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

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.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Metastatic Breast Cancer; Drug-Related Side Effects and Adverse Reactions; Pharmacogenetic Variant
• Intervention / Treatment: Drug: Sacituzumab Govitecan; Drug: Trastuzumab deruxtecan; Drug: Datopotamab Deruxtecan

• Study Type: Observational
• Enrollment (Estimated): 70

Contacts and Locations

• Study Contact: Name: Isabel Blancas López-Barajas, MD, PhD; Phone Number: +34 958 023265; Email: ensayosclinicosom.husc.sspa@juntadeandalucia.es

Study Locations

• Spain
  • Granada
    • Granada, Granada, Spain, 18016
      • Recruiting
      • Hospital Universitario Clínico San Cecilio
      • Contact: Isabel Blancas López-Barajas, MD, PhD; Phone Number: +34 958 023265; Email: ensayosclinicosom.husc.sspa@juntadeandalucia.es
      • Principal Investigator: Isabel Blancas López-Barajas, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients undergoing treatment with sacituzumab govitecan; Standard clinical dose of sacituzumab govitecan administered as per routine clinical practice.	Drug: Sacituzumab Govitecan; Administered according to standard clinical practice and product label.
Patients undergoing treatment with trastuzumab-deruxtecan; Standard clinical dose of trastuzumab-deruxtecan administered as per routine clinical practice.	Drug: Trastuzumab deruxtecan; Administered according to standard clinical practice and product label.
Patients undergoing treatment with datopotamab deruxtecan; Standard clinical dose of datopotamab deruxtecan administered as per routine clinical practice.	Drug: Datopotamab Deruxtecan; Administered according to standard clinical practice and product label.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From the start of treatment until the end of the follow-up period (up to 2 years).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of UGT1A1*28 Allele	Distribution and allelic frequency of the UGT1A1*28 variant in the study population of breast cancer patients.	At baseline (once the genetic study is performed).
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.	Analyzed at the completion of the 2-year study period.
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.	At the end of the study (2 years).

Collaborators and Investigators

• Sponsor: Fundación Pública Andaluza para la Investigación Biomédica Andalucía Oriental

Publications and helpful links

General 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.
• 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.
• 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-Negative Breast Cancer. N Engl J Med. 2021 Apr 22;384(16):1529-1541. doi: 10.1056/NEJMoa2028485.

Helpful Links

• FIBAO - Fundación para la Investigación Biosanitaria de Andalucía Oriental.

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: May 6, 2026
• First Submitted That Met QC Criteria: May 6, 2026
• First Posted (Actual): May 13, 2026

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 6, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Breast Cancer; Toxicity; polymorphism; Datopotamab Deruxtecan; Trastuzumab Deruxtecan; UGT1A1; Genetic Variants; Sacituzumab Govitecan
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Chemically-Induced Disorders; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Drug-Related Side Effects and Adverse Reactions; trastuzumab deruxtecan; sacituzumab govitecan
• Other Study ID Numbers: FIB-MAM-2025-04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared to ensure patient confidentiality and compliance with data protection regulations. Aggregate results will be available through scientific publications.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No