Disseminated tumor cells as selection marker and monitoring tool for secondary adjuvant treatment in early breast cancer. Descriptive results from an intervention study

1030 Background: Detection of disseminated tumor cells (DTC) in the bone marrow (BM) of early breast cancer (EBC) patients before the administration of systemic therapy is associated with poor outcome. The aim of this study was to evaluate the impact of DTC on overall survival (OS) and disease free survival (DFS) in a large cohort of EBC patients after the administration of systemic therapy. Methods: EBC patients receiving systemic therapy (endocrine therapy and/or chemotherapy +/- HER2-directed treatment) either prior to surgery (neoadjuvant systemic therapy, NST) or after surgery (adjuvant systemic therapy, AST) at Tuebingen University Hospital, Germany between 01/2003 and 06/2012 were available for this analysis. BM aspirates were collected during surgery / one year after surgery in patients receiving NST / AST. DTC were identified by immunocytochemistry (pancytokeratin antibody A45/B3) and cytomorphology. Survival was analyzed using univariate (log-rank test) and multivariate analysis (cox regression). Results: DTC were detected in 201 of 608 (35%) patients. 175 of 419 (42%) patients treated with NST and 35 of 189 (19%) patients treated with AST were DTC-positive. Chemotherapy / endocrine therapy was administered prior to BM aspiration in 399 (96%) / 19 (5%) of the patients receiving NST and in 99 (52%) / 158 (84%) of the patients receiving AST. On univariate analysis, the detection of DTC was a significant predictor of poor DFS (HR: 2.27, 95% CI: 1.48 – 3.48, p<0.001) and poor OS (HR: 1.89, 95% CI: 1.19 – 3.00, p=0.007). On multivariate analysis (considering all clinicopathological factors and the DTC-status), independent factors for DFS were DTC-status (negative vs. positive), grading (G2-3 vs. G3), nodal-status (negative vs. positive), and the ER-status (negative vs. positive). Independent factors for OS were grading, PR-status (negative vs. positive) and nodal-status. Conclusions: The persistence of DTC in the BM of EBC patients after systemic treatment is a strong and independent marker of poor prognosis. Determination of the DTC-status is thus promising to monitor the effect of systemic therapy and to identify patients that are in need of additional adjuvant therapy.

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Clinical Outcome With Correlation to Disseminated Tumor Cell (DTC) Status After DTC-Guided Secondary Adjuvant Treatment With Docetaxel in Early Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2014.56.9327 ◽

2014 ◽

Vol 32 (34) ◽

pp. 3848-3857 ◽

Cited By ~ 38

Author(s):

Bjørn Naume ◽

Marit Synnestvedt ◽

Ragnhild Sørum Falk ◽

Gro Wiedswang ◽

Kjetil Weyde ◽

...

Keyword(s):

Breast Cancer ◽

Early Breast Cancer ◽

Adjuvant Treatment ◽

Cox Regression ◽

Surrogate Marker ◽

Disseminated Tumor Cells ◽

Rank Test ◽

Cox Regression Analysis ◽

Risk Patients

Purpose The presence of disseminated tumor cells (DTCs) in bone marrow (BM) predicts survival in early breast cancer. This study explores the use of DTCs for identification of patients insufficiently treated with adjuvant therapy so they can be offered secondary adjuvant treatment and the subsequent surrogate marker potential of DTCs for outcome determination. Patients and Methods Patients with early breast cancer who had completed six cycles of adjuvant fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapy underwent BM aspiration 2 to 3 months (BM1) and 8 to 9 months (BM2) after FEC. Presence of DTCs in BM was determined by immunocytochemistry using pan-cytokeratin monoclonal antibodies. If one or more DTCs were present at BM2, six cycles of docetaxel (100 mg/m2, once every 3 weeks) were administered, followed by DTC analysis 1 and 13 months after the last docetaxel infusion (after treatment). Cox regression analysis was used to evaluate disease-free interval (DFI). Results Of 1,066 patients with a DTC result at BM2 and available follow-up information (median follow-up, 71.9 months from the time of BM2), 7.2% were DTC positive. Of 72 docetaxel-treated patients analyzed for DTCs after treatment, 15 (20.8%) had persistent DTCs. Patients with remaining DTCs had markedly reduced DFI (46.7% experienced relapse) compared with patients with no DTCs after treatment (adjusted hazard ratio, 7.58; 95% CI, 2.3 to 24.7). The docetaxel-treated patients with no DTCs after treatment had comparable DFI (8.8% experienced relapse) compared with those with no DTCs both at BM1 and BM2 (12.7% experienced relapse; P = .377, log-rank test). Conclusion DTC status identifies high-risk patients after FEC chemotherapy, and DTC monitoring status after secondary treatment with docetaxel correlated strongly with survival. This emphasizes the potential for DTC analysis as a surrogate marker for adjuvant treatment effect in breast cancer.

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