Endotrophin: Analysis of a fibroinflammatory biomarker during breast cancer therapy.

Abstract

e15056 Background: A major challenge in breast cancer research is identifying actionable biomarkers that enable the precise molecular characterization of complex metabolic and immunological interactions. Endotrophin (ETP) is a proteolytic fragment of collagen VIα3 associated with inflammation and fibrosis that has been linked to cardiometabolic outcomes. Elevated ETP levels have been observed in patients with breast cancer. Also, pre-clinical studies have demonstrated that targeting ETP improves cancer outcomes. The dynamic response of circulating ETP levels to cancer treatments remains unknown. Methods: This study aims to evaluate blood ETP levels in breast cancer patients undergoing cancer therapy or surgery. We prospectively collected blood samples (n = 102) from patients treated with three modalities: (1) neoadjuvant therapy (15 patients); (2) up-front surgery (12 patients); and systemic therapy for metastatic breast (9 patients). Plasma samples were obtained at baseline and during each treatment cycle, up to a maximum of six cycles, or pre- and post-surgery. ETP levels were measured using an enzyme-linked immunosorbent assay. We excluded patients with active cardiac or renal disease, uncontrolled diabetes (A1c > 8), or infectious/inflammatory conditions requiring therapy. Enrollment began in January 2024 and is ongoing at the SCCC. Results: Comparative analyses of breast cancer subtypes revealed that estrogen receptor positive (ER+) patients had significantly higher baseline and overall ETP levels than triple-negative (TNBC) patients (baseline medians 17.7 ng/mL vs. 9.5 ng/mL for ER+ v. TNBC, p = 0.03; overall medians 31.3, 19.0, 19.2 ng/mL for ER+, HER2+, TNBC, respectively; p = 0.0003 v. TNBC+; p = 0.04 v. HER2+). ETP levels in metastatic breast cancer patients were significantly higher compared to those undergoing neoadjuvant therapy (p < 0.0001) and up-front surgery (p = 0.003). In the metastatic setting, ETP levels demonstrated a strong correlation with treatment response. Declining ETP levels were associated with favorable outcomes, whereas rising or fluctuating levels indicated disease progression or poor therapeutic response. Notably, this correlation was not observed in the neoadjuvant or surgical settings. Conclusions: Plasma ETP levels were readily detectable in breast cancer patients, they were significantly elevated in ER+ disease and tracked with the response to therapy in the metastatic setting. ETP levels may be a useful biomarker to guide therapeutic strategies for existing systemic therapies, and should be further explored as a predictive biomarker for metabolic and inflammatory therapies, especially ETP-blocking agents.