The metabolism of anticancer drugs is influenced by genetic variants that affect their bioavailability and toxicity. In the case of antibody-drug conjugates (ADCs), such as sacituzumab-govitecan (SG), trastuzumab-deruxtecan (T-DXd), and datopotamab-deruxtecan (Dato-DXd), the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) plays a central role in the glucuronidation and elimination of their cytotoxic components. In particular, the metabolism of SN-38, the active metabolite of irinotecan and SG, is highly influenced by variants in UGT1A1, leading to drug accumulation and the development of severe toxicities. Patients with variants such as UGT1A1\*28 (rs3064744) and UGT1A1\*6 (rs4148323) exhibit reduced enzyme activity, increasing the risk of neutropenia and severe diarrhea.
The relevance of UGT1A1 is not limited to sacituzumab-govitecan; its role in the elimination of camptothecin derivatives suggests it could also impact the toxicity of trastuzumab-deruxtecan and datopotamab-deruxtecan, which contain deruxtecan, a cytotoxic agent 10 times more potent than irinotecan. Despite strong evidence linking the UGT1A1 genotype to irinotecan toxicity, there are currently no established pharmacogenetic recommendations for antidiuretic peptides (ADCs) in metastatic breast cancer.
Patients aged 18 years or older.
Patients diagnosed with breast cancer starting or undergoing treatment with Sacituzumab Govitecan, Trastuzumab Deruxtecan, or Datopotamab Deruxtecan.
Provision of signed informed consent for the genetic study.
Patients who are ultimately not treated with the specified Antibody-Drug Conjugates.
Refusal to provide informed consent for genetic analysis.
Patients with early, locally advanced, or metastatic breast cancer treated with antibody-drug conjugates in a real-world clinical setting at a single tertiary hospital.
Cohort
Other
Sacituzumab Govitecan
DrugAdministered according to standard clinical practice and product label.
Trastuzumab deruxtecan
DrugAdministered according to standard clinical practice and product label.
Datopotamab Deruxtecan
DrugAdministered according to standard clinical practice and product label.
Incidence of Severe Drug-Related Toxicities (Grade ≥ 3)
Number of patients experiencing severe hematological or gastrointestinal toxicities (defined as Grade 3 or higher according to CTCAE v5.0) that are definitely, probably, or possibly related to the treatment with Sacituzumab Govitecan, Trastuzumab Deruxtecan, or Datopotamab Deruxtecan.
Frequency of UGT1A1*28 Allele
Distribution and allelic frequency of the UGT1A1\*28 variant in the study population of breast cancer patients.
Correlation Between Genetic Variants and Toxicity Severity
Statistical association (using Odds Ratio) between the identified genetic variants (rs4148323, rs35350906, rs3064744, rs887829, rs111741722) and the severity of adverse events.
Predictive Model for Severe Toxicity
Design of a predictive model based on genetic markers to anticipate the appearance of severe toxicities for each ADC studied.
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