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.