Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter?
BACKGROUND
Hypoxia-inducible factor 1 alpha (hif-1alpha) furnishes tumor cells with the means of adapting to stress parameters like tumor hypoxia and promotes critical steps in tumor progression and aggressiveness. We investigated the role of hif-1alpha expression in patients with node-positive breast cancer.


METHODS
Tumor samples from 77 patients were available for immunohistochemistry. The impact of hif-1alpha immunoreactivity on survival endpoints was determined by univariate and multivariate analyses, and correlations to clinicopathological characteristics were determined by cross-tabulations.


RESULTS
hif-1alpha was expressed in 56% (n = 43/77) of the patients. Its expression correlated with progesterone receptor negativity (P = 0.002). The Kaplan-Meier curves revealed significantly shorter distant metastasis-free survival (DMFS) (P = 0.04, log-rank) and disease-free survival (DFS) (P = 0.04, log-rank) in patients with increased hif-1alpha expression. The difference in overall survival (OS) did not attain statistical significance (5-year OS, 66% without hif-1alpha expression and 55% with hif-1alpha expression; P = 0.21). The multivariate analysis failed to reveal an independent prognostic value for hif-1alpha expression in the whole patient group. The only significant parameter for all endpoints was the T stage (T3/T4 versus T1/T2: DMFS, relative risk = 3.16, P = 0.01; DFS, relative risk = 2.57, P = 0.03; OS, relative risk = 3.03, P = 0.03). Restricting the univariate and multivariate analyses to T1/T2 tumors, hif-1alpha expression was a significant parameter for DFS and DMFS.


CONCLUSIONS
hif-1alpha is expressed in the majority of patients with node-positive breast cancer. It can serve as a prognostic marker for an unfavorable outcome in those with T1/T2 tumors and positive axillary lymph nodes.
Gruber
Günther
G
Department of Radiation Oncology, University of Bern, Switzerland.
Greiner
Richard H
RH
Hlushchuk
Ruslan
R
Aebersold
Daniel M
DM
Altermatt
Hans J
HJ
Berclaz
Gilles
G
Djonov
Valentin
V
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy; D015331:Cohort Studies; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015993:Life Tables; D008207:Lymphatic Metastasis; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis / Q000502:physiology*; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D011980:Receptors, Progesterone / Q000032:analysis; D012306:Risk; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use; D043823:Taxoids / Q000008:administration & dosage; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology*; D014750:Vincristine / Q000008:administration & dosage
D018931:Antineoplastic Agents, Hormonal; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D011980:Receptors, Progesterone; D043823:Taxoids; D014157:Transcription Factors; D013629:Tamoxifen; D000077143:Docetaxel; D015251:Epirubicin; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D005472:Fluorouracil; D011241:Prednisone; D008727:Methotrexate