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.

Diastolic Dysfunction Following Anthracycline-Based Chemotherapy in Breast Cancer Patients: Incidence and Predictors

“…We found an elevation of hsTnT levels over upper normal limits in visit 1 and 2 and a significant difference between groups DD1 and DD2 at visit 2 that was consistent with evidence of cardiac damage. Ky et al [24], in an multicenter study in 78 breast cancer patients treated with doxorubicin and trastuzumab, found increases in troponin I levels at patients' 3-month visits that were associated with an elevated risk for cardiotoxicity. With a sampling protocol similar to our study, they found an increase in levels of troponins of identical magnitude to those found in our study (3.2 times the levels between baseline and first follow-up visit).…”

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

“…Cardiac troponins are well‐established markers of myocardial injury and appear to correlate best with incident cardiac dysfunction following chemotherapy. Three studies have reported that elevated and increasing troponin I following chemotherapy, particularly if such increase persists at 1 month after treatment,84 is associated with subsequent cardiac dysfunction as well as with lower likelihood of cardiac recovery in patients receiving trastuzumab 85, 86, 87. During treatment, negative cardiac troponin has a high negative predictive value; however, minute elevations can be commonly detected in patients following chemotherapy and have low positive predictive value 88.…”

“…The recently published guidelines from the American Society of Clinical Oncology gives a moderate strength of recommendation for routine use of biomarkers and echocardiographic‐derived strain imaging for surveillance of cardiotoxicity, citing intermediate quality of evidence 53. Baseline N‐terminal pro–B‐type natriuretic peptide, a marker of hemodynamic stress, high‐sensitivity C‐reactive protein and growth differentiation factor‐15, markers of inflammation and oxidative stress, placental growth factor, a marker of angiogenesis, galectin‐3, a marker of fibrosis, soluble fms‐like tyrosine kinase receptor‐1, and others, have not shown significant association with future cardiac dysfunction 83, 85. Increases in N‐terminal pro–B‐type natriuretic peptide over time appear to correlate with changes in cardiac function; however, no thresholds have been established 87…”

Cardiac Imaging: Multimodality Advances and Surveillance Strategies in Detection of Cardiotoxicity

“…The risk of cardiotoxicity was not significantly associated with baseline levels of any of these biomarkers. However, the early changes in Tn-I and MPO, the combination of increasing biomarkers and finally the persistence of an increase in MPO beyond 3 months, were predictors of cardiotoxicity risk over the duration of doxorubicin/ trastuzumab therapy [61,62].…”

“…The authors propose a strategy that include, in addition to LVEF assessment, the GLS calculation and the baseline chosen biomarker measurement, all for prospective comparison with baseline data. Indeed, addition of monitored parameters via a multimodality surveillance strategy increases sensitivity of subclinical LV dysfunction detection [61,62]. However, only a few studies have explored the value of such a combined approach for the diagnosis and risk stratification of CTRCD ( Table 2, Fig.…”