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.
調査の概要
状態
研究の種類
入学 (推定)
連絡先と場所
研究連絡先
- 名前：Isabel Blancas López-Barajas, MD, PhD
- 電話番号：+34 958 023265
- メール：ensayosclinicosom.husc.sspa@juntadeandalucia.es
研究場所
-
-
Granada
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Granada、Granada、スペイン、18016
- 募集
- Hospital Universitario Clínico San Cecilio
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コンタクト：
- Isabel Blancas López-Barajas, MD, PhD
- 電話番号：+34 958 023265
- メール：ensayosclinicosom.husc.sspa@juntadeandalucia.es
-
主任研究者：
- Isabel Blancas López-Barajas, MD, PhD
-
-
参加基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
サンプリング方法
調査対象母集団
説明
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.
研究計画
研究はどのように設計されていますか？
デザインの詳細
コホートと介入
グループ/コホート |
介入・治療 |
|---|---|
|
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.
|
|
Patients undergoing treatment with trastuzumab-deruxtecan
Standard clinical dose of trastuzumab-deruxtecan administered as per routine clinical practice.
|
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.
|
Administered according to standard clinical practice and product label.
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Incidence of Severe Drug-Related Toxicities (Grade ≥ 3)
時間枠：From the start of treatment until the end of the follow-up period (up to 2 years).
|
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).
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Frequency of UGT1A1*28 Allele
時間枠：At baseline (once the genetic study is performed).
|
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
時間枠：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
時間枠：At the end of the study (2 years).
|
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).
|
協力者と研究者
出版物と役立つリンク
一般刊行物
- 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.
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- FIB-MAM-2025-04
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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