Clonality of circulating tumor cells in breast cancer brain metastasis patients
Creators
- Riebensahm, Carlotta1
- Joosse, Simon A.1
- Mohme, Malte2
- Hanssen, Annkathrin1
- Matschke, Jakob3
- Goy, Yvonne4
- Witzel, Isabell5
- Lamszus, Katrin2
- Kropidlowski, Jolanthe1
- Petersen, Cordula4
- Kolb-Kokocinski, Anja6
- Sauer, Sascha7
- Borgmann, Kerstin8
- Glatzel, Markus3
- Müller, Volkmar5
- Westphal, Manfred2
- Riethdorf, Sabine1
- Pantel, Klaus1
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Wikman, Harriet1
- 1. Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- 2. Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- 3. Department of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- 4. Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- 5. Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- 6. Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
- 7. Max Delbrück Center for Molecular Medicine (BIMSB and BIH), Berlin, Germany
- 8. Laboratory of Radiobiology and Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Description
Background: The incidence of brain metastases in breast cancer (BCBM) patients is increasing. These patients have a very poor prognosis, and therefore, identification of blood-based biomarkers, such as circulating tumor cells (CTCs), and understanding the genomic heterogeneity could help to personalize treatment options.
Methods: Both EpCAM-dependent (CellSearch® System) and EpCAM-independent Ficoll-based density centrifugation methods were used to detect CTCs from 57 BCBM patients. DNA from individual CTCs and corresponding primary tumors and brain metastases were analyzed by next-generation sequencing (NGS) in order to evaluate copy number aberrations and single nucleotide variations (SNVs).
Results: CTCs were detected after EpCAM-dependent enrichment in 47.7% of the patients (≥ 5 CTCs/7.5 ml blood in 20.5%). The CTC count was associated with ERBB2 status (p = 0.029) of the primary tumor as well as with the prevalence of bone metastases (p = 0.021). EpCAM-independent enrichment revealed CTCs in 32.6% of the patients, especially among triple-negative breast cancer (TNBC) patients (70.0%). A positive CTC status after enrichment of either method was significantly associated with decreased overall survival time (p < 0.05). Combining the results of both enrichment methods, 63.6% of the patients were classified as CTC positive. In three patients, the matched tumor tissue and single CTCs were analyzed by NGS showing chromosomal aberrations with a high genomic clonality and mutations in pathways potentially important in brain metastasis formation.
Conclusion: The detection of CTCs, regardless of the enrichment method, is of prognostic relevance in BCBM patients and in combination with molecular analysis of CTCs can help defining patients with higher risk of early relapse and suitability for targeted treatment.