Differential prognostic impact of the cyclins E and B in premenopausal and postmenopausal women with lymph node‐negative breast cancer

Abstract

Searching for new prognostic factors, we investigated the influence of cyclin expression on breast cancer prognosis. A total of 273 archival tumor specimens from patients with pT1/pT2 N0 breast cancers treated by surgery and local irradiation were immunostained for cyclins E, A and B. Outcome was evaluated as metastasis-free (MFS) and diseasespecific survival (DSS) over a median observation period of 99 months. In postmenopausal women, DSS was significantly predicted by cyclin E, and in premenopausal patients by cyclin B. No statistical significance was found for cyclin A. When the prognostic impact of cyclins was compared to that of standard prognostic indicators in a multivariate analysis, both cyclin E and cyclin B were selected as independent predictors of survival in postmenopausal and premenopausal patients, respectively. After inclusion of Ki-67 in the model, cyclin E lost its significance, whereas cyclin B remained the only independent prognostic factor with a hazard ratio of 4.5 (p ‫؍‬ 0.026) for tumor-related death. Assessment of cyclin expression may, therefore, refine current prognostic models if considered in relation to menopausal status. The prognostic relevance of cyclins is likely attributable to an influence on proliferation, cell survival and genetic instability. Awareness of the molecular mechanisms leading to deregulated cyclin expression may guide decisions for risk-adapted therapy regimens.

High cyclin B1 expression is associated with poor survival in breast cancer

“…The association of high cyclin B1 expression with large tumour size, positive nodal status, high grade, and ER and PR negativity is similar to previous reported data Rudolph et al, 2003). One smaller study did not find any correlation to N, T, ER and p53 status, but the small sample size (73 tumours) may explain this discrepancy (Winters et al, 2001).…”

“…Cyclin B1 expression was not associated with tumour size, nodal status, grade, oestrogen receptor (ER) status or p53 immunohistochemical expression. In another study with 332 T1-2 N-negative breast cancers Rudolph et al, 2003), high cyclin B1 expression associated with high grade, high Ki67, cyclin A and E expression, and ER and progesterone receptor (PR) negativity and predicted relapse-free and overall survival in univariate analysis but was not an independent prognostic factor in multivariate analysis including Ki67 as a covariate . Among the 273 tumours treated with surgery and postoperative radiation only, cyclin B1 was an independent predictor of poor overall survival among premenopausal but not postmenopausal or all patients .…”

Cyclin A as a marker for prognosis and chemotherapy response in advanced breast cancer

“…We used a cutoff value of 10.5% for the high and low cyclin A positivity groups. This is in line with three other studies, where median values varying between 8 and 11% have been used (Michalides et al, 2002;Michels et al, 2002;Kuhling et al, 2003;Rudolph et al, 2003). In the fourth study, four different categories were used for cyclin A positivity and the median category was between 15 and 30% (Bukholm et al, 2001).…”

“…A fourth study, however, in node-negative patients showed no correlation between cyclin A and prognosis Rudolph et al, 2003). Several studies have revealed an association between a high proliferation index measured by other means and favourable chemotherapy response.…”

“…Cyclin A is essential in the S phase for DNA replication, it is also involved in G2 -M-phase transition (Zindy et al, 1992;Fan and Bertino, 1997), and is therefore one of the most useful markers signifying proliferating cells. Overexpression of cyclin A has been associated with worse prognosis for breast cancer in several studies (Bukholm et al, 2001;Michalides et al, 2002;Michels et al, 2002), but the results have not been consistent Rudolph et al, 2003). Since the lack of prognostic significance of cyclin A is mainly seen in patients with lymph node-negative breast cancer, it is possible that cyclin A plays a more important role in aggressive tumours and metastatic disease .…”