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.