Abstract 14368: FAPI-PET Imaging Detects Anthracycline-Induced Cardiotoxicity Before Echocardiography

Abstract

Introduction: We aimed to validate a PET imaging biomarker for the detection of incipient anthracycline-induced cardiotoxicity. This condition affects >5% of all pediatric cancer patients, leading to long-term health deficits. We hypothesized that fibroblast activation protein (FAP) would be a suitable candidate due to its role in extracellular matrix remodeling and fibrosis during early cardiac injury and the availability of high-affinity PET probes. Methods: Cardiotoxicity was established in male C57BL/6J mice by administering a cumulative 24 mg/kg dose of doxorubicin (DOX) intraperitoneally over 2 weeks [1]. The DOX mice were imaged serially with echocardiography and [68Ga]Ga-FAPI-04 PET over 12 weeks and compared to age- and sex-matched controls. Fractional shortening (FS) was determined from the echocardiograms, and cardiac uptake of [68Ga]Ga-FAPI-04 was quantified and expressed as percent injected dose per cubic centimeter (%ID/cm3). Heart tissue samples were collected and used for the analysis of bulk RNA-seq, RT-qPCR, Western blot, in situ hybridization (ISH), and histological staining. Finally, we used the DAVID tools and STRING database to confirm the relationship between PET signal and gene expression. Results: DOX mice exhibited decreased body weight (33% by 9 weeks after end-of-treatment) and heart weight-to-tibia length ratio (HW/TL, 39%). Cardiac [ 68 Ga]Ga-FAPI-04 PET signal was significantly higher (1.7-fold) in DOX mice from 2 weeks through the study endpoint. By contrast, no cardiac dysfunction was evident by echocardiography until 10 weeks after end-of-treatment, at which point FS was significantly reduced relative to the control group (30%). Transcription and translation of FAP were elevated in the DOX hearts, in agreement with the PET data. In the heatmap generated from the RNA-seq data, genes related to cell adhesion and extracellular remodeling were significantly upregulated in the DOX mice relative to controls. The H-score of FAP ISH was linearly related to the cardiac signal of [ 68 Ga]Ga-FAPI-04 PET (p = 0.001). Conclusions: FAP is a suitable imaging biomarker for cardiotoxicity and FAPI-PET is a promising tool for identifying patients at risk of cardiotoxicity during or after anthracycline chemotherapy.