Impact of Genetic Variants on the Toxicity of Antibody-Drug Conjugates in Locally Advanced or Metastatic Breast Cancer: The Role of the UGT1A1 Gene as a Predictive Biomarker of Therapeutic Response

Recruiting · NCT07582887 · Observational (researchers observe without assigning treatment) · Lead sponsor: Fundación Pública Andaluza para la Investigación Biomédica Andalucía Oriental

View the official record on ClinicalTrials.gov →

Breast Cancer

Interventions studied

Datopotamab Deruxtecan Sacituzumab Govitecan Trastuzumab deruxtecan

What this trial is about

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.

Who can take part

Age range

18 Years and older

Sex

All (male and female)

Healthy volunteers

No - a diagnosis or condition is required

Phase

Not specified

Study type

Observational (researchers observe without assigning treatment)

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.

Where it is running

1 location listed.

Hospital Universitario Clínico San Cecilio - Granada, Granada, Spain

Read the full protocol, contacts and eligibility on ClinicalTrials.gov →