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Unexpected outcomes in breast cancer demand a refinement of prognostic criteria. This study therefore investigated the prognostic relevance of cyclin expression in a cohort of 332 T1-T2 N0 infiltrating ductal carcinomas with long-term follow-up (median 99 months). By univariate analysis, tumour size, histopathological grade, hormone receptor content, cyclin E, cyclin B, and the Ki-S5 (Ki-67) index significantly predicted disease-specific and metastasis-free survival. Cyclin A did not achieve statistical significance. In a multivariate analysis, both cyclin E [relative risk (RR) 2.01, p = 0.021] and cyclin B (RR 1.85, p = 0.033) were selected as independent prognosticators of metastasis-free survival when the Ki-67 index was omitted, but only cyclin E expression was associated with disease-specific survival (RR 2.56, p = 0.006). When Ki-67 was included as a covariate, cyclin E lost its significance with respect to disease-specific survival but remained significant for metastasis-free survival. In an analogous analysis including Ki-67, the number of concurrently overexpressed cyclins did not attain statistical significance regarding disease-specific survival but was selected as the leading predictor of metastatic disease. It is concluded that combined overexpression of cyclins may imply genetic instability enhancing metastatic potential, but that survival ultimately depends on the proliferative activity of tumour cells.

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.

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Cellular proliferation is a major determinant of the biologic behavior of breast cancer. Prognosis is apparently best indicated by the percentage of cells in S through M phases of the cell cycle. Measurement of the Ki-S2 labeling index of a tumor sample may improve a clinician's ability to make an accurate prognosis and to identify patients with a low risk of recurrence who may not need adjuvant therapy.

Maspin is an inhibitor of serine proteinases with tumour suppressor activity. Its expression appears to be reduced in advanced stages of breast cancer. A large series of archival breast tissue specimens has been examined, including normal glands (n=7), fibrocystic change (n=22), ductal carcinoma in situ (DCIS, n=12), infiltrating carcinomas (n=128) and their lymph node metastases (n=65), using a specific monoclonal antibody. Myoepithelium invariably showed strong maspin expression. In epithelial cells, the strongest expression was found in normal breast and fibrocystic change. A significant stepwise decrease in maspin expression (p<0.0001) occurred in the sequence DCIS - invasive cancer - lymph node metastasis. However, a subset of infiltrating carcinomas showed strong maspin expression, significantly associated with a lower rate of lymph node metastasis at the time of diagnosis (p<0.01). This was independent of tumour size and grade. The in vivo observations presented here are in keeping with data obtained in prior in vitro experiments. Maspin emerges as an indicator of tumour progression and metastatic potential, and might be exploited to predict breast cancer prognosis. According to in vitro data, its tumour suppressor activity is likely to involve both the modulation of cell motility/invasiveness and the inhibition of angiogenesis.

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