Blanco JG, Sun C, Landier W, and... Bhatia S. Anthracycline-related cardiomyopathy in childhood cancer survivors and association with polymorphisms in the carbonyl reductase genes: A Children's Oncology Group study. American Society of Clinical Oncology (ASCO) 2010 Annual Meeting. Abstract 9512. June 7, 2010. J Clin Oncol 28:7s, 2010 (suppl; abstr 9512)
http://abstract.asco.org/AbstView_74_48317.html
Anthracycline-related cardiomyopathy in childhood cancer survivors and association with polymorphisms in the carbonyl reductase genes: A Children's Oncology Group study.
Sub-category: Other
Category: Pediatric Oncology
Meeting: 2010 ASCO Annual Meeting
Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr 9512)
Abstract No: 9512
Session: Pediatric Oncology II
Type: Oral Abstract Session
Time: Monday June 7, 9:30 AM to 12:30 PM
Location: S504
Author(s): J. G. Blanco, C. Sun, W. Landier, L. Chen, K. C. Oeffinger, M. M. Hudson, J. P. Neglia, A. K. Ritchey, M. V. Relling, S. Bhatia; Department of Pharmaceutical Sciences, State University of New York at Buffalo, Amherst, NY; City of Hope, Duarte, CA; Children's Oncology Group, Arcadia, CA; Memorial Sloan-Kettering Cancer Center, New York, NY; St. Jude Children's Research Hospital, Memphis, TN; University of Minnesota, Minneapolis, MN; Children's Hospital of Pittsburgh, Pittsburgh, PA
Abstract:
Background: Anthracycline-related cardiomyopathy is a well-recognized dose-limiting complication. Inter-individual variability in risk exists, potentially due to genetic susceptibility. Carbonyl reductases (CBR) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR3 V244M and CBR1 G1096A impact CBR activity. We examined the role of functional polymorphisms in CBR3 and CBR1 on risk of cardiomyopathy. Methods: Using a case-control design, 165 cases with documented cardiomyopathy and 323 controls (cancer survivors with no cardiomyopathy; matched on primary diagnosis, follow-up, race/ethnicity) provided germline DNA. Therapeutic exposures were summarized. Results: Primary diagnoses included acute leukemia (164), lymphoma (111), sarcoma (120) and others (93); 51% were females; 77% whites; median age at cancer diagnosis: 7.5 years; time to cardiomyopathy: 7.1 years; median anthracycline dose - cases: 300mg/m2; controls: 140mg/m2. Multivariate analysis revealed anthracycline dose (per 100mg/m2: OR=1.8, p<0.001), and chest radiation (OR=3.13, p=0.05) to be associated with cardiomyopathy. The role of polymorphisms in CBR3/CBR1 was then examined, adjusting for chest radiation. There was a borderline association between CBR3 V244M and cardiomyopathy (OR=1.5, p=0.08 for GG vs. GA/A); and no association for CBR1 G1096A (OR=1.0, p=0.9). However, upon stratification by anthracycline does, the association with CBR3 V244M became stronger among subjects exposed to ≤250mg/m2 (OR=6.4, p=0.006), but disappeared for those exposed to >250mg/m2 (OR=0.9, p=0.8). Similar but non-significant associations were observed for CBR1 (OR=3.3, p=0.10; OR=0.8, p=0.7, respectively). Conclusions: Using the largest cohort of documented cardiomyopathy, this report demonstrates a clear dose-response relation between anthracyclines and cardiomyopathy, and selectively greater impact of CBR3 on risk of cardiomyopathy after low-dose anthracycline exposure. These data identify a definable subset of patients that may benefit from cardioprotection, surveillance or pharmacologic interventions.