Molecular markers of outcome after radiotherapy in patients with prostate carcinoma: Ki-67, bcl-2, bax, and bcl-x.
BACKGROUND
Abnormal expression of key proteins of the apoptotic pathway has been associated with poor prognosis, although there have been few studies of these correlations in patients with prostate carcinoma who are treated with radiotherapy. The current study examined the association between expression levels of Ki-67, bcl-2, bax, and bcl-x in pretreatment biopsy specimens and patient outcome after definitive radiotherapy alone.


METHODS
Archival pretreatment prostate biopsy tumor tissue was retrieved from 106 patients with Stage T1-T3 prostate carcinoma who were treated at the University of Texas M. D. Anderson Cancer Center with external beam radiotherapy between 1987 and 1993. Expression levels of Ki-67 (MIB-1 staining; n = 106 patients), bcl-2 (n = 77 patients), bax (n = 70 patients), and bcl-x (both long and short splice variants; n = 72 patients) were determined by immunohistochemical staining. The Ki-67 labeling index (Ki67-LI) was available for all patients and was derived from the percentage of Ki-67 positive cells. Biochemical failure after radiotherapy was defined as three consecutive rises in prostate specific antigen level on follow-up. The median follow-up was 62 months.


RESULTS
High Ki67-LI (> 3.5%) expression was observed in 33% of patients, overexpression of bcl-2 was observed in 16% of patients, altered bax expression was observed in 23% of patients, and altered bcl-x expression was observed in 53% of patients. There was no correlation found between the biomarkers. Kaplan-Meier survival estimates of freedom from biochemical failure (bNED) and the log-rank test revealed significantly lower rates in association with high Ki67-LI, positive bcl-2, and altered bax staining. No correlation was observed between bcl-x staining and bNED. Cox proportional hazards multivariate analysis confirmed that bcl-2 and bax were independent of pretreatment PSA level, Gleason score, disease stage, and Ki67-LI in predicting bNED.


CONCLUSIONS
Abnormalities in the expression levels of bcl-2 and bax were associated with increased failure after patients were treated for prostate carcinoma with external beam radiotherapy. These biomarkers appeared to be useful in categorizing patient risk further, beyond Ki-67 staining and conventional clinical prognostic factors.
Pollack
Alan
A
Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. pollack@fccc.edu
Cowen
Didier
D
Troncoso
Patricia
P
Zagars
Gunar K
GK
von Eschenbach
Andrew C
AC
Meistrich
Marvin L
ML
McDonnell
Timothy
T
D014408:Biomarkers, Tumor / Q000032:analysis*; D001706:Biopsy; D002277:Carcinoma / Q000378:metabolism* / Q000532:radiotherapy*; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D013997:Time Factors; D016896:Treatment Outcome; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494826:BAX protein, human; C494811:BCL2L1 protein, human; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein