title: The predictive value of bcl-2, bax, bcl-xL, bag-1, fas, and fasL for chemotherapy response in advanced breast cancer.
abstract: 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.
authors.affiliation: Department of Oncology, Helsinki University Central Hospital, Finland. johanna.sjostrom@hus.fi
authors.forename: Johanna
authors.initials: J
authors.lastname: Sjöström
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Kristina
authors.initials: K
authors.lastname: von Boguslawski
authors.forename: Nils-Olof
authors.initials: NO
authors.lastname: Bengtsson
authors.forename: Ingvil
authors.initials: I
authors.lastname: Mjaaland
authors.forename: Per
authors.initials: P
authors.lastname: Malmström
authors.forename: Björn
authors.initials: B
authors.lastname: Ostenstadt
authors.forename: Erik
authors.initials: E
authors.lastname: Wist
authors.forename: Vahur
authors.initials: V
authors.lastname: Valvere
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takayama
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Eero
authors.initials: E
authors.lastname: Saksela
mesh_terms: 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*
chemical_list: 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