The predictive value of bcl-2, bax, bcl-xL, bag-1, fas, and fasL for chemotherapy response in advanced breast cancer.
OBJECTIVE
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.


METHODS
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.
Sjöström
Johanna
J
Department of Oncology, Helsinki University Central Hospital, Finland. johanna.sjostrom@hus.fi
Blomqvist
Carl
C
von Boguslawski
Kristina
K
Bengtsson
Nils-Olof
NO
Mjaaland
Ingvil
I
Malmström
Per
P
Ostenstadt
Björn
B
Wist
Erik
E
Valvere
Vahur
V
Takayama
Shinichi
S
Reed
John C
JC
Saksela
Eero
E
D000293:Adolescent; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D053222:Fas Ligand Protein; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D018299:Neoplasms, Ductal, Lobular, and Medullary / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015996:Survival Rate; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019014:fas Receptor / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; C494826:BAX protein, human; C091732:BCL2-associated athanogene 1 protein; C494811:BCL2L1 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019014:fas Receptor; D005472:Fluorouracil; D008727:Methotrexate