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

NCT07582887 | Recruiting DMC

• 1 other identifier: FIB-MAM-2025-04
• Study Type: observational
• Target: 70
• Locations: 1 country
• Sites: 1

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.

Conditions

Metastatic Breast Cancer; Pharmacogenetic Variant; Breast Cancer; Drug-Related Side Effects and Adverse Reactions

Keywords

UGT1A1; Genetic Variants; Toxicity; polymorphism; Breast Cancer; Sacituzumab Govitecan; Trastuzumab Deruxtecan; Datopotamab Deruxtecan

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Frequency of UGT1A1*28 Allele

  At baseline (once the genetic study is performed).

• Correlation Between Genetic Variants and Toxicity Severity

  Analyzed at the completion of the 2-year study period.

• Predictive Model for Severe Toxicity

  At the end of the study (2 years).

Study Arms (3)

Patients undergoing treatment with sacituzumab govitecan

Standard clinical dose of sacituzumab govitecan administered as per routine clinical practice.

Drug: Sacituzumab Govitecan

Patients undergoing treatment with trastuzumab-deruxtecan

Standard clinical dose of trastuzumab-deruxtecan administered as per routine clinical practice.

Drug: Trastuzumab deruxtecan

Patients undergoing treatment with datopotamab deruxtecan

Standard clinical dose of datopotamab deruxtecan administered as per routine clinical practice.

Drug: Datopotamab Deruxtecan

Interventions

Sacituzumab Govitecan DRUG

Administered according to standard clinical practice and product label.

Patients undergoing treatment with sacituzumab govitecan

Trastuzumab deruxtecan DRUG

Administered according to standard clinical practice and product label.

Patients undergoing treatment with trastuzumab-deruxtecan

Datopotamab Deruxtecan DRUG

Administered according to standard clinical practice and product label.

Patients undergoing treatment with datopotamab deruxtecan

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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.

You may not qualify if:

• Patients who are ultimately not treated with the specified Antibody-Drug Conjugates.
• Refusal to provide informed consent for genetic analysis.

Sponsors & Collaborators

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

Study Sites (1)

Hospital Universitario Clínico San Cecilio

Granada, Granada, 18016, Spain

RECRUITING

Related Publications (3)

• 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 RESULT

• 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 RESULT

• 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.

  PMID: 33882206 RESULT

Related Links

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

MeSH Terms

Conditions

Breast Neoplasms; Drug-Related Side Effects and Adverse Reactions

Interventions

sacituzumab govitecan; trastuzumab deruxtecan

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Chemically-Induced Disorders

Central Study Contacts

Isabel Blancas López-Barajas, MD, PhD

CONTACT

+34 958 023265; ensayosclinicosom.husc.sspa@juntadeandalucia.es

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: OTHER
• Target Duration: 2 Years
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr.

Study Record Dates

• First Submitted: May 6, 2026
• First Posted: May 13, 2026
• Study Start: July 15, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): March 31, 2027
• Last Updated: May 13, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1)