Carbonic anhydrase IX and response to postmastectomy radiotherapy in high-risk breast cancer: a subgroup analysis of the DBCG82 b and c trials

Marianne Kyndi¹^,2 , Flemming B Sørensen² , Helle Knudsen³ , Jan Alsner¹ , Marie Overgaard⁴ , Hanne M Nielsen¹ and Jens Overgaard¹

¹Department of Experimental Clinical Oncology, Århus University Hospital, Nørrebrogade, 8000 Århus C, Denmark

²Department of Pathology, Århus University Hospital, Nørrebrogade, 8000 Århus C, Denmark

³Department of Pathology, Herlev Hospital, Herlev Ringvej, 2730 Herlev, Denmark

⁴Department of Oncology, Århus University Hospital, Nørrebrogade, 8000 Århus C, Denmark

author email corresponding author email

Breast Cancer Research 2008, 10:R24doi:10.1186/bcr1981


Published:	20 March 2008

Abstract

Introduction

A significant survival improvement after postmastectomy radiotherapy was identified in the Danish Breast Cancer Cooperative Group (DBCG82) b and c studies and in the British Columbia Randomized Radiation Trial. Recently, potential predictive value regarding response to postmastectomy radiotherapy was reported for carbonic anhydrase (CA) IX in a study (reported in abstract form) that included 160 patients. The purpose of the present study was to examine the importance of CA IX to response to postmastectomy radiotherapy in the larger scaled DBCG82 b and c studies.

Methods

The DBCG82 b and c studies included 3,083 high-risk Danish breast cancer patients. The women were randomly assigned to postmastectomy radiotherapy plus systemic therapy (cyclophosfamide, methotrexate and fluorouracil in premenopausal women; and tamoxifen in postmenopausal women) or to systemic therapy alone. Cores from invasive tumour-containing paraffin blocks from 1,000 patients (more than seven nodes surgically removed) were transferred to tissue microarrays. Tissue microarray sections were stained immunohistochemically for CA IX (M75). The median follow up for patients remaining alive was 17 years. Clinical end-points were loco-regional recurrence, distant metastases, disease-specific survival and overall survival. Statistical analyses included κ statistics, χ²or exact tests, Kaplan-Meier probability plots, Log-rank test and Cox regression analyses.

Results

CA IX was assessable in 945 cores. The percentage of tumours positive for CA IX was 16% (≥ 10% invasive tumour staining). CA IX was not an independent prognostic marker for survival, distant metastases, or locoregional recurrence in the subgroup of 945 patients or within either of the two randomization arms. In subgroup analyses, however, CA IX was an independent prognostic marker for overall survival among postmenopausal women (P = 0.001), women with one to three positive nodes (P = 0.02) and hormone receptor positive women (P = 0.001). Fifteen-year probabilities of overall survival were improved by 9% and 7% after postmastectomy radiotherapy for the subgroups of CA IX negative and CA IX positive patients, respectively.

Conclusion

Within this series of 945 high-risk premenopausal and postmenopausal women, positivity for CA IX was not overall an independent prognostic marker for survival; only in subgroup analyses was it found to have prognostic value. The improvement in 15-year survival after postmastectomy radiotherapy was of similar magnitude in the two subgroups of CA IX positive and CA IX negative patients.