Tissue and imaging biomarkers for hypoxia predict poor outcome in endometrial cancer

// Anna Berg 1, 2 , Kristine E. Fasmer 3 , Karen K. Mauland 1, 2 , Sigmund Ytre-Hauge 3, 4 , Erling A. Hoivik 1, 2 , Jenny A. Husby 3, 4 , Ingvild L. Tangen 1, 2 , Jone Trovik 1, 2 , Mari K. Halle 1, 2 , Kathrine Woie 2 , Line Bjørge 1, 2 , Atle Bjørnerud 5, 6 , Helga B. Salvesen 1, 2 , Henrica M. J. Werner 1, 2 , Camilla Krakstad 2, 7, * , Ingfrid S. Haldorsen 3, 4, * 1 Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway 2 Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway 3 Department of Radiology, Haukeland University Hospital, Norway 4 Section of Radiology, Department of Clinical Medicine, University of Bergen, Norway 5 Department of Physics, University of Oslo, Norway 6 The Intervention Center, Oslo University Hospital, Norway 7 Center for Cancer Biomarkers, Department of Biomedicine, University of Bergen, Norway * These authors contributed equally to this work Correspondence to: Anna Berg, email: anna.berg@uib.no Keywords: endometrial carcinoma, endometrial hyperplasia, HIF-1α, MRI, FDG-PET/CT Received: July 02, 2016 Accepted: September 04, 2016 Published: September 13, 2016 ABSTRACT Hypoxia is frequent in solid tumors and linked to aggressive phenotypes and therapy resistance. We explored expression patterns of the proposed hypoxia marker HIF-1α in endometrial cancer (EC) and investigate whether preoperative functional imaging parameters are associated with tumor hypoxia. Expression of HIF-1α was explored both in the epithelial and the stromal tumor component. We found that low epithelial HIF-1α and high stromal HIF-1α expression were significantly associated with reduced disease specific survival in EC. Only stromal HIF-1α had independent prognostic value in Cox regression analysis. High stromal HIF-1α protein expression was rare in the premalignant lesions of complex atypical hyperplasia but increased significantly to invasive cancer. High stromal HIF-1α expression was correlated with overexpression of important genes downstream from HIF-1α, i.e. VEGFA and SLC2A1 ( GLUT1 ). Detecting hypoxic tumors with preoperative functional imaging might have therapeutic benefits. We found that high stromal HIF-1α expression associated with high total lesion glycolysis (TLG) at PET/CT. High expression of a gene signature linked to hypoxia also correlated with low tumor blood flow at DCE-MRI and increased metabolism measured by FDG-PET. PI3K pathway inhibitors were identified as potential therapeutic compounds in patients with lesions overexpressing this gene signature. In conclusion, we show that high stromal HIF-1α expression predicts reduced survival in EC and is associated with increased tumor metabolism at FDG-PET/CT. Importantly; we demonstrate a correlation between tissue and imaging biomarkers reflecting hypoxia, and also possible treatment targets for selected patients.