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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients undergoing treatment with sacituzumab govitecan | Standard clinical dose of sacituzumab govitecan administered as per routine clinical practice. |
| |
| Patients undergoing treatment with trastuzumab-deruxtecan | Standard clinical dose of trastuzumab-deruxtecan administered as per routine clinical practice. |
| |
| Patients undergoing treatment with datopotamab deruxtecan | Standard clinical dose of datopotamab deruxtecan administered as per routine clinical practice. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sacituzumab Govitecan | Drug | Administered according to standard clinical practice and product label. |
|
| 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). |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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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.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Isabel Blancas López-Barajas, MD, PhD | Contact | +34 958 023265 | ensayosclinicosom.husc.sspa@juntadeandalucia.es |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Universitario Clínico San Cecilio | Recruiting | Granada | Granada | 18016 | Spain |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29411933 | Result | 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. | |
| 35324390 | 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. |
| Label | URL |
|---|---|
| FIBAO - Fundación para la Investigación Biosanitaria de Andalucía Oriental. | View source |
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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.
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| Trastuzumab deruxtecan | Drug | Administered according to standard clinical practice and product label. |
|
| Datopotamab Deruxtecan | Drug | Administered according to standard clinical practice and product label. |
|
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). |
| 33882206 | 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. |
| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| D064420 | Drug-Related Side Effects and Adverse Reactions |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D064419 | Chemically-Induced Disorders |
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| ID | Term |
|---|---|
| C000608132 | sacituzumab govitecan |
| C000614160 | trastuzumab deruxtecan |
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