ≥ 3) in both the univariate (O.R.= 5.66; 95% C.I.= 1.35 – 23.67; p= 0.014) and multivariate analyses (O.R.= 5.73; 95% C.I.= 1.41 – 28.77; p= 0.019). This makes it a candidate variant for implementation in clinical practice.