The present study aimed to investigate the clinical relevance of disseminated tumor cells (DTC) in breast cancer patients before and after high-dose adjuvant chemotherapy with or without progenitor stem-cell support. One hundred and eighteen high-risk stage II breast cancer patients entering the Scandinavian Study Group multicenter trial were randomized to 9 cycles of tailored and dose-escalated FEC (5-flurouracil, epirubicin, cyclophosphamide) or 3 cycles of standard FEC followed by high-dose chemotherapy. Bone marrow (BM) samples at diagnosis and 6 months after completion of chemotherapy were assessed for the presence of cytokeratin positive (CK1) cells. Before treatment, 29% of the patients were CK1 (21% in the dose-escalated group and 36% in the high-dose-group). Six months after treatment, 17% of the patients were CK1 (17 and 16% respectively). Of the 95 patients who were evaluated 6 months after treatment, 60% were consistently CK2. CK1 cells in BM was evaluated as a prognostic and predictive marker and compared to other defined prognostic factors of the primary tumor. Monitoring BM changes at the time of diagnosis and 6 months posttreatment is an independent predictive factor for breast-cancer-specific survival (BCS) (p 5 0.001). Those who have consistent CK negative (2) BM findings constitute a group of patients with good prognosis. Our results suggest that changes in CK1 cells in BM before and after chemotherapy can be used clinically as a surrogate maker to predict outcome in breast cancer patients. ' 2005 Wiley-Liss, Inc.Key words: disseminated tumor cells; high-dose chemotherapy; prediction High-dose chemotherapy with stem-cell support has been studied in breast cancer patients with both metastatic and earlystage, high-risk disease. Phase II studies 1,2 suggested that the outcome of patients treated with high-dose therapy was superior to standard-dose chemotherapy. To confirm these results, several large randomized studies have been conducted. Even if a longer follow-up is required until final conclusions can be drawn, the results reported show that progenitor stem-cell-supported highdose therapy does not appear to be sufficient as tumor reductive therapy. [3][4][5] Several breast cancer studies 6,7 have shown a significant association between the detection of tumor cells in the BM, both at diagnosis and in follow-up, and increased risk of systemic relapse. Both Braun et al. 8 and Wiedswang et al. 9 reported that presence of cytokeratin (CK) staining cells in the BM after adjuvant conventional chemotherapy of breast cancer patients was associated with distant metastases and cancer-related death.The Scandinavian Breast Cancer Group (9401 protocol) published their first results of a randomized adjuvant study in highrisk breast cancer in year 2000. 4 Patients treated with 9 cycles of tailored and dose-escalated high-dose FEC with granulocyte colony-stimulating factor (G-CSF) support had significantly fewer breast cancer relapses compared with those treated with 3 cycles of FEC plus cyclophosphamide, ...
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