Key result
Higher cathepsin C linked to ~39% lower risk of cardiotoxicity-induced cardiac dysfunction.
Why the study?
The study sought to define relationships between the circulating proteome and metabolome and cardiac structure and function in breast cancer patients receiving cardiotoxic therapies.
Do circulating proteomic and metabolomic biomarkers predict cardiac structure and function changes in breast cancer patients receiving cardiotoxic therapies?
Cohort (n=547)
Blinded for core lab and omics analyses
Yes
Do circulating proteomic and metabolomic biomarkers predict cardiac structure and function changes in breast cancer patients receiving cardiotoxic therapies?
Proteomic and metabolomic profiling identifies novel circulating biomarkers, such as Cathepsin C, that are associated with early cardiac remodelling and dysfunction in breast cancer patients undergoing cardiotoxic treatments.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Cardiotoxicity from cancer therapy is a real and growing concern for patients and oncologists, and more sensitive, specific biomarkers are urgently needed to improve cardiotoxicity risk prediction. We were able to contribute deep metabolomic profiling, looking across tens of thousands of metabolites and lipids per sample from breast cancer patients on cardiotoxic therapies, to identify novel associations between metabolites and cardiac remodelling and dysfunction over time – those that would not have been found through more traditional targeted metabolomics approaches.”
“Today oncologists largely rely on periodic echocardiograms to monitor for cardiotoxicity, but they catch damage after it has already occurred. These research findings show the real potential of discovery metabolomics and proteomics applied at scale to identify novel circulating biomarkers – both metabolites and proteins which change dynamically in response to therapeutic pressure – to support earlier diagnosis and even prediction of cancer therapy-related cardiac dysfunction and remodelling.”
“In this issue of the European Heart Journal, the study by Ky and colleagues represents an important step forward in addressing these critical knowledge gaps. In a longitudinal cohort of 547 patients with breast cancer receiving anthracyclines and/or trastuzumab, the investigators integrated plasma proteomic and metabolomic profiling with echocardiographic phenotyping across three prospectively collected time points (baseline, 2–3 months, and 12 months after therapy initiation). This longitudinal framework is especially relevant in cardio-oncology, particularly in the setting of anthracycline-based chemotherapy, where the transition from subclinical myocardial injury to overt cardiac dysfunction may evolve over months or even years.”
Cathepsin C may support risk stratification during cardiotoxic therapy; hypothesis-generating for proteomic biomarkers until validated in prospective trials.
BACKGROUND AND AIMS: The objective of this study was to define the relationships between the circulating proteome and metabolome with cardiac structure and function in patients with breast cancer receiving cardiotoxic therapies. METHODS: Proteomics and metabolomics profiling was performed in a longitudinal, prospective cohort study of breast cancer patients receiving anthracyclines and/or trastuzumab, using the Olink Explore 3072 platform and rapid liquid chromatography-mass spectrometry, respectively. Multivariable linear mixed-effect models evaluated the contemporaneous (same visit) and lagged (subsequent visit) associations between repeated measures of individual proteins or metabolites with quantitative echocardiographic measures of cardiac structure [left ventricular (LV) mass and left atrial volume index] and function [LV ejection fraction (LVEF), longitudinal and circumferential strain, E/e', and ventricular-arterial coupling]. Cox regression and pathway enrichment analyses were conducted for biomarkers demonstrating significant associations with cardiac function. RESULTS: Across 547 breast cancer participants (median age 50 years), 203 unique proteins and 16 unique metabolites were significantly associated with measures of cardiac structure and function in contemporaneous and lagged analyses. Notably, cathepsin C was associated with LVEF [false discovery rate (FDR), P = .017], longitudinal strain (FDR, P = .046), left atrial volume index (FDR, P = .035), and incident cardiac dysfunction, defined by an LVEF decline ≥10% to <50% (hazard ratio .61, 95% confidence interval .41, .90). The 147 proteins associated with cardiac function were enriched in biological processes reflective of protein deubiquitination, protein modification by small protein removal, macromolecule catabolic processes, and global metabolic pathways. Individual metabolites significantly associated with cardiac function (LVEF, longitudinal strain) included n-acetylglutamine, aspartic acid, acetylasparagine, alanyl-alanine, and prolyl-glycine (FDR, P-value < .001), and belonged to amino acids and derivatives and peptides. CONCLUSIONS: These findings provide translational insights into cancer therapy-related cardiac dysfunction and remodelling and identify potential new biomarkers of cardiotoxicity. There is an important need for validation of these findings and a deeper understanding of the biology of these biomarkers.
No takes yet. Share an insight, caveat, or question.
Ky et al. (2026) conducted a cohort in Breast cancer receiving cardiotoxic therapies (n=547). Circulating proteomic and metabolomic biomarkers (e.g., Cathepsin C) was evaluated on Incident cardiac dysfunction (LVEF decline ≥10% to <50%) associated with baseline Cathepsin C levels (HR 0.61, 95% CI 0.41-0.90). Baseline circulating levels of cathepsin C were significantly associated with incident cardiac dysfunction (HR 0.61) in breast cancer patients receiving cardiotoxic therapies.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: