The molecular mechanisms underlying the development of bone metastases in breast cancer remain unclear. Disseminated tumour cells (DTCs) in the bone marrow of breast cancer patients are commonly identified, even in early stage disease, but their potential to initiate metastases is not known. The mechanism whereby DTCs become overt metastatic tumour cells (MTCs) is therefore, an area of considerable interest. This study explored the analysable yield of genetic material from human biopsy samples in order to describe differences in gene expression between DTCs and bone MTCs. Thirteen breast cancer patients with bone metastases underwent a CT-guided bone metastasis biopsy and a bone marrow biopsy. Tumour cells were enriched and gene expression profiling was conducted to identify differentially expressed genes. The analysable yield of sufficient RNA for microarray analysis was 60% from bone metastasis biopsies and 80% from bone marrow biopsies. A signature of 133 candidate genes differentially expressed between DTCs and MTCs was identified. Several genes relevant to breast cancer metastasis to bone (osteopontin, CTGF, parathyroid hormone receptor, EGFR) were significantly overexpressed in MTCs as compared to DTCs. Biopsies of bone metastases and bone marrow rarely yield enough tissue for robust molecular biology studies using clinical samples. The findings obtained however are interesting and seem to overlap with the bone metastasis gene expression signature described in murine xenograft models. Larger biopsy specimens or improved RNA extraction techniques may improve analysable yield and feasibility of these techniques.
Purpose: Decisions about systemic treatment of women with metastatic breast cancer are often based on estrogen receptor (ER), progesterone receptor (PgR), and HER2/neu status of the primary tumour. This study prospectively investigated concordance in receptor status between primary tumour and distant metastases at various stages of progression and assessed the impact of any discordance on patient management.Methods: Biopsies of suspected metastatic lesions were obtained from patients and analyzed for ER/PgR and HER2/neu. Receptor status of metastases was compared to the primary tumour. The treating physician completed questionnaires before and after biopsy to determine whether the biopsy result lead to a change in treatment plan.Results: One hundred and sixteen women were enrolled and 102 underwent biopsy. Of these 52 (51%) were newly diagnosed with metastatic disease, 17 (17%) had received one line of metastatic treatment and 35 (34%) had received 2 or more lines of treatment in the metastatic setting. 86/102 (84%) of samples were sufficient analysis; of these 5/86 biopsies (6%) showed benign disease and one biopsy (1%) confirmed a different malignancy (indolent lymphoma). Changes in hormone receptor status were observed in 33%. Among these, ER discordance was seen in 11%, PgR discordance in 27% and discordance in both ER and PgR in 5%. Loss of PgR was the most common change in hormone receptor status (25%). HER2/neu showed 4% discordance. Three patients (3%) gained and one patient (1%) lost HER2/neu expression. Biopsy results led to a change of management in 12% of patients. Patients with newly diagnosed metastatic disease were more likely to show discordance than those previously treated in the metastatic setting. Among triple negative primary tumours, no changes in receptor expression of metastases were seen.Conclusions: This is the largest prospective biopsy study we are aware of. Results demonstrate the presence of substantial discordance in receptor status between primary tumour and metastases. The number needed to biopsy to alter immediate management was 8.5, although biopsy information could also be useful in planning subsequent treatments. Tissue confirmation should therefore, be considered in all patients with suspicion of metastatic recurrence or progression. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2023.
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