Doxorubicin-induced early-onset chronic progressive cardiotoxicity, pharmacogenetics and survival among breast cancer patients in Zimbabwe.

BACKGROUND

Early-onset chronic progressive cardiotoxicity (ECPC) is a significant cause of morbidity and mortality among patients who receive doxorubicin-based chemotherapy for breast cancer.

OBJECTIVE

To establish incidence of ECPC in black Zimbabwean women with breast cancer treated with doxorubicin and the resultant survival, and to describe the pharmacogenomic biomarkers' association with prognosis.

METHOD: A prospective observational study was conducted in Zimbabwe with 50 participants who received doxorubicin-based treatment and were actively followed up to 12 months, with 3-monthly echocardiography and vital status determined at 60 months for all-cause mortality analysis.

RESULTS

ECPC was observed in 10% of participants. Median survival for participants who developed ECPC and those without was 11.9 v. 40.8 months. Participants with ECPC had 5-year overall survival (OS) of 0% v. 42% (hazard ratio (HR) 4.19, 95% confidence interval (CI) 1.27 - 13.79; p=0.018) for participants with no ECPC recorded. Median survival was significantly shorter for patients on calcium channel blockers (p=0.01). Cardiotoxicity, pre-existing hypertension and histological grade showed no significant association. Using multivariate analysis, poor OS was observed with ECPC (HR 4.19, 95% CI 1.27 - 13.79; p=0.018) and calcium channel blocker use (HR 2.38, 95% CI 1.07 - 5.32; p=0.034); no association was observed with pharmacogenomic biomarker risk categorisation based on SLC28A3, UGT1A6 and RARG (HR 1.39, 95% CI 0.46 - 4.25; p=0.561).

CONCLUSION

Breast cancer patients with doxorubicin-induced ECPC had poorer OS. The risk of doxorubicin cardiotoxicity and poor survival could not be explained using SLC28A3-scoring pharmacogenomic profile. Breast cancer therapies with lower cardiotoxicity are needed in Zimbabwe and other low-resource settings.