Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab

Abstract

Objectives: The aim of this study was to determine if individual or multiple biomarkers are associated with cardiotoxicity in patients with breast cancer undergoing cancer therapy.

Background: Current methods to identify patients at risk for cardiotoxicity from cancer therapy are inadequate.

Methods: We measured 8 biomarkers in a multicenter cohort of 78 patients with breast cancer undergoing doxorubicin and trastuzumab therapy: ultrasensitive troponin I (TnI), high-sensitivity C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt)-1, and galectin (gal)-3. Cardiotoxicity, defined by the Cardiac Review and Evaluation Committee criteria, was assessed every 3 months for up to 15 months. Hazard ratios (HRs) of cardiotoxicity risk were assessed for each biomarker at baseline, at visit 2 (3 months), and as a function of the difference between visit 2 and baseline. Joint models were assessed for the most promising biomarkers.

Results: TnI, CRP, GDF-15, MPO, PlGF, and sFlt-1 levels increased from baseline to visit 2 (p < 0.05). A greater risk of cardiotoxicity was associated with interval changes in TnI (HR: 1.38 per SD; 95% confidence interval: 1.05 to 1.81; p = 0.02) and MPO (HR: 1.34 per SD; 95% confidence interval: 1.00 to 1.80; p = 0.048) and in models combining both markers (p = 0.007 and p = 0.03, respectively). The risk of cardiotoxicity was 46.5% in patients with the largest changes in both markers (ΔTnI >121.8 μg/l; ΔMPO >422.6 pmol/l).

Conclusions: Early increases in TnI and MPO levels offer additive information about the risk of cardiotoxicity in patients undergoing doxorubicin and trastuzumab therapy. Independent validation of these findings is necessary before application to clinical practice.

Keywords: cardio-oncology; chemotherapy cardiotoxicity; trastuzumab cardiotoxicity.

Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Study Protocol

Participants were studied before chemotherapy and at standardized intervals every 3 months during anthracycline, paclitaxel, and trastuzumab therapy using serial questionnaires and echocardiograms for a total of 6 study visits per participant. Biomarkers were measured at baseline (visit 1), 3 months (visit 2), and 6 months.

Figure 2. Model-Based Probability of Cardiotoxicity According to Percentile Changes in TnI and MPO Between Baseline and Visit 2

(A) Bars represent the probability of cardiotoxicity at the 10th, 50th, and 90th percentiles of interval changes (baseline and visit 2) in TnI and MPO. These quantiles were −0.9, 13.9, and 121.8 μg/l for TnI and −64.8, 26.3, and 422.6 pmol/l for MPO. (B) Curves represent the probability of cardiotoxicity at the 10th, 50th, and 90th percentiles of interval changes (baseline and visit 2) in TnI and MPO. MPO = myeloperoxidase; TnI = troponin I.

Figure 3. Model-Based Probability of Cardiotoxicity According to Changes in MPO and TnI Levels

(A) Bars represent the probability of cardiotoxicity according to changes in biomarkers in both TnI and MPO at standardized time intervals. “Both Low” refers to no elevations in either biomarker (quantiles of 0.1, 0.5), “One High” notes elevations in 1 biomarker (quantile of 0.9 in either TnI or MPO and quantile of 0.1 or 0.5 for the other biomarker), and “Both High” notes elevations in both biomarkers (quantiles of 0.9). (B) Curves represent the probability of cardiotoxicity according to changes in biomarkers, where “None,” One High,” and “Two High” represent the same categories as in A. The results are displayed as shaded areas on the graph representing the upper and lower values of the probability region for each of the 3 categories. Abbreviations as in Figure 2.