Correlation Between Genetic Variants and Long-term Cardiac Effects Induced by Doxorubicin in Breast Cancer Patients

Study Overview
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Brief Summary
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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
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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.

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 21 years Signed informed consent from patient or legal representative. Exclusion Criteria: Pregnancy Breast feeding.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Breast cancer,Doxorubicin<br>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. | Drug: Doxorubicin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change the functional variants in genes involved in doxorubicin pharmacology with doxorubicin-induced cardiomyopathy in adult breast cancer survivors. | 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. | 1 year |