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CA IX is an Independent Prognostic Marker in Premenopausal Breast Cancer Patients with One to Three Positive Lymph Nodes and a Putative Marker of Radiation Resistance

Authors' Affiliations: ¹ UCD School of Biomolecular and Biomedical Science, ² UCD School of Medicine and Medical Science, UCD Conway Institute, University College, Dublin; ³ Department of Pathology and Laboratory Medicine, St. Vincent's University Hospital, Dublin, Ireland; ⁴ Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden; and ⁵ Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina

Requests for reprints: William M. Gallagher, UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. Phone: 353-1-716-6743; Fax: 353-1-2837211; E-mail: william.gallagher{at}ucd.ie.

Purpose: Hypoxia in breast cancer is associated with poor prognosis and down-regulation of the estrogen receptor. Carbonic anhydrase IX (CA IX) is a hypoxia-inducible gene that has been associated with poor outcome in many epithelial cancers. Previous studies of CA IX in breast cancer have been carried out on mixed cohorts of premenopausal and postmenopausal patients with locally advanced disease and varying treatment regimens. We examined the potential prognostic and predictive role of CA IX in premenopausal breast cancer patients.

Experimental Design: Using tissue microarrays, we analyzed CA IX expression in 400 stage II breast cancers from premenopausal women. The patients had previously participated in a randomized control trial comparing 2 years of tamoxifen to no systemic adjuvant treatment. Median follow-up was 13.9 years.

Results: CA IX expression correlated positively with tumor size, grade, hypoxia-inducible factor 1, Ki-67, cyclin E, and cyclin A2 expression. CA IX expression correlated negatively with cyclin D1, estrogen receptor, and progesterone receptor. CA IX expression was associated with a reduced relapse-free survival (P = 0.032), overall survival (P = 0.022), and breast cancer–specific survival (P = 0.005). Multivariate analysis revealed that CA IX was an independent prognostic marker in untreated patients with one to three positive lymph nodes (hazard ratio, 3.2; 95% confidence interval, 1.15-9.13; P = 0.027).

Conclusion: CA IX is marker of poor prognosis in premenopausal breast cancer patients and it is an independent predictor of survival in patients with one to three positive lymph nodes. As all these patients received locoregional radiation therapy, CA IX may be associated with resistance to radiotherapy.

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