REDUCED EXPRESSION OF PROAPOPTOTIC GENE BAX IS ASSOCIATED WITH POOR RESPONSE RATES TO COMBINATION CHEMOTHERAPY AND SHORTER SURVIVAL IN WOMEN WITH METASTATIC BREAST ADENOCARCINOMA

Bax is a homologue of Bcl-2 that promotes apoptosis. Bar protein level s were assessed by immunohistochemical methods in primary tumors deriv ed from 119 women with metastatic breast cancer. These patients had re ceived combination chemotherapy either with a once a month dosage sche dule or in 4 weekly divided doses. The BAX immunostaining results were retrospectively compared with overall survival, time to tumor progres sion (TTP), and response, as well as several laboratory markers. Norma l breast epithelium and in situ carcinomas immunostained positively fo r Bar, Marked reductions in Bar immunostaining were observed in 40 (34 %) of 119 evaluable tumors. Reduced Bar correlated with shorter overal l survival (median, 8.1 versus 15.7 months; P = 0.04), faster TTP (med ian, 2.0 versus 6.3 months; P = 0.009), and failure to respond (comple te response, partial responses; 6% versus 42%, P = 0.01) in the subgro up of patients who received divided dose therapy, Reduced Bar immunost aining was not significant in the monthly dose group. When the two gro ups were combined, however, reduced Bar was significantly correlated i n 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), Bar immunostaining was not significantl y correlated with tumor histology, S-phase fraction, aneuploidy, p53 H ER2, or cathepsin D, but was positively associated with Bcl-2 (P = 0.0 05). In multivariate analysis (Bar, tumor grade, and treatment group), reduced Bar was strongly associated with faster TTP (P congruent to 0 .009) and shorter survival (P congruent to 0.001), Although highly pre liminary, the finding suggest that loss of Bar immunostaining represen ts a novel prognostic indicator of poor response to chemotherapy and s horter survival in women with metastatic breast cancer, and raise the possibility that the subgroup of women with Bar-negative tumors may be nefit from more aggressive therapy.