Artikel
Her2/neu expression on disseminated tumor cells in the bone marrow and on the primary tumor – an insight into tumor biology
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Veröffentlicht: | 20. März 2006 |
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Gliederung
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Background: While the prognostic impact of disseminated tumor cells in bone marrow (DTC) at primary diagnosis of breast cancer has reached LOE I (Braun et al., NEJM 2005), there is also growing evidence that the presence of DTC during follow-up indicates an increased risk for subsequent recurrence (Janni, Cancer 2005). Therefore, DTC might proof as potential target for tailored treatment options in these patients. Aim of this study was to establish a new method to analyse cytokeratin-positive (CK+) cells for her2/neu gene amplification.
Methods: DTC were detected using a standardized immunoassay with monoclonal antibody A45-B/B3, directed against cytokeratin 8,18,19 (CK) and stained according to the APAAP-technique. 2 x 106 cells per patient were screened by bright field microscopy. Subsequently, cytospins with CK-positive cells were further characterized by fluorescence in situ hybridisation (FISH) using a her2/neu DNA probe (Zymed, Germany) or a multi-colour probe (Vysis,Il., USA) for hybridisation of centromer 17 (polyploidy) and the her2/neu growth factor gene. A ratio of her2/neu and centromer chr. 17 signals of at least two was regarded as amplification.
Results: 232 bone marrow aspirates of 156 patients with breast cancer were analyzed at the time of primary diagnosis and during follow-up. DTC were detected in 68 samples (29%) in this patient group. The median number of detected cells was 2 (range 1 – 58). In 45 randomly assigned aspirates with DTC, the her2/neu status on these cells was evaluated and 13 samples were diagnosed with her2/neu amplification on DTC (29%). In 41 cases, both the her2/neu status of the primary tumor and on CK+ cells was available. In comparison, in 31 cases (76%) her2/neu status on the primary tumor corresponded to the her2/neu status on DTC. 7 patients (17%), however, with her2/neu overexpression or amplification on the primary tumor showed her2/neu negative DTC, whereas in 3 patients (7%) with her2/neu negative tumors we found DTC with her2/neu amplification.
Conclusion: In a relevant subgroup of patients, heterogeneity of antigen expression results in a discrepancy of her2/neu status between the primary tumor and DTC in the bone marrow. Therefore, the amplification of her2/neu on persisting DTC may proof useful to stratify patients for tailored treatment strategies. Ongoing clinical trials are evaluating the effect of trastuzumab in these patients.
Figure1 [Fig. 1]