healthmedicinet

The clinicopathological role of Bcl-2 in breast cancer was systematically investigated
in 634 cases without any adjuvant therapy and 447 cases with tamoxifen monotherapy
using full sections from routinely processed archival materials as used in the clinical
setting. As others reported 18], 31], Bcl-2 expression was positively correlated with ER and PR expression, but negatively
correlated with HER2 expression, grade, and tumor size, confirming Bcl-2’s association
with favorable prognostic factors or differentiated markers in both groups with and
without tamoxifen (Table 1). In patients who did not receive adjuvant therapy, Bcl-2 expression significantly
correlated with premenopausal status (Table 1). Correlation of Bcl-2 expression with premenopausal status has been previously reported
by Zhang et al. 36], whereas Hellmans et al. found no relation 23]. Higher premenopausal serum estrogen may promote Bcl-2 expression through ER 37], although this may be offset by the commonly observed correlation of ER expression
with postmenopausal status 38], leading to inconsistent results.

In the tamoxifen-treated group, Bcl-2 positivity correlated with better OS in overall
patients and in the subgroup with ER-positive and/or PR-positive tumors, but with
poor OS in the subgroups with ER-negative and PR-negative tumors or with triple-negative
tumors (Fig. 3); however, Bcl-2 was not an independent predictor of clinical outcome in overall
patients or subgroups when ER/PR or HER2 status is taken into consideration (Table 3). In the group without adjuvant therapy, there was no evidence that Bcl-2 positivity
was a favorable prognostic factor in the entire group or in the subgroup with ER-positive
and/or PR-positive tumors (Fig. 2). The finding that a favorable prognosis with Bcl-2 positivity was more evident in
the tamoxifen-treated group than in the no adjuvant group is consistent with other
reports 18], 21]–26], 31]. The favorable prognosis reported for Bcl-2-positive tumors therefore seems to at
least partly reflect the indirect effect of coexpressed hormone receptors.

In the group of patients that did not receive adjuvant therapy, Bcl-2 positivity significantly
correlated with poor clinical outcome in patients with hormone receptor-negative (ER-negative
and PR-negative) or triple-negative tumors (Fig. 2). In multivariate analysis, Bcl-2 positivity independently predicted recurrence/mortality
in the entire group of patients and in hormone receptor-negative or triple-negative
cases, but not in ER-positive and/or PR-positive cases (Table 2). It seems that the anti-apoptotic effect of Bcl-2, which usually correlates with
poor clinical outcome or resistance to therapy in tumors other than breast cancer
5], 7], 8], is evident only in cases without hormone receptors and without adjuvant therapy.
In the tamoxifen-treated group, Bcl-2 positivity was also significantly correlated
with poor OS among patients with hormone receptor-negative or triple-negative tumors,
but that did not reach statistical significance in DFS, probably due to the small
number of cases in that group (Fig. 3). Only a few studies have examined the clinical importance of Bcl-2 in subgroups
considering the status of hormone receptors or HER2. Tawfik et al. reported that Bcl-2
expression was an independent poor prognostic factor in 124 triple-negative breast
cancers; however, multivariate analysis in that study did not include tumor size or
nodal status, which are the most powerful prognostic factors. Further, information
about adjuvant therapy was not described in that study 39]. Ryu et al. did not find Bcl-2 useful in predicting clinical outcome in 94 triple-negative
cancers 40]. In a study by Dawson et al., the hazard ratio for Bcl-2 positive vs. negative expression
was reportedly larger in ER-negative, PR-negative, and triple-negative than ER-positive,
PR-positive, and non-triple-negative cancers, respectively, which is in line with
our present study; however, adjuvant therapy was not considered in each comparison
28].

Interestingly, the prognostic value of Bcl-2 in hormone receptor-negative or triple-negative
cases without any adjuvant therapy was more evident in postmenopausal, but diminished
in premenopausal, women (Fig. 4). In other words, postmenopausal patients with Bcl-2-negative and hormone receptor-negative
(or triple-negative) cancers exhibited quite favorable clinical outcome even without
adjuvant chemotherapy (Fig. 4a-d). The reason is not known; however, the present results suggest the need for a reevaluation
of adjuvant chemotherapy for these patients.

In the present study, a 30 % cut-off was used to determine Bcl-2 status, as proposed
by Silvestrini et al., who examined the outcome predictive power of Bcl-2 status using
several cut-offs, and showed that a 30–40 % cut-off yielded the best result; however,
a 10 % cut-off has been more frequently used by others 20]. We obtained similar results using a 10 % cut-off for Bcl-2, but the outcome predictive
power decreased compared with the Bcl-2 status determined by a 30 % cut-off (data
not shown). The reason for this is not known, but the usefulness of a 30 % cut-off
for Bcl-2 status as reported in our study seems to validate Silvestrini’s results.
Since the overall results were essentially the same irrespective of whether the cut-off
value was 10 % or 30 %, it is unlikely that the different cut-off value we used in
this study is the reason why our results are different from studies showing that bcl-2
positivity is a predictor of favorable outcome.

Bcl-2 antisense therapy has been suggested for various tumors in an in vitro setting 11]–13]. The development of Bcl-2 inhibitors has been explored 41], 42], and small-molecule inhibitors of Bcl-2 such as ABT–737 and ABT-199 have recently
been introduced 10], 15]. These Bcl-2 inhibitors were shown to be effective in prolonging survival in animal
models bearing lymphoid malignancies 10], 14]. Emerging evidence also suggests the usefulness of this type of therapy in breast
cancer 9], 43], 44]. ABT-199 has been reported to improve the response of ER-positive tumors to tamoxifen
43], 44]. Oakes et al. reported that ABT–737 sensitized primary basal-like breast cancers
with elevated Bcl-2 levels to docetaxel and improved response and OS in an in vivo setting, suggesting that elevated Bcl-2 expression constitutes a predictive response
marker in breast cancer 9]. This recently demonstrated usefulness of Bcl-2 inhibitors in basal-like breast cancers
expressing Bcl-2, together with our present finding that Bcl-2 positivity is correlated
with poor clinical outcome in patients with hormone receptor-negative or triple-negative
tumors, suggest that Bcl-2-targeted therapy may improve the poor clinical outcome
of patients with such tumors expressing Bcl-2. This evidence warrants a clinical study
of Bcl-2-targeted therapy in breast cancer. Bcl-2 examination is expected to improve
prediction of the clinical outcome or to predict response to Bcl-2-targeted therapy
in breast cancer.