Immunologic proliferation marker Ki-S2 as prognostic indicator for lymph node-negative breast cancer

Background: Proper treatment of lymph node-negative breast cancer depends o n an accurate prognosis. To improve prognostic models for this disease, we evaluated whether an immunohistochemical marker for proliferating cells, Ki -S2 (a monoclonal antibody that binds to a 100-kd nuclear protein expressed in S, G(2), and M phases of the cell cycle), is an accurate indicator of p rognosis. Methods: We studied 371 Swedish women with lymph node-negative br east cancer; the median follow-up time was 95 months. The fraction of tumor cells in S phase was assessed by flow cytometry, and tumor cell proliferat ion was measured immunohistochemically with the monoclonal antibodies Ki-S2 and Ki-S5 (directed against the nuclear antigen Ki-67), A combined prognos tic index was calculated on the basis of the S-phase fraction, progesterone receptor content, and tumor size. Results: In multivariate analyses that d id or did not (263 and 332 observations, respectively) include the S-phase fraction and the combined prognostic index, the Ki-S2 labeling index (perce ntage of antibody-stained tumor cell nuclei) emerged as the most statistica lly significant predictor of overall survival, disease-specific survival, a nd disease-free survival (all two-sided P<.0001). In the risk group defined by a Ki-S2 labeling index of 10% or less, life expectancy was not statisti cally significantly different from that of age-matched women without breast cancer, whereas the group with a high Ki-S2 labeling index had an increase d risk of mortality of up to 20-fold. Conclusions: Cellular proliferation i s a major determinant of the biologic behavior of breast cancer. Prognosis is apparently best indicated by the percentage of cells in S through M phas es of the cell cycle. Measurement of the Ki-S2 labeling index of a tumor sa mple 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.