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

Breast Cancer Clinical Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02078388
• Other study ID #: 2013/01090
• Status: Recruiting
• Phase: Phase 2/Phase 3
• First received: December 8, 2013
• Last updated: March 3, 2014
• Start date: November 2013

Study information

• Verified date: March 2014
• Source: National University Hospital, Singapore
• Contact: Soo Chin Lee, MBBS
• Phone: 6779 5555
• Email: soo_chin_lee[@]nuhs.edu.sg
• Is FDA regulated: No
• Health authority: Singapore: Domain Specific Review Boards
• Study type: Observational

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. primary completion date: October 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 21 Years and older

Eligibility

Inclusion Criteria:

• Age >= 21 years

• Signed informed consent from patient or legal representative.

Exclusion Criteria:

• Pregnancy

• Breast feeding.

Study Design

Observational Model: Case-Only, Time Perspective: Prospective

Related Conditions & MeSH terms

• Breast Cancer

Intervention

Drug:
• Doxorubicin

Locations

Country	Name	City	State
Singapore	National University Hospital	Singapore

Sponsors (1)

Lead Sponsor	Collaborator
National University Hospital, Singapore

Country where clinical trial is conducted

Singapore, 

References & Publications (2)

Blanco JG, Sun CL, Landier W, Chen L, Esparza-Duran D, Leisenring W, Mays A, Friedman DL, Ginsberg JP, Hudson MM, Neglia JP, Oeffinger KC, Ritchey AK, Villaluna D, Relling MV, Bhatia S. Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes--a report from the Children's Oncology Group. J Clin Oncol. 2012 May 1;30(13):1415-21. doi: 10.1200/JCO.2011.34.8987. Epub 2011 Nov 28. — View Citation

Fan L, Goh BC, Wong CI, Sukri N, Lim SE, Tan SH, Guo JY, Lim R, Yap HL, Khoo YM, Iau P, Lee HS, Lee SC. Genotype of human carbonyl reductase CBR3 correlates with doxorubicin disposition and toxicity. Pharmacogenet Genomics. 2008 Jul;18(7):621-31. doi: 10.1097/FPC.0b013e328301a869. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No