Isolated tumor cells in the bone marrow (ITC-BM) of breast cancer patients before and after anthracyclin based therapy: influenced by the HER2- and Topoisomerase IIα-status of the primary tumor?
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Purpose: The presence of isolated tumor cells in the bone marrow (ITC-BM) is an independent prognostic factor in all stages of breast cancer. Both the expression/amplification of human epithelial growth factor receptor 2 (HER2) and Topoisomerase IIα (TOP IIa), a key enzyme of DNA replication and main target of anthracyclins, in breast cancer tissue seem to have predictive value regarding the effectiveness of systemic therapies. Methods: To investigate the correlation between these factors and their influence on clinical outcome, tumor tissue of 54 patients who were screened for ITC-BM before and after anthracyclin-based chemotherapy (abCTX) was examined for HER2 and TOP IIa by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Results: By IHC, 31% of the tumors showed positive for HER2 (2+/3+), 14.6% were amplified in FISH. TOP IIa expression (>50%) was found in 13/53 patients (25%), FISH was positive in 5/47 cases (11%). TOP IIa amplification was not seen in cases without HER2 amplification, five of the seven HER2 amplified cases also were amplified for TOP IIa (71% co-amplification). Forty-three patients had adjuvant, seven neo-adjuvant, four palliative abCTX. ITC-BM were present in 24% of patients before and 31% after CTX. Patients with HER2 (IHC, P=0.29) and TOP IIa (FISH, P=0.16) positive tumors tended to stay or become negative in BM status after abCTX and vice versa. After a median follow-up of 44 months (6–127), none of the factors reached significance for overall survival. Yet, patients with HER2 (P=0.16) and TOP IIa (P=0.09) positive tumors showed a trend towards prolonged disease-free survival. Remarkably, none of the TOP IIa FISH-positive patients developed distant metastases (P=0.099) or died (P=0.19) after CTX so far. Conclusions: HER2- and TOP IIa positivity seem to improve the effect of abCTX. The combination of the prognostic value of ITC-BM and the predictive capacity of HER2 and TOP IIa could help to stratify patients for certain therapies. The direct examination of those factors on ITC-BM is the focus of ongoing studies.
KeywordsBreast cancer Isolated tumor cells Bone marrow Minimal residual disease Her2 Topoisomerase Anthracyclin Chemotherapy Prognosis
Alkaline phosphatase anti-alkaline phosphatase technique
- CEP 17
Centromer enumeration probe chromosome 17
Distant disease-free survival
Fluorescence in situ hybridization
Human epithelial growth factor receptor 2
Isolated tumor cells
- Top IIa
We thank Mrs. S. Schulze for excellent technical assistance. This study contains materials analyzed by Mrs. Anke Kornmeier in preparation of her thesis to achieve the degree of MD at Ludwig-Maximilians University, Medical Faculty, in Munich, Germany.
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