Levels of hypoxia‐inducible factor‐1α independently predict prognosis in patients with lymph node negative breast carcinoma

Abstract BACKGROUND Hypoxia‐inducible factor‐1 (HIF‐1) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis to survive cellular hypoxia. Increased levels of HIF‐1α, the O 2 ‐regulated subunit of HIF‐1, were noted during breast carcinogenesis. In this study, the prognostic value of HIF‐1α expression and its correlation with various clinicopathologic variables in patients with invasive breast carcinoma were investigated. METHODS Expression levels of HIF‐1α, HER‐2/ neu , estrogen receptor, and progesterone receptor were analyzed in 150 patients with early‐stage breast carcinoma by immunohistochemistry. HER‐2/ neu gene amplification was investigated with automated fluorescent in situ hybridization. The mitotic activity index, histologic grade, and tumor type were assessed in hematoxylin and eosinstained specimens. Clinical data included disease‐free survival, overall survival, lymph node status, and tumor size. The data were analyzed with two‐sided univariate and multivariate tests, with P values < 0.05 considered significant. RESULTS High levels of HIF‐1α had an association of borderline significance with decreased overall survival ( P = 0.059) and disease‐free survival ( P = 0.110) that was ascribed completely to the subgroup of women with lymph node negative tumors ( n = 81 patients; P = 0.008 and P = 0.004, respectively). HER‐2/ neu immunoreactivity ( P < 0.001) and gene amplification ( P < 0.001), vascular endothelial growth factor expression ( P = 0.016), and Ki‐67 expression ( P < 0.001) were correlated strongly with HIF‐1α positivity, although none of those factors had an independent effect on survival. CONCLUSIONS Increased levels of HIF‐1α were associated independently with shortened survival in patients with lymph node negative breast carcinoma. Therefore, the use of immunohistochemical assessment of HIF‐1α as a new predictor of poor outcome may improve clinical decision‐making regarding adjuvant treatment of patients with lymph node negative breast carcinoma. Cancer 2003;97:1573–81. © 2003 American Cancer Society. DOI 10.1002/cncr.11246