Hypoxia-regulated Carbonic Anhydrase IX Expression is Associated with Poor Survival in Patients with Invasive Breast Cancer

Overview

Journal Br J Cancer

Specialty Oncology

Date 2007 Jan 11

PMID 17213826

Citations 91

Authors

S A Hussain

R Ganesan

G Reynolds

L Gross

A Stevens

J Pastorek

P G Murray

B Perunovic

M S Anwar

L Billingham

N D James

D Spooner

C J Poole

D W Rea

D H Palmer

Affiliations

Soon will be listed here.

Abstract

Tumour hypoxia is a microenvironmental factor related to poor response to radiation, chemotherapy, genetic instability, selection for resistance to apoptosis, and increased risk of invasion and metastasis. Hypoxia-regulated carbonic anhydrase IX (CA IX) has been studied in various tumour sites and its expression has been correlated with the clinical outcome. The purpose of this study was to investigate the correlation of CA IX expression with outcome in patients with invasive breast cancer. We conducted a retrospective study examining the effects of carbonic anhydrase IX (CA IX) on survival in patients with breast cancer. To facilitate the screening of multiple tissue blocks from each patient, tissue microarrays were prepared containing between two and five representative samples of tumour per patient. Immunohistochemistry was used to examine expression of CA IX in patients with breast cancer. The study includes a cohort of 144 unselected patients with early invasive breast cancer who underwent surgery, and had CA IX expression and follow-up data available for analysis. At the time of analysis, there were 28 deaths and median follow-up of 48 months with 96% of patients having at least 2 years of follow-up. CA IX was negative for 107 patients (17 deaths) and positive for 37 patients (11 deaths). Kaplan-Meier survival curves show that survival was superior in the CA IX-negative group with a 2-year survival of 97% for negatives and 83% for positives (log-rank test P=0.01). Allowing for potential prognostic variables in a Cox regression analysis, CA IX remained a significant independent predictor of survival (P=0.035). This study showed in both univariate and multivariate analysis that survival is significantly inferior in patients with tumour expressing CA IX. Prospective studies are underway to investigate this correlation in clinical trial setting.

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References

Knocke T, Weitmann H, Feldmann H, Selzer E, Potter R . Intratumoral pO2-measurements as predictive assay in the treatment of carcinoma of the uterine cervix. Radiother Oncol. 2000; 53(2):99-104. DOI: 10.1016/s0167-8140(99)00139-5. View

Wykoff C, Beasley N, Watson P, Turner K, Pastorek J, Sibtain A . Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 2001; 60(24):7075-83. View

Chia S, Wykoff C, Watson P, Han C, Leek R, Pastorek J . Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol. 2001; 19(16):3660-8. DOI: 10.1200/JCO.2001.19.16.3660. View

Loncaster J, Harris A, Davidson S, Logue J, Hunter R, WYCOFF C . Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res. 2001; 61(17):6394-9. View

Fyles A, Milosevic M, Hedley D, Pintilie M, Levin W, Manchul L . Tumor hypoxia has independent predictor impact only in patients with node-negative cervix cancer. J Clin Oncol. 2002; 20(3):680-7. DOI: 10.1200/JCO.2002.20.3.680. View

Turner K, Crew J, Wykoff C, Watson P, Poulsom R, Pastorek J . The hypoxia-inducible genes VEGF and CA9 are differentially regulated in superficial vs invasive bladder cancer. Br J Cancer. 2002; 86(8):1276-82. PMC: 2375338. DOI: 10.1038/sj.bjc.6600215. View

Reynolds G, Billingham L, Gray L, Flavell J, Najafipour S, Crocker J . Interleukin 6 expression by Hodgkin/Reed-Sternberg cells is associated with the presence of 'B' symptoms and failure to achieve complete remission in patients with advanced Hodgkin's disease. Br J Haematol. 2002; 118(1):195-201. DOI: 10.1046/j.1365-2141.2002.03575.x. View

Kaanders J, Wijffels K, Marres H, Ljungkvist A, Pop L, van den Hoogen F . Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res. 2002; 62(23):7066-74. View

Swinson D, Jones J, Richardson D, Wykoff C, Turley H, Pastorek J . Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer. J Clin Oncol. 2003; 21(3):473-82. DOI: 10.1200/JCO.2003.11.132. View

10.

Murray P, Lissauer D, Junying J, Davies G, Moore S, Bell A . Reactivity with A monoclonal antibody to Epstein-Barr virus (EBV) nuclear antigen 1 defines a subset of aggressive breast cancers in the absence of the EBV genome. Cancer Res. 2003; 63(9):2338-43. View

11.

Hoskin P, Sibtain A, Daley F, Wilson G . GLUT1 and CAIX as intrinsic markers of hypoxia in bladder cancer: relationship with vascularity and proliferation as predictors of outcome of ARCON. Br J Cancer. 2003; 89(7):1290-7. PMC: 2394309. DOI: 10.1038/sj.bjc.6601260. View

12.

Hussain S, Palmer D, Ganesan R, Hiller L, Gregory J, Murray P . Carbonic anhydrase IX, a marker of hypoxia: correlation with clinical outcome in transitional cell carcinoma of the bladder. Oncol Rep. 2004; 11(5):1005-10. View

13.

Peto R, Pike M, Armitage P, Breslow N, Cox D, Howard S . Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer. 1977; 35(1):1-39. PMC: 2025310. DOI: 10.1038/bjc.1977.1. View

14.

Vaupel P, Schlenger K, Knoop C, Hockel M . Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res. 1991; 51(12):3316-22. View

15.

Pastorekova S, Zavadova Z, Kostal M, Babusikova O, Zavada J . A novel quasi-viral agent, MaTu, is a two-component system. Virology. 1992; 187(2):620-6. DOI: 10.1016/0042-6822(92)90464-z. View

16.

Galea M, Blamey R, Elston C, Ellis I . The Nottingham Prognostic Index in primary breast cancer. Breast Cancer Res Treat. 1992; 22(3):207-19. DOI: 10.1007/BF01840834. View

17.

Hockel M, Knoop C, Schlenger K, Vorndran B, Knapstein P, Vaupel P . Intratumoral pO2 histography as predictive assay in advanced cancer of the uterine cervix. Adv Exp Med Biol. 1994; 345:445-50. DOI: 10.1007/978-1-4615-2468-7_59. View

18.

Brizel D, Rosner G, Prosnitz L, Dewhirst M . Patterns and variability of tumor oxygenation in human soft tissue sarcomas, cervical carcinomas, and lymph node metastases. Int J Radiat Oncol Biol Phys. 1995; 32(4):1121-5. DOI: 10.1016/0360-3016(95)00106-9. View

19.

Graeber T, Osmanian C, Jacks T, Housman D, Koch C, Lowe S . Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996; 379(6560):88-91. DOI: 10.1038/379088a0. View

20.

Brizel D, Scully S, Harrelson J, Layfield L, Bean J, Prosnitz L . Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 1996; 56(5):941-3. View