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
For patients and families
In plain language
An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.
- What is being studied
- The protocol lists: Sacituzumab Govitecan, Trastuzumab deruxtecan, Datopotamab Deruxtecan.
- Who it may be relevant to
- Registry conditions: Breast Cancer, Metastatic Breast Cancer, Drug-Related Side Effects and Adverse Reactions, Pharmacogenetic Variant. Basic parameters: from 18 years · All.
- What needs checking
- Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
- Where it takes place
- Spain
- Next step
- Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →
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Overview
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
- Drug Sacituzumab Govitecan
Administered according to standard clinical practice and product label. - Drug Trastuzumab deruxtecan
Administered according to standard clinical practice and product label. - Drug Datopotamab Deruxtecan
Administered according to standard clinical practice and product label.
Primary outcome measures
- Incidence of Severe Drug-Related Toxicities (Grade ≥ 3) [Time frame: From the start of treatment until the end of the follow-up period (up to 2 years).]
Secondary outcome measures (3)
- Frequency of UGT1A1*28 Allele [Time frame: At baseline (once the genetic study is performed).]
- Correlation Between Genetic Variants and Toxicity Severity [Time frame: Analyzed at the completion of the 2-year study period.]
- Predictive Model for Severe Toxicity [Time frame: At the end of the study (2 years).]
Eligibility criteria
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.
Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.
Healthy volunteers: No
Study design
- Observational model
- Cohort
Study locations
Spain · 1 center
- Hospital Universitario Clínico San Cecilio — Granada
Publications
- Trita AS, Biafora A, Pichette Drapeau M, Weber P, Goossen LJ. Regiospecific ortho-C-H Allylation of Benzoic Acids. Angew Chem Int Ed Engl. 2018 Oct 26;57(44):14580-14584. doi: 10.1002/anie.201712520. Epub 2018 Mar 5. PMID 29411933
- Sony M, Antony J, McDermott O. The Impact of Healthcare 4.0 on the Healthcare Service Quality: A Systematic Literature Review. Hosp Top. 2023;101(4):288-304. doi: 10.1080/00185868.2022.2048220. Epub 2022 Mar 24. PMID 35324390
- Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortes J, O'Shaughnessy J, Dieras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS; ASCENT Clinical Trial Investigators. Sacituzumab Govitecan in Metastatic Triple PMID 33882206
Identifiers
NCT: NCT07582887 · FIB-MAM-2025-04