The HER2 phenotype of circulating tumor cells in HER2-positive early breast cancer: A translational research project of a prospective randomized phase III trial

B A S Jaeger, J Neugebauer, U Andergassen, C Melcher, F Schochter, D Mouarrawy, G Ziemendorff, M Clemens, E V Abel, G Heinrich, K Schueller, A Schneeweiss, P Fasching, M W Beckmann, Ch Scholz, T W P Friedl, K Friese, K Pantel, T Fehm, W Janni, B Rack, B A S Jaeger, J Neugebauer, U Andergassen, C Melcher, F Schochter, D Mouarrawy, G Ziemendorff, M Clemens, E V Abel, G Heinrich, K Schueller, A Schneeweiss, P Fasching, M W Beckmann, Ch Scholz, T W P Friedl, K Friese, K Pantel, T Fehm, W Janni, B Rack

Abstract

Background: HER2 is one of the predominant therapeutic targets in breast cancer. The metastatic selection process may lead to discrepancies between the HER2 status of the primary tumor and circulating tumor cells (CTCs). This study analyzed the HER2 status of CTCs in patients with HER2-positive primary breast cancer at the time of diagnosis. Aim of the study was to assess potential discordance of HER2 status between primary tumor and CTCs, as this may have important implications for the use of HER2-targeted therapy.

Methods: The number and HER2 status of CTCs out of 30ml peripheral blood were assessed in 642 patients using the CellSearch System (Janssen Diagnostics, USA). The cutoff for CTC positivity was the presence of at least 1 CTC, and the cutoff for HER2 positivity of CTCs was the presence of at least 1 CTC with a strong HER2 staining.

Results: 258 (40.2%) of the 642 patients were positive for CTCs (median 2; range 1-1,689). 149 (57.8%) of these 258 patients had at least 1 CTC with strong HER2 staining. The presence of HER2-positive CTCs was not associated with tumor size (p = 0.335), histopathological grading (p = 0.976), hormone receptor status (ER: p = 0.626, PR: p = 0.263) or axillary lymph node involvement (p = 0.430). Overall, 83 (32.2%) of the CTC-positive patients exclusively had CTCs with strong HER2 staining, whereas 31 (12.0%) had only CTCs with negative HER2 staining. Within-sample variation in the HER2 status of CTCs was found in 86 (57.8%) of the 149 patients with more than 1 CTC.

Conclusion: This study demonstrated that discordance between the HER2 expression of CTCs and that of the primary tumor frequently occurs in early breast cancer. Future follow-up evaluation will assess whether this discrepancy may contribute to trastuzumab resistance.

Conflict of interest statement

Competing Interests: I have read the journal's policy and the authors of this manuscript have the following financial relationships: Sanofi Aventis (WJ, BR), Lilly (WJ, BR), Chugai (WJ, BR), Novartis (WJ, BR), Roche (WJ, BR) and Janssen Diagnostics (WJ, BR). The competing interests of some authors do not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Flow chart illustrating study flow…
Fig 1. Flow chart illustrating study flow and patient selection.
Fig 2. The distribution of samples (n…
Fig 2. The distribution of samples (n = 642) according to CTC status and the highest HER2 staining intensity of CTCs in the samples.
Fig 3. The prevalence of HER2-positive CTCs…
Fig 3. The prevalence of HER2-positive CTCs (i.e., CTCs with strong HER2 staining) in relation to the number of CTCs detected in the blood samples (n = 258).
Fig 4. The frequency and percentage (out…
Fig 4. The frequency and percentage (out of 258 CTC-positive samples) of samples with selected characteristics regarding the HER2 status of CTCs.

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