Bcl-2 was overexpressed in 229 (45.6%) of the cases studied. Altered Bax was seen in 185 (53.9%) cases: 26 (7.6%) cases had Bax underexpression, and 159 (46.4%) cases had Bax over-expression. In prior studies, either type of abnormal Bax expression was associated with an adverse outcome (13
); thus, they were considered together here.
Comparisons were made between cases that were assessed for Bcl-2 (n = 502) and those that were not (n = 1,016). There were no significant differences in age, iPSA, or T stage. Those with Bcl-2 data had a greater proportion of Gleason score 7 to 10 (65.5% versus 55.9%; P = 0.0005), and more cases were assigned to the LTAD+RT arm (53.6% versus 47.9%; P = 0.0382). Likewise for Bax, the distributions of patients by pretreatment characteristics were similar, except a greater proportion in the Bax cohort had Gleason score 7 to 10 (64% versus 57.7%; P = 0.0423), and more cases were assigned to LTAD+RT (55.4% versus 48.2%; P = 0.0186) compared with the cases in which Bax staining was not available. There were no statistical differences between the biomarker (Bcl-2 or Bax) available and unavailable groups in terms of outcome by all the end points (overall mortality, cause-specific mortality, distant metastasis, local failure, biochemical failure, or any failure) tested.
shows the distribution of patients by Bcl-2 and Bax staining, pretreatment prognostic factors, and assigned treatment. Bcl-2 overexpression was significantly related to Gleason score 7 to 10 disease (70.7% versus 61.2%; P = 0.0305), whereas altered Bax expression and the combined results were not related to any pretreatment factor (age, Gleason score, iPSA, and T stage) or assigned treatment.
Distribution of patients by Bcl-2 (n = 502) and Bax results (n = 343)
In the univariate analyses, Bcl-2 positivity was significantly related to overall mortality [relative risk (RR), 1.31; 95% confidence interval (95% CI), 1.03–1.67; P = 0.0307] and distant metastasis (RR, 1.51; 95% CI, 1.02–2.23; P = 0.0387). However, in multivariate analyses, Bcl-2 overexpression was not independently related to these or any of the other end points tested, although the RRs for failure were higher for overall mortality, cause-specific mortality, distant metastasis, and local failure (). In univariate analyses, altered Bax expression was not significantly associated with any of the end points tested, although there was a trend for any failure (RR, 1.30; 95% CI, 0.97–1.73; P = 0.0806). In the multivariate analyses (), abnormal Bax expression was significantly associated with any failure (RR, 1.43; 95% CI, 1.05–1.95; P = 0.0226) and marginally with biochemical failure using the ASTRO definition (RR, 1.37; 95% CI, 0.96–1.97; P = 0.0851).
Multivariate analysis of Bcl-2 staining (n = 470)
Multivariate analysis of Bax intensity (n = 317)
Because both Bcl-2 and Bax seem to contribute to the apoptotic response of prostate tumor cells to radiation and androgen deprivation (22
), the two biomarkers were examined together. We first divided the patients into three groups: negative Bcl-2 and normal Bax expression (negative Bcl-2/normal Bax) versus either positive Bcl-2 or abnormal Bax expression versus positive Bcl-2/abnormal Bax expression. The first group was segregated from the other two. The results displayed summarize the comparisons of negative Bcl-2/normal Bax versus the other possible combinations of positive Bcl-2 and/or altered Bax expression. In univariate analyses, negative Bcl-2/normal Bax was significantly related to both any failure (RR, 1.44; 95% CI, 1.01–2.03; P
= 0.0408) and ASTRO BF (RR, 1.62; 95% CI, 1.06–2.48; P
= 0.0242). In the multivariate analyses (), the relationships remained significant for any failure (RR, 1.45; 95% CI, 1.01–2.10; P
= 0.0457) and biochemical failure (RR, 1.60; 95% CI, 1.03–2.49; P
= 0.0359). The failure curves for these end points are displayed in . These results seemed more robust than the relationships seen with Bax alone.
Multivariate analysis of combined Bcl-2/Bax intensities
A, failure curve of ASTRO BF by combined Bcl-2/Bax expression. B, failure curve of any failure by combined Bcl-2/Bax expression.
Finally, the relationship of Bcl-2/Bax expression to length of androgen deprivation therapy (assigned treated in the protocol) was tested. shows that the 5-year failure rates (biochemical failure and any failure) were much greater for patients who had positive Bcl-2 and/or altered Bax tumors when STAD+RT was used. Although there was a trend for worse outcome in patients with negative Bcl-2/normal Bax tumors after STAD+RT, compared with LTAD+RT, the association was much less apparent. In the setting of LTAD+RT, positive Bcl-2 and/or altered Bax expression was not related to increased failure; the failure rates were about the same as for patients with negative Bcl-2/normal Bax expression.
Five-year rates by length of treatment using combined Bcl-2/Bax intensities (n = 326)