Molecular Subtype Conversion between Primary and Metastatic Breast Cancer Corresponding to the Dynamics of Apoptotic and Intact Circulating Tumor Cells

The presence of circulating tumor cells (CTCs), detected as a form of liquid biopsy is associated with poor survival in both early and metastatic breast cancer. Monitoring tumor biology based on intrinsic subtypes delivers treatment-relevant information on the heterogeneity or biomarker conversion between primary and metastatic tumors. This study aimed to correlate the change of the apoptotic and intact CTC counts with mRNA-assessed intrinsic subtype change. Thirty-four breast cancer patients with available triplets of primary tumors, distant metastasis biopsies and data on intact and apoptotic CTC dynamics were included in the analysis. The intrinsic subtype was determined per RT-qPCR quantification of the gene expression ESR1, PGR, ERBB2 and MKI67. Both luminal (p = 0.038) and triple negative (p = 0.035) patients showed a significant downregulation of apoptotic CTCs. Repeated biopsies of distant metastatic sites, as well as determining a potential shift of the intrinsic subtype, combined with data on intact and apoptotic CTC dynamics from liquid biopsies might help personalize systemic therapy and generate additional surrogate markers for successful systemic therapy.

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The Efficacy of Lapatinib in Metastatic Breast Cancer with HER2 Non-Amplified Primary Tumors and EGFR Positive Circulating Tumor Cells: A Proof-Of-Concept Study

PLoS ONE ◽

10.1371/journal.pone.0062543 ◽

2013 ◽

Vol 8 (5) ◽

pp. e62543 ◽

Cited By ~ 24

Author(s):

Justin Stebbing ◽

Rachel Payne ◽

Justine Reise ◽

Adam E. Frampton ◽

Miranda Avery ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Metastatic Breast ◽

Proof Of Concept ◽

Primary Tumors ◽

Concept Study

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Molecular characterization of circulating tumor cells from patients with metastatic breast cancer reflects evolutionary changes in gene expression under the pressure of systemic therapy

Oncotarget ◽

10.18632/oncotarget.17271 ◽

2017 ◽

Vol 8 (28) ◽

pp. 45544-45565 ◽

Cited By ~ 12

Author(s):

Kristina E. Aaltonen ◽

Vendula Novosadová ◽

Pär-Ola Bendahl ◽

Cecilia Graffman ◽

Anna-Maria Larsson ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Metastatic Breast Cancer ◽

Tumor Cells ◽

Molecular Characterization ◽

Circulating Tumor Cells ◽

Systemic Therapy ◽

Metastatic Breast ◽

Evolutionary Changes

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Gene expression profiles of circulating tumor cells versus primary tumors in metastatic breast cancer

Cancer Letters ◽

10.1016/j.canlet.2015.03.020 ◽

2015 ◽

Vol 362 (1) ◽

pp. 36-44 ◽

Cited By ~ 29

Author(s):

Wendy Onstenk ◽

Anieta M. Sieuwerts ◽

Marleen Weekhout ◽

Bianca Mostert ◽

Esther A. Reijm ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Metastatic Breast Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Metastatic Breast ◽

Primary Tumors

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Impact of mRNA-Assessed Molecular Subtype Conversion, Intact and Apoptotic Circulating Tumor Cells on Survival of Metastatic Breast Cancer Patients: Proof of Principle

Diagnostics ◽

10.3390/diagnostics10060369 ◽

2020 ◽

Vol 10 (6) ◽

pp. 369

Author(s):

Stefan Stefanovic ◽

Thomas M. Deutsch ◽

Ralph Wirtz ◽

Andreas Hartkopf ◽

Peter Sinn ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Metastatic Breast Cancer ◽

Triple Negative ◽

Molecular Subtype ◽

Metastatic Breast ◽

Intrinsic Subtype ◽

Breast Cancer Patients ◽

Liquid Biopsies ◽

Primary Tumors

Breast cancers (BC) can mutate, allowing metastatic tumors (MT) to sometimes differ to primary tumors (PT) in gene expression. Despite contemporary metastatic breast cancer (MBC) therapy, subtype conversion seems prognostically disadvantageous. We strived to determine the influence of mRNA-assessed intrinsic subtype stability comparing PT and MT biopsies and circulating tumor cell (CTC)-based liquid biopsies on progression free survival (PFS) and overall survival (OS). Additional analyzed prognostic factors were PT subtype, MT subtype and hormone receptor loss. Kaplan-Meier curves and the log rank tests were used to compare PFSs and OSs. The proportions of luminal B and triple negative subtype MTs were increased compared to those observed in PTs. Fifteen patients were found to have tumors that underwent intrinsic subtype conversion and their OS was significantly decreased (p = 0.038). No such difference was observed when it comes to PFS. The majority of these tumors switched to a more aggressive intrinsic subtype. No significant differences in PFSs or OSs were observed between subtype converters with triple negative PTs compared to those with luminal subtype PTs. The same is true of subtype stable patients. Total CTC, iCTC and aCTC counts decreased with therapy, but there were no significant differences between subtype converters and subtype stable patients. Our data confirm a poorer overall survival of the intrinsic subtype converters and emphasize the importance of acquiring biopsies and re-biopsies of all available metastatic lesions alongside with CTC-based liquid biopsies for earlier recognition of patients with poorer prognosis and in need of altered individualized therapy regimens.

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