Candidate Plasma Biomarkers to Detect Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors: A Case Control Study in the Dutch Childhood Cancer Survivor Study

Abstract

Background Plasma biomarkers may aid in the detection of anthracycline-related cardiomyopathy (ACMP). However, the currently available biomarkers have limited diagnostic value in long-term childhood cancer survivors. This study sought to identify diagnostic plasma biomarkers for ACMP in childhood cancer survivors. Methods and Results We measured 275 plasma proteins in 28 ACMP cases with left ventricular ejection fraction <45%, 29 anthracycline-treated controls with left ventricular ejection fraction ≥53% matched on sex, time after cancer, and anthracycline dose, and 29 patients with genetically determined dilated cardiomyopathy with left ventricular ejection fraction <45%. Multivariable linear regression was used to identify differentially expressed proteins. Elastic net model, including clinical characteristics, was used to assess discrimination of proteins diagnostic for ACMP. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and the inflammatory markers CCL19 (C-C motif chemokine ligands 19) and CCL20, PSPD (pulmonary surfactant protein-D), and PTN (pleiotrophin) were significantly upregulated in ACMP compared with controls. An elastic net model selected 45 proteins, including NT-proBNP, CCL19, CCL20 and PSPD, but not PTN, that discriminated ACMP cases from controls with an area under the receiver operating characteristic curve (AUC) of 0.78. This model was not superior to a model including NT-proBNP and clinical characteristics (AUC=0.75; P=0.766). However, when excluding 8 ACMP cases with heart failure, the full model was superior to that including only NT-proBNP and clinical characteristics (AUC=0.75 versus AUC=0.50; P=0.022). The same 45 proteins also showed good discrimination between dilated cardiomyopathy and controls (AUC=0.89), underscoring their association with cardiomyopathy. Conclusions We identified 3 specific inflammatory proteins as candidate plasma biomarkers for ACMP in long-term childhood cancer survivors and demonstrated protein overlap with dilated cardiomyopathy.

Keywords: anthracycline‐related cardiomyopathy; biomarkers; cancer therapy–related cardiac dysfunction; cardio‐oncology; chemokine ligands; childhood cancer survivors.

Figure 1. Study design of the LATER CARD biomarker case‐control study.

ACMP indicates anthracycline‐related cardiomyopathy; DCCSS LATER 2 CARD, Dutch Childhood Cancer Survivor Study, LATER cohort, part 2, cardiology; DCM, dilated cardiomyopathy; LMNA, lamin A/C; LOD, limit of detection; LVEF, left ventricular ejection fraction; QC, quality control; and UMC, University Medical Center.

Figure 2

Volcano plot, showing fold changes (x axis) and P values (y axis) of 222 plasma proteins in anthracycline‐related cardiomyopathy (ACMP) compared with matched anthracycline‐treated controls. Fold changes and P values were estimated with multivariable linear regression analysis, adjusted for sex, time since cancer diagnosis, anthracycline dose, and chest‐directed radiotherapy dose. Significantly upregulated proteins (q value <0.1) are shown in red. Proteins selected by the elastic net in >40% of the cross‐validation folds are shown as a triangle. CCL indicates C‐C motif chemokine ligand; CD40, cluster of differentiation 40; CXCL10, C‐X‐C motif chemokine ligand 10; FGF21, fibroblast growth factor 21; JAMA, junctional adhesion molecule A; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; PSPD, pulmonary surfactant protein D; and PTN, pleiotrophin.