Endotrophin is a circulating fibroinflammatory biomarker associated with treatment response in human metastatic ER+ breast cancer

Abstract Purpose: Soluble factors emanating from fibroinflammatory processes are emerging as cancer biomarkers and therapeutic targets. Endotrophin (ETP), a collagen VI proteolytic fragment, is elevated in human breast cancer patients and drives tumor progression in rodent breast cancer models, an effect which neutralizing antibodies can abrogate. This implies that tracking or targeting elevated ETP levels could inform breast cancer therapeutic strategies. However, we lack precise knowledge about the impact of ETP in specific breast cancer subtypes and whether circulating levels provide predictive or prognostic information. Experimental Design: To address these gaps, we assessed circulating ETP levels among breast cancer patients (n=191 samples from 98 patients) undergoing various treatment modalities, as well as patients with ovarian neoplasia (n=29) and healthy controls (n=19). Results: We observed higher circulating ETP levels in estrogen receptor-positive (ER+/HER2−) tumors compared with triple-negative breast cancer (TNBC) in both early-stage and metastatic settings (median [IQR]: 35.98 [25.31–55.05] vs. 19.67 [9.23–42.07] ng/mL, respectively). However, circulating ETP levels were associated with treatment response only in the metastatic setting. ETP was readily detected in tumor specimens (n=54) and adjacent benign sections (n=28) from various breast tumor types, suggesting that both autocrine and paracrine ETP production may be important drivers of tumor growth. Conclusions: In summary, these findings identify circulating ETP as a potential biomarker in ER+ metastatic breast cancer and support further investigation of its relationship with disease activity and the development of endotrophin-targeting agents.