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The AA Genotype of the Regulatory BCL2 Promoter Polymorphism (–938C>A) Is Associated with a Favorable Outcome in Lymph Node–Negative Invasive Breast Cancer Patients

Authors' Affiliations: Institutes of ¹ Pharmacogenetics and ² Pathology and Neuropathology; ³ Clinic of Obstetrics and Gynaecology; and ⁴ Department of Haematology, Medical Faculty, University of Duisburg-Essen; ⁵ West German Cancer Center Essen (WTZE); and ⁶ University Breast Cancer Center Essen, Essen, Germany

Requests for reprints: Hagen S. Bachmann, Institut für Pharmakogenetik, Universitätsklinikum Essen, Hufelandstraße 55, D-45147 Essen, Germany. Phone: 49-201-723-3459; Fax: 49-201-723-5968; E-mail: hagen.bachmann{at}uk-essen.de.

Purpose: Expression of the antiapoptotic and antiproliferative protein Bcl-2 has been repeatedly shown to be associated with better clinical outcome in breast cancer. We recently showed a novel regulatory (–938C>A) single-nucleotide polymorphism (SNP) in the inhibitory P2 BCL2 gene promoter generating significantly different BCL2 promoter activities.

Experimental Design: Paraffin-embedded neoplastic and nonneoplastic tissues from 274 patients (161 still alive after a follow-up period of at least 80 months) with primary unilateral invasive breast carcinoma were investigated. Bcl-2 expression of tumor cells was shown by immunohistochemistry; nonneoplastic tissues were used for genotyping. Both the Bcl-2 expression and the (–938C>A) genotypes were correlated with the patients' survival.

Results: Kaplan-Meier curves revealed a significant association of the AA genotype with increased survival (P = 0.030) in lymph node–negative breast cancer patients, whereas no genotype effect could be observed in lymph node–positive cases. Ten-year survival rates were 88.6% for the AA genotype, 78.4% for the AC genotype, and 65.8% for the CC genotype. Multivariable Cox regression identified the BCL2 (–938CC) genotype as an independent prognostic factor for cancer-related death in lymph node–negative breast carcinoma patients (hazard ratio, 3.59; P = 0.032). Immunohistochemical Bcl-2 expression was significantly associated with the clinical outcome of lymph node–positive but not of lymph node–negative breast cancer patients. In lymph node–negative cases, the (–938C>A) SNP was both significantly related with the immunohistochemically determined level of Bcl-2 expression (P = 0.044) and the survival of patients with Bcl-2–expressing carcinomas (P = 0.006).

Conclusions: These results suggest the (–938C>A) polymorphism as a survival prognosticator as well as indicator of a high-risk group within patients with lymph node–negative breast cancer.