Breast Cancer, Drug-Related Side Effects and Adverse Reactions, Metastatic Breast Cancer, Pharmacogenetic Variant
Conditions
Keywords
UGT1A1, Genetic Variants, Toxicity, polymorphism, Breast Cancer, Sacituzumab Govitecan, Trastuzumab Deruxtecan, Datopotamab Deruxtecan
Brief summary
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.
Interventions
DRUGSacituzumab Govitecan
Administered according to standard clinical practice and product label.
DRUGTrastuzumab deruxtecan
Administered according to standard clinical practice and product label.
DRUGDatopotamab Deruxtecan
Administered according to standard clinical practice and product label.
Sponsors
Fundación Pública Andaluza para la Investigación Biomédica Andalucía Oriental
Study design
Observational model
COHORT
Time perspective
OTHER
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* Patients who are ultimately not treated with the specified Antibody-Drug Conjugates. * Refusal to provide informed consent for genetic analysis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Severe Drug-Related Toxicities (Grade ≥ 3) | From the start of treatment until the end of the follow-up period (up to 2 years). | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of UGT1A1*28 Allele | At baseline (once the genetic study is performed). | Distribution and allelic frequency of the UGT1A1\*28 variant in the study population of breast cancer patients. |
| Correlation Between Genetic Variants and Toxicity Severity | Analyzed at the completion of the 2-year study period. | 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 | At the end of the study (2 years). | Design of a predictive model based on genetic markers to anticipate the appearance of severe toxicities for each ADC studied. |
Countries
Spain
Contacts
CONTACTIsabel Blancas López-Barajas, MD, PhD
Outcome results
None listed