Presence of Apoptotic and Non Apoptotic Disseminated Tumor Cells Reflect Response to Neoadjuvant Systemic Therapy (NST) in Breast Cancer

Tanja Fehm; Sven Becker; Graziella Becker-Pergola; Karl Sotlar; Gerhard Gebauer; Silke Dürr-Störzer; Hans Neubauer; Diethelm Wallwiener; Erich-Franz Solomayer


Breast Cancer Res. 2006;8(5) 

In This Article

Abstract and Introduction


Introduction: Neoadjuvant systemic therapy (NST) is an established strategy to reduce tumor size in breast cancer patients prior to breast-conserving therapy. The effect of NST on tumor cell dissemination in these patients is not known. The aim of this study was to investigate the incidence of disseminated tumor cells (DTC), including apoptotic DTC, in breast cancer patients after NST, and to investigate the correlation of DTC status with therapy response.
Methods: Bone marrow aspiration was performed in 157 patients after NST. DTC were detected by immunocytochemistry using the A45--B/B3 anticytokeratin antibody. To detect apoptotic DTC the antibody M30 (Roche Diagnostics, Germany) was used, which detects a neo-epitope expressed only after caspase cleavage of cytokeratin 18 during early apoptosis.
Results: The incidence of DTC in breast cancer patients was 53% after completion of NST. Tumor dissemination was observed more frequently in patients with no change/progressive disease (69%) than in patients with partial remission or complete remission of the primary tumor (46%) (P < 0.05). Ten out of 24 patients with complete remission, however, were still bone marrow positive. Apoptotic DTC were present in 36 of 157 (23%) breast cancer patients. Apoptotic cells only were detected in 14% of the patients with partial remission or complete remission, but were detected in just 5% of the patients with stable disease. Apoptotic DTC were detectable in none of the patients with tumor progression.
Conclusion: The pathological therapy response in breast cancer patients is reflected by the presence of apoptotic DTC. Patients with complete remission, however, may still have nonapoptotic DTC. These patients may also benefit from secondary adjuvant therapy.


Neoadjuvant systemic therapy (NST) has become the standard treatment for locally advanced breast cancer. The major aim of systemic therapy in these patients is to facilitate breast-conserving surgery. In recent years NST has also been offered to patients with smaller tumors who were expected to receive systemic therapy, since NST offers the possibility for in vivo chemosensitivity testing.[1,2,3,4] Moreover, prognostic information can be obtained based on the pathologic response to chemotherapy. Patients with complete remission of the primary tumor have a better clinical outcome compared with those with partial remission or compared with nonresponders .[5,6]

Local therapy response is normally assessed by palpation and imaging techniques including ultrasound and mammography. The efficacy of neoadjuvant treatment on disseminated tumor cells (DTC) is assumed to be correlated to local therapy response. Complete remission is considered a surrogate marker for complete eradication of micrometastatic disease. However, 13--25% of patients with pathological complete response develop metastatic disease over 5 years.[1,5,6,7,8]

Eradication of a minimal residual disease may be monitored by serial bone marrow analysis during NST, offering new insights into the effects of systemic therapy on minimal residual disease. DTC can be detected in 30--40% of untreated primary breast cancer patients prior to surgery.[9,10,11,12] Tumor cell persistence after removal of the primary tumor and adjuvant chemotherapy has been suggested to indicate chemotherapy resistance and poor clinical outcome.[13,14,15] The efficacy of neoadjuvant chemotherapy may therefore be indicated by bone marrow negativity or by the presence of disseminated apoptotic cells that were susceptible to cytotoxic agents.

The main focus of this study was to investigate the incidence of DTC, including apoptotic DTC, in patients with breast cancer after primary chemotherapy, and to investigate the correlation of the DTC status with pathological therapy response.


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