Introduction
Doxorubicin is one of the most commonly used anthracyclines for the treatment of different types of cancers in adults and children1,2. Its clinical utility is limited due to side effects including cardiotoxicity when it exceeds the recommended cumulative dosage of 400 mg/m2 - 550 mg/m2 in adults and > 300 mg/m2 in children 3,4. The risk of developing cardiotoxicity increases when the cumulative dose of doxorubicin exceeds these thresholds, with 700 mg/m2having a risk of 48% 3,5,6. The gold standard for monitoring risk for doxorubicin induced cardiotoxicity (DIC) is using left ventricular ejection fraction (LVEF) measured via echocardiogram7,8.
Candidate gene and genome-wide association studies have established genetic variants associated with DIC 9–13 .These include genetic variations in genes involved in anthracycline metabolism and transportation. A meta-analysis by Aminkeng et al showed that the evidence was strongest and most consistent for an association of RARG (retinoic acid receptor gamma) rs2229774, SLC28A3 (solute carrier family 28 member 3) rs7853758, and UGT1A6 (UDP glucuronosyltransferase family 1 member A6), rs17863783 variants with DIC. Based on current evidence, Canadian Pharmacogenomics Network for Drug Safety (CPNDS) recommends genotyping children who are taking doxorubicin for UGT1A6*4 (rs17863783), SLC28A3 (rs7853758) and RARG (rs2229774) haplotypes9.
As most of these pharmacogenomics studies have been performed in pediatric patients receiving doxorubicin 14–18, the generalizability of these findings to adults and other anthracyclines is unknown. In addition to the three genetic markers that have been identified in children, there are other genetic markers that have been associated with the DIC9, however they are not well characterized and they have not been replicated in most of the studies. Further research is thus required in adults and other understudied populations to help improve the predictive and prognostic role in predicting DIC .This study was therefore conducted to establish the frequency of DIC in adult black Zimbabwean breast cancer patients treated with doxorubicin and to test the DIC predictive power of genetic biomarkers in this cohort.