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Reduced Expression of Proapoptotic Gene BAX Is Associated with Poor Response Rates to Combination Chemotherapy and Shorter Survival in Women with Metastatic Breast Adenocarcinoma¹

La Jolla Cancer Research Foundation, Oncogene and Tumor Suppressor Gene Program, La Jolla, California 92037 [S. K., M. K., J. C. R.], and University of Helsinki, Departments of Radiotherapy and Oncology [C. B., K. F., V-M. W., E. N.] and Pathology [S. N.], Haartmanninkatu 4, Helsinki, SF-00290 Finland

Bax is a homologue of Bcl-2 that promotes apoptosis. Bax protein levels were assessed by immunohistochemical methods in primary tumors derived from 119 women with metastatic breast cancer. These patients had received combination chemotherapy either with a once a month dosage schedule or in 4 weekly divided doses. The BAX immunostaining results were retrospectively compared with overall survival, time to tumor progression (TTP), and response, as well as several laboratory markers. Normal breast epithelium and in situ carcinomas immunostained positively for Bax. Marked reductions in Bax immunostaining were observed in 40 (34%) of 119 evaluable tumors. Reduced Bax correlated with shorter overall survival (median, 8.1 versus 15.7 months; P = 0.04), faster TTP (median, 2.0 versus 6.3 months; P = 0.009), and failure to respond (complete response, partial responses; 6% versus 42%, P = 0.01) in the subgroup of patients who received divided dose therapy. Reduced Bax immunostaining was not significant in the monthly dose group. When the two groups were combined, however, reduced Bax was significantly correlated in univariate analysis with failure to respond (21 versus 43% achieving complete response or partial response; P = 0.02), faster TTP (median, 3.7 versus 9.0 months; P = 0.02), and shorter survival (median, 10.7 versus 17.1 months; P = 0.04). Bax immunostaining was not significantly correlated with tumor histology, S-phase fraction, aneuploidy, p53 HER2, or cathepsin D, but was positively associated with Bcl-2 (P = 0.005). In multivariate analysis (Bax, tumor grade, and treatment group), reduced Bax was strongly associated with faster TTP (P 0.009) and shorter survival (P 0.001). Although highly preliminary, the finding suggest that loss of Bax immunostaining represents a novel prognostic indicator of poor response to chemotherapy and shorter survival in women with metastatic breast cancer, and raise the possibility that the subgroup of women with Bax-negative tumors may benefit from more aggressive therapy.

¹ Supported in part by grants from the American Cancer Society (DHP32C) and National Cancer Institute (CA-60381). J. C. R. Is a Scholar of the Leukemia Society of America.

² To whom requests for reprints should be addressed, at La Jolla Cancer Research Foundation, Oncogene and Tumor Suppressor Gene Program, 10901 North Torrey Pines Road, La Jolla, CA 92037.

Received 5/ 4/95. Accepted 8/17/95.

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