bcl‐2 and apoptosis in lymph node positive breast carcinoma

BACKGROUND Because bcl‐2 can block apoptosis in vitro, and because lower levels of apoptosis might lead to malignant cell accumulation and therefore to a more aggressive clinical course, the authors tested the hypothesis that high bcl‐2 and low apoptosis would result in a worse prognosis for breast carcinoma patients. METHODS Primary breast tumor specimens from 979 patients with positive axillary lymph nodes were evaluated for bcl‐2 protein expression by immunohistochemistry (IHC). Apoptosis was evaluated by using IHC to detect 3' DNA fragments end‐labeled with biotinylated uridine. Results were analyzed with respect to patient characteristics, prognostic factors, and clinical outcome. Median follow‐up was 61 months. RESULTS High bcl‐2 expression was significantly associated with a number of favorable prognostic factors, including a lower number of positive lymph nodes, absence of p53 protein accumulation, estrogen receptor (ER) and progesterone receptor (PR) positivity, diploidy, and a lower proliferative rate. However, although bcl‐2 is generally considered a negative regulator of apoptosis, in these tumors there was no significant association between bcl‐2 and apoptosis. Patients with high bcl‐2 expression had significantly improved disease free survival (DFS) (P < 0.0001) and overall survival (OS) (P < 0.0001). In a multivariate analysis, bcl‐2 expression was independently associated with better DFS (P = 0.004). Regarding apoptosis, the presence of ≥1% apoptotic cells was significantly associated with a greater number of positive lymph nodes, p53 protein expression, ER and PR negativity, aneuploidy, and a higher proliferation rate, although there was no significant association with a worse clinical outcome when this dichotomized cutoff was used. CONCLUSIONS For lymph node positive breast carcinoma patients, high bcl‐2 expression is associated with a number of good prognostic factors and is independently associated with better clinical outcome. Apoptosis is associated with a number of poor prognostic factors but not with a significantly worse outcome. Cancer 1998;82:1296‐302. © 1998 American Cancer Society. High bcl‐2 expression identifies a more indolent phenotype of lymph node positive breast carcinoma. Unexpectedly, bcl‐2 expression is not associated with apoptosis in the primary tumor.