Abstract
Resistance to systemic therapy is a major problem in metastatic breast cancer (MBC) that can be explained by initial tumor heterogeneity as well as by evolutionary changes during therapy and tumor progression. Circulating tumor cells (CTCs) detected in a liquid biopsy can be sampled and characterized repeatedly during therapy in order to monitor treatment response and disease progression.Our aim was to investigate how CTC derived gene expression of treatment predictive markers (ESR1/HER2) and other cancer associated markers changed in patient blood samples during six months of first-line systemic treatment for MBC. CTCs from 36 patients were enriched using CellSearch (Janssen Diagnostics) and AdnaTest (QIAGEN) before gene expression analysis was performed with a customized gene panel (TATAA Biocenter).Our results show that antibodies against HER2 and EGFR were valuable to isolate CTCs unidentified by CellSearch and possibly lacking EpCAM expression. Evaluation of patients with clinically different breast cancer subgroups demonstrated that gene expression of treatment predictive markers changed over time. This change was especially prominent for HER2 expression.In conclusion, we found that changed gene expression during first-line systemic therapy for MBC could be a possible explanation for treatment resistance. Characterization of CTCs at several time-points during therapy could be informative for treatment selection.
Highlights
Tumor heterogeneity poses a large problem for therapeutic strategies in patients with metastatic breast cancer (MBC)
We found that only a subset of patients with clinically diagnosed HR+ breast cancer expressed Estrogen receptor 1 (ESR1) in Circulating tumor cells (CTCs) and ESR1 expression was in all cases absent after initiation of endocrine treatment or chemotherapy
This is in line with previous studies that have reported a low level of Estrogen receptor (ER)/ESR1 expression in CTCs compared with the primary tumor in MBC [29, 30, 48, 49]
Summary
Tumor heterogeneity poses a large problem for therapeutic strategies in patients with metastatic breast cancer (MBC). Sub-clonal tumor cell populations from the primary tumor or early spread cancer cells are not always eradicated by the selected therapies and these cells might continue to proliferate and metastasize. Circulating tumor cells (CTCs) found in the blood during therapy are possible representatives of these treatment resistant sub-clonal cell populations and provide an opportunity to study the characteristics of minimal residual disease by a simple blood sample – a liquid biopsy. It is possible that new and combined treatment strategies can be used to avoid development of resistance and thereby prolong patient survival [3]
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