An Endothelial Gene Signature Score Predicts Poor Outcome in Patients with Endocrine-Treated, Low Genomic Grade Breast Tumors

• Published in: Clinical cancer research Vol. 22; no. 10; pp. 2417 - 2426
• Main Authors: Tobin, Nicholas P, Wennmalm, Kristian, Lindström, Linda S, Foukakis, Theodoros, He, Liqun, Genové, Guillem, Östman, Arne, Landberg, Göran, Betsholtz, Christer, Bergh, Jonas
• Format: Journal Article
• Language: English
• Published: United States 15.05.2016
• Subjects: 1st-line; Angiogenesis Inhibitors - therapeutic use; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer and Oncology; Cancer och onkologi; cancer patients; chemotherapy; Cohort Studies; expression signatures; Female; Gene Expression - drug effects; Gene Expression - genetics; Genomics; Hemangioendothelioma - drug therapy; Hemangioendothelioma - pathology; Hormones - therapeutic use; Humans; Indoles - therapeutic use; Medicin och hälsovetenskap; metaanalysis; microvessel density; Microvessels - drug effects; Microvessels - pathology; Middle Aged; Oncology; open-label; phase-3 trial; Prognosis; Pyrroles - therapeutic use; survival; Taxoids - therapeutic use; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; treatment
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-15-1691

The ability of vascular genes to provide treatment predictive information in breast cancer patients remains unclear. As such, we assessed the expression of genes representative of normal endothelial microvasculature (MV) in relation to treatment-specific patient subgroups. We used expression data from 993 breast tumors to assess 57 MV genes (summarized to yield an MV score) as well as the genomic grade index (GGI) and PAM50 signatures. MV score was compared with CD31 staining by correlation and gene ontology (GO) analysis, along with clinicopathologic characteristics and PAM50 subtypes. Uni-, multivariate, and/or t-test analyses were performed in all and treatment-specific subgroups, along with a clinical trial cohort of patients with metastatic breast cancer, seven of whom received antiangiogenic therapy. MV score did not correlate with microvessel density (correlation = 0.096), but displayed enrichment for angiogenic GO terms, and was lower in Luminal B tumors. In endocrine-treated patients, a high MV score was associated with decreased risk of metastasis [HR 0.58; 95% confidence interval (CI), 0.38-0.89], even after adjusting for histologic grade, but not GGI or PAM50. Subgroup analysis showed the prognostic strength of the MV score resided in low genomic grade tumors and MV score was significantly increased in metastatic breast tumors after treatment with sunitinib + docetaxel (P = 0.031). MV score identifies two groups of better and worse survival in low-risk endocrine-treated breast cancer patients. We also show normalization of tumor vasculature on a transcriptional level in response to an angiogenic inhibitor in human breast cancer samples. Clin Cancer Res; 22(10); 2417-26. ©2016 AACR.