Discussion
The incidence of cardiotoxicity (11%) in our population was comparable to rates in the literature 21–23 which ranged from 9%-12%. However, it is important to note that these studies were performed in Western populations and are associated with late-onset DIC, with a sample size of more than 1000 and longer follow up time of 5 years contrary to our study which had a smaller sample size with follow up time of 1 year. Other studies conducted in Asia24–26 reported higher incidence of DIC (> 30%) . This suggests that our patients may be experiencing higher incidence of cardiotoxicity or an early onset cardiotoxicity.
In this study we could not verify clinical risk factors to be significant risk factors for developing DIC, of which previous studies have identified hypertension, female sex, age, cumulative anthracycline dose, as risk factors for DIC 3,14,27 . It may be possible that the small sample size in our study could have reduced the statistical power to demonstrate the significance of association of the clinical risk factors with DIC 12,28–33
If we considered doxorubicin cumulative dose, we observe that there was no clear association between cumulative doxorubicin dose and cardiotoxicity (p = 0.357), which is not as expected11,12,18,34–38. However, the high frequency (60.7%) of the cardioprotective variant could have influenced this dose relationship in our study. The cardioprotective variant (SLC28A3 rs7853758) is important because it affects the pharmacology of doxorubicin and reduce incidence of cardiotoxicity39,40.
The UGT1A6 rs17863783 variant results in altered enzymatic activity, increasing the risk of developing DIC in those carrying at least one copy of the variant 9,18,30 . One of the patients who carried UGT1A6 rs17863783 developed DIC in our study. RARG rs2229774 variant occurred at a significantly low frequencies (14.3%) in our study, compared to Asian populations (21.6%) suggesting a possible decreased expression of the topoisomerase II gene (TOP2B). A reduction in expression of this gene has been shown to be cardioprotective1,14,18,30. None of the patients who developed DIC carried RARG rs2229774.
PPV and NPV are influenced by the prevalence of the disease that is being screened. In our study the prevalence of DIC was 11% and resultantly our PPV and NPV was 33.3% and 72.0% respectively. This was comparable to PPV of 34.4% and NPV 90.9% obtained in other studies9,19,41. With current care, the estimated average lifetime cost of DIC is $8,667 per treated patient42. Our test will reduce DIC related life cost and deaths in 33% of patients who carry the risk variants.
To our knowledge, this study presents the first documentation of the prevalence DIC in black Zimbabwean breast cancer patients and the first attempt to evaluate the predictive value of genetic biomarkers for cardiotoxicity. The lack of significant association between the DIC and the biomarkers is either due to the small sample size or the insufficient predictive power of these biomarkers. Future studies in adults will be needed to further evaluate the possible use of these biomarkers in guiding treatment in adults. A larger sample size with a longer follow up time will be necessary for future studies to increase the predictive power of these biomarkers because chronic cardiotoxicity occurs after a long period of time. There is also need to develop African specific DIC scoring system that incorporates both genotypes and clinical data like electrocardiogram (ECG) scores and cardiac enzymes like troponins to better predict DIC.