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.
연구 개요
상태
연구 유형
등록 (추정된)
연락처 및 위치
연구 연락처
- 이름: Isabel Blancas López-Barajas, MD, PhD
- 전화번호: +34 958 023265
- 이메일: ensayosclinicosom.husc.sspa@juntadeandalucia.es
연구 장소
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Granada
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Granada, Granada, 스페인, 18016
- 모병
- Hospital Universitario Clínico San Cecilio
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연락하다:
- Isabel Blancas López-Barajas, MD, PhD
- 전화번호: +34 958 023265
- 이메일: ensayosclinicosom.husc.sspa@juntadeandalucia.es
-
수석 연구원:
- Isabel Blancas López-Barajas, MD, PhD
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참여기준
자격 기준
공부할 수 있는 나이
- 성인
- 고령자
건강한 자원 봉사자를 받아들입니다
샘플링 방법
연구 인구
설명
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.
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
코호트 및 개입
그룹/코호트 |
개입 / 치료 |
|---|---|
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Patients undergoing treatment with sacituzumab govitecan
Standard clinical dose of sacituzumab govitecan administered as per routine clinical practice.
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Administered according to standard clinical practice and product label.
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Patients undergoing treatment with trastuzumab-deruxtecan
Standard clinical dose of trastuzumab-deruxtecan administered as per routine clinical practice.
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Administered according to standard clinical practice and product label.
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Patients undergoing treatment with datopotamab deruxtecan
Standard clinical dose of datopotamab deruxtecan administered as per routine clinical practice.
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Administered according to standard clinical practice and product label.
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연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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Incidence of Severe Drug-Related Toxicities (Grade ≥ 3)
기간: From the start of treatment until the end of the follow-up period (up to 2 years).
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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.
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From the start of treatment until the end of the follow-up period (up to 2 years).
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2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
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Frequency of UGT1A1*28 Allele
기간: At baseline (once the genetic study is performed).
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Distribution and allelic frequency of the UGT1A1*28 variant in the study population of breast cancer patients.
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At baseline (once the genetic study is performed).
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Correlation Between Genetic Variants and Toxicity Severity
기간: Analyzed at the completion of the 2-year study period.
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Statistical association (using Odds Ratio) between the identified genetic variants (rs4148323, rs35350906, rs3064744, rs887829, rs111741722) and the severity of adverse events.
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Analyzed at the completion of the 2-year study period.
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Predictive Model for Severe Toxicity
기간: At the end of the study (2 years).
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Design of a predictive model based on genetic markers to anticipate the appearance of severe toxicities for each ADC studied.
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At the end of the study (2 years).
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공동 작업자 및 조사자
간행물 및 유용한 링크
일반 간행물
- 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.
연구 기록 날짜
연구 주요 날짜
연구 시작 (실제)
기본 완료 (추정된)
연구 완료 (추정된)
연구 등록 날짜
최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (실제)
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
- FIB-MAM-2025-04
개별 참가자 데이터(IPD) 계획
개별 참가자 데이터(IPD)를 공유할 계획입니까?
IPD 계획 설명
약물 및 장치 정보, 연구 문서
미국 FDA 규제 의약품 연구
미국 FDA 규제 기기 제품 연구
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