Abstract
AIMS: This study aims to (1) evaluate the diagnostic utility of myeloperoxidase (MPO), growth differentiation factor-15 (GDF-15), C-reactive protein (CRP), placental growth factor (PLGF) and galectin-3 (Gal-3) for cancer therapy-related cardiac dysfunction (CTRCD) in breast cancer patients through meta-analysis and (2) investigate causal roles using Mendelian randomization (MR). METHODS: We conducted a dual-phase analysis. First, a PRISMA-compliant (ID: CRD42023453369) meta-analysis of 12 studies (11 prospective cohorts, 1 RCT; 917 patients; age 50.4 ± 16.0 years; median follow-up 12 months) from five databases (PubMed/Web of Science/Embase/Cochrane/ClinicalTrials.gov) quantified post-treatment biomarker changes using weighted/standardized mean differences (WMD/SMD) and CTRCD risk via hazard ratios (HRs). Second, two-sample MR analysis leveraged MPO-associated single nucleotide polymorphisms (SNPs) to assess causality with heart failure (HF) and cardiomyopathy, employing IVW, MR-Egger, weighted median and simple mode methods with heterogeneity testing. RESULTS: The meta-analysis demonstrated significant post-treatment elevations in: MPO [US patients: SMD = 0.78, 95% confidence interval (CI) 0.45-1.12; I(2) = 72%; P < 0.00001], GDF-15 (SMD = 0.64, 95% CI 0.24-1.05; I(2) = 77%; P = 0.002), PLGF (SMD = 0.87, 95% CI 0.10-1.63; I(2) = 95%; P = 0.03), and CRP (WMD = 0.83, 95% CI 0.46-1.20; I(2) = 18%; P < 0.0001). Subgroup analyses eliminated heterogeneity for GDF-15 (I(2) = 0%) and PLGF (I(2) = 0%), while partially reducing heterogeneity for MPO (I(2) = 72%). Elevated MPO levels predicted increased CTRCD risk in patients receiving cancer treatment (HR = 1.30, 1.10-1.54; I(2) = 0%; P = 0.002). MR analysis suggested causal relationships between MPO and both HF [odds ratio (OR) = 1.06, 95% CI 1.02-1.09; P = 0.001] and cardiomyopathy (OR = 1.09, 95% CI 1.02-1.17; P = 0.02), with significant heterogeneity detected in heart failure SNPs (Cochran's Q = 61.63, P = 0.04). CONCLUSIONS: Our study suggested that MPO was associated with both diagnostic biomarker profiles and mechanistic pathways in CTRCD pathogenesis. These preliminary findings highlighted MPO as a possible target for further investigation of early CTRCD detection in breast cancer patients.