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The Predictive Value of bcl-2, bax, bcl-xL, bag-1, fas, and fasL for Chemotherapy Response in Advanced Breast Cancer¹

Department of Oncology, Helsinki University Central Hospital [J. S.], and Department of Pathology, the Hartman Institute and Helsinki University Central Hospital [K. v. B., E. S.], 00290 Helsinki, Finland; University Hospital, Uppsala, Sweden [C. B.]; University Hospital, Umeå, Sweden [N-O. B.]; University Hospital, Lund, Sweden [P. M.]; Rogaland Central Hospital, Stavanger, Norway [I. M.]; Ullevål Hospital, Oslo, Norway [B. O.]); University Hospital of Tromsoe, Norway [E. W.]; Estonian Cancer Center, Estonia [V. V.]; and The Burnham Institute, La Jolla, California [S. T., J. C. R.]

Purpose: The purpose was to evaluate the utility of some bcl-2 family proteins fas and fasL as predictive indicators for chemotherapy response in advanced breast cancer.

Experimental Design: Between October 1994 and October 1997, 283 patients with advanced breast cancer were included in a multicenter randomized study comparing docetaxel (D) to sequential methotrexate and 5-fluorouracil (MF) after anthracycline failure. The response rates (complete response + partial response) were 42 and 21% in the D and MF arms, respectively (P < 0.001). In 126 patients, histological blocks of primary tumors were available for immunohistochemical analysis of bax, bcl-2, bcl-xL, bag-1, fas and fasL.

Results: Of the investigated factors, bag-1 correlated positively with bax, bcl-2, and fasL, and fasL correlated positively with fas and bax. None of these apoptosis-related factors was associated with a response to chemotherapy either in the whole patient population or in the D or MF arms. Interestingly, low bcl-2 expression was associated with shorter time to progression (P = 0.02) and shorter overall survival (OS; P = 0.001). High fasL expression showed a trend toward shorter OS. In multivariate backwards stepwise Cox analysis, in which histological grade and estrogen receptor status (ER) were also included, bcl-2 (P = 0.01) and fasL (P = 0.005) remained highly significantly associated with OS, whereas histological grade and ER lost their significance.

Conclusions: None of the investigated apoptosis-related factors of primary tumor could predict the later response to either D or MF treatment. However, fasL and bcl-2 were strong prognostic factors. Patients who had tumors with high fasL and low bcl-2 expression had the shortest OS.

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