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Early Increases in Multiple Biomarkers Predict Subsequent Cardiotoxicity in Breast Cancer Patients Treated With Doxorubicin, Taxanes, and Trastuzumab
Study Questions:
Can early biomarkers predict future cardiotoxicity in breast cancer patients treated with doxorubicin, taxanes, and trastuzumab?
Methods:
This was a multicenter cohort in 78 breast cancer patients who underwent treatment with doxorubicin and trastuzumab. Biomarkers and echocardiography data were collected at baseline and at 3-month intervals for a total of six study visits per participant. The majority of biomarkers were measured at baseline and remeasured at the 3-month visit in 90-95% of patients and in 5-10% of patients at 6 months. These included: ultrasensitive troponin I (TnI), high-sensitivity C-reactive protein (CRP), N-terminal-prohormone of B-type natriuretic peptide (NT-proBNP), growth differentiation factor-15 (GDF-15), myeloperoxidase (MPO), placental growth factor (P1GF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and galectin-3 (gal-3). Cardiotoxicity, defined by Cardiac Review and Evaluation Committee criteria, was assessed at every 3 months for up to 15 months. This includes a reduction of left ventricular ejection fraction (LVEF) of ≥5% to <55% with symptoms of heart failure or asymptomatic reduction of LVEF of ≥10% to <55%. Hazard ratios (HRs) of cardiotoxicity were then assessed for each biomarker. Joint models were also assessed for the most promising biomarkers.
Results:
Cardiotoxicity occurred in 24% of the patients and was associated with changes in TnI (HR, 1.38 per standard deviation [SD]; 95% confidence interval [CI], 1.05-1.81; p = 0.02) and MPO (HR, 1.34 per standard deviation; 95% CI, 1.00-1.80; p = 0.048), and in models combining both markers (p = 0.007 and p = 0.03, respectively). The remaining biomarkers were not significantly predictive at these early time points, with none being significant at baseline. Risk of cardiotoxicity was 46.5% in patients with the largest changes in both markers (∆TnI >121.8 µg/L and ∆MPO >422.6 pmol/L).
Conclusions:
Early increases in TnI and MPO are associated with subsequent cardiotoxicity, and may be helpful in predicting cardiotoxicity risk in patients receiving doxorubicin and trastuzumab. The combination of multiple markers may also have increased utility. This study is the first to describe an association between MPO and cardiotoxicity induced by doxorubicin and trastuzumab.
Perspective:
There has been some success in the prediction of cardiotoxicity with biomarkers. Elevations in TnI soon after high-dose chemotherapy are predictive of cardiotoxicity, and treatment with enalapril decreases cardiac events in troponin-positive patients. This current study suggests that early biomarkers such as troponin may be predictive of later cardiotoxicity and may be additive to additional biomarkers such as MPO. Troponin is a marker of cardiomyocyte injury, while MPO is a marker of oxidative stress, both implicated mechanisms in cardiotoxicity. However, these data need to be independently validated in a larger sample size. An elevation in biomarkers may also be very specific to certain chemotherapy regimens causing specific damage to the myocardium, in this case, doxorubicin (60 mg/m2), cyclophosphamide (600 mg/m2) followed by paclitaxel (80 mg/m2) with trastuzumab. Biomarkers were collected early in the regimen, and it is unclear if biomarkers will have the same predictive value if drawn further from the chemotherapy regimen.
Keywords: Antibodies, Monoclonal, Humanized, Enalapril, Oxidative Stress, Vascular Endothelial Growth Factor Receptor-1, Breast Neoplasms, Galectin 3, Taxoids, Paclitaxel, Doxorubicin, Cyclophosphamide, C-Reactive Protein, Biomarkers, Troponin I, Growth Differentiation Factor 15, Heart Failure, Peroxidase, Stroke Volume, Confidence Intervals, Myocytes, Cardiac, Natriuretic Peptide, Brain, Echocardiography, Troponin
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