Correlation Between Genetic Variants and Long-term Cardiac Effects Induced by Doxorubicin in Breast Cancer Patients
Overview[ - collapse ][ - ]
| Purpose | The purpose of this study is to identify the genetic variants that are associated with higher risk of doxorubicin-induced cardiotoxicity can contribute towards developing a predictive algorithm comprising both clinical and genetic factors to select patients who should avoid treatment with anthracyclines. Hypothesis of this study is certain functional variants in genes that encode for metabolizing enzymes and/or targets in the doxorubicin pharmacology pathway may increase the risk of doxorubicin-induced cardiomyopathy |
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| Condition | Breast Cancer |
| Intervention | Drug: Doxorubicin |
| Phase | Phase 2/Phase 3 |
| Sponsor | National University Hospital, Singapore |
| Responsible Party | National University Hospital, Singapore |
| ClinicalTrials.gov Identifier | NCT02078388 |
| First Received | December 8, 2013 |
| Last Updated | March 3, 2014 |
| Last verified | March 2014 |
Tracking Information[ + expand ][ + ]
| First Received Date | December 8, 2013 |
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| Last Updated Date | March 3, 2014 |
| Start Date | November 2013 |
| Estimated Primary Completion Date | Not Provided |
| Current Primary Outcome Measures | Change the functional variants in genes involved in doxorubicin pharmacology with doxorubicin-induced cardiomyopathy in adult breast cancer survivors. [Time Frame: 1 year] [Designated as safety issue: No]Identification of genetic variants that are associated with higher risk of doxorubicin-induced cardiotoxicity can contribute towards developing a predictive algorithm comprising both clinical and genetic factors to select patients who should avoid treatment with anthracyclines. |
| Current Secondary Outcome Measures | Not Provided |
Descriptive Information[ + expand ][ + ]
| Brief Title | Correlation Between Genetic Variants and Long-term Cardiac Effects Induced by Doxorubicin in Breast Cancer Patients |
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| Official Title | Not Provided |
| Brief Summary | The purpose of this study is to identify the genetic variants that are associated with higher risk of doxorubicin-induced cardiotoxicity can contribute towards developing a predictive algorithm comprising both clinical and genetic factors to select patients who should avoid treatment with anthracyclines. Hypothesis of this study is certain functional variants in genes that encode for metabolizing enzymes and/or targets in the doxorubicin pharmacology pathway may increase the risk of doxorubicin-induced cardiomyopathy |
| Detailed Description | Doxorubicin is one of the cornerstone therapies in adjuvant chemotherapy in early stage breast cancer. Cumulative doses of 240mg/m2 (4 cycles of doxorubicin/cyclophosphamide) and 300mg/m2 (6 cycles of doxorubicin/cyclophosphamide) are typically administered in the adjuvant setting, which is associated with <1% chance of severe cardiotoxicity, and are thus considered 'safe dose ranges'. However, Blanco et al recently reported childhood cancer survivors with the CBR3 (a metabolizing enzyme of doxorubicin) V244M homozygous G genotypes to be at increased risk of cardiomyopathy following exposure to anthracyclines doses as low as 101-150mg/m2, suggesting that there is no safe dose threshold for individuals with certain genotypes. We have previously studied several genes in the doxorubicin pharmacology pathway, including CBR1, CBR3, and AKR1C3, and found correlation between functional variants in CBR3 and AKR1C3 with doxorubicin-induced myelosuppression. The CBR3 G allele is present in about 50-60% of the Singapore population, and we postulate that these common variants may similarly modify the risk of anthracyclines-induced cardiomyopathy in adult breast cancer patients. Post-treatment echocardiography is not routinely performed in patients who complete adjuvant anthracyclines-containing chemotherapy. We believe that some of these high-risk individuals may have subclinical reduced left ventricular ejection fraction that may in the future increase the risk of congestive cardiac failure in the presence of other risk factors (eg hypertension, anemia, serious infection, etc). Identifying these individuals could therefore be important as early treatment with ACE inhibitors may improve cardiac function. Confirming the correlation between genetic variants including the CBR3 V244M can also help to develop a predictive algorithm in the future to identify patients in whom anthracyclines should be avoided. |
| Study Type | Observational |
| Study Phase | Phase 2/Phase 3 |
| Study Design | Observational Model: Case-Only, Time Perspective: Prospective |
| Condition | Breast Cancer |
| Intervention | Drug: Doxorubicin |
| Study Arm (s) | Breast cancer,Doxorubicin Breast cancer patients who received at least one cycle of doxorubicin-containing adjuvant chemotherapy for treatment of early stage breast cancer at least 12 months ago and who had a pre-doxorubicin echocardiography done at NUHS will be enrolled. Study subjects will donate one sample of blood (20ml) for genetic and biomarker studies related to breast cancer and anthracyclines pharmacodynamics. An echocardiography will be performed to measure left ventricular ejection fraction, and compared with the subject's pre-doxorubicin echocardiography done at NUH. Correlative analysis will be performed between genetic variants and left ventricular ejection change. |
Recruitment Information[ + expand ][ + ]
| Recruitment Status | Recruiting |
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| Estimated Enrollment | 500 |
| Estimated Completion Date | Not Provided |
| Estimated Primary Completion Date | October 2015 |
| Eligibility Criteria | Inclusion Criteria: - Age >= 21 years - Signed informed consent from patient or legal representative. Exclusion Criteria: - Pregnancy - Breast feeding. |
| Gender | Female |
| Ages | 21 Years |
| Accepts Healthy Volunteers | No |
| Contacts | Contact: Soo Chin Lee, MBBS 6779 5555 soo_chin_lee@nuhs.edu.sg |
| Location Countries | Singapore |
Administrative Information[ + expand ][ + ]
| NCT Number | NCT02078388 |
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| Other Study ID Numbers | 2013/01090 |
| Has Data Monitoring Committee | No |
| Information Provided By | National University Hospital, Singapore |
| Study Sponsor | National University Hospital, Singapore |
| Collaborators | Not Provided |
| Investigators | Principal Investigator: Soo Chin Lee, MBBS National University Hospital, Singapore |
| Verification Date | March 2014 |
Locations[ + expand ][ + ]
| National University Hospital | Singapore, Singapore, 119074 Contact: Soo Chin Lee, MBBS | (65) 6779 5555 | soo_chin_lee@nuhs.edu.sgPrincipal Investigator: Soo Chin Lee, MBBS Recruiting |
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