Comparison of HER2 Expression in Primary Tumor and Disseminated Tumor Cells in the Bone Marrow of Breast Cancer Patients

Rack, Brigitte; Zombirt, E; Trapp, Elisabeth; Jückstöck, Julia; Andergassen, Ulrich; J, Neugebauer; Kost, Bernd; Weißenbacher, Tobias; Jeschke, Udo; Scheffold, Christian; Janni, Wolfgang; Alunni-Fabbroni, Marianna

doi:10.1159/000442986

Cited by 17 publications

(16 citation statements)

References 51 publications

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“…We observed high discordance between ESR1 (40%) and ERRB2 (43%) status in DTCs vs. the clinical ER and HER2 status of the corresponding primary tumors, suggesting plasticity of biomarker status over the course of the disease. 61 Previous studies have also shown discordance in ER (28% 62 ; 53% 63 ) and HER2 (29–42% 64,65 ) status between DTCs and matched primary tumors. In contrast, a study using fluorescence in situ hybridization analysis showed that HER2 status in DTCs is highly concordant with that of the corresponding primary tumors.…”

Section: Discussionmentioning

confidence: 97%

Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer

et al. 2018

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Detection of disseminated tumor cells (DTCs) in bone marrow is an established negative prognostic factor. We isolated small pools of (~20) EPCAM-positive DTCs from early breast cancer patients for genomic profiling. Genome-wide copy number profiles of DTC pools (n = 45) appeared less aberrant than the corresponding primary tumors (PT, n = 16). PIK3CA mutations were detected in 26% of DTC pools (n = 53), none of them were shared with matched PTs. Expression profiling of DTC pools (n = 30) confirmed the upregulation of EPCAM expression and certain oncogenes (e.g., MYC and CCNE1), as well as the absence of hematopoietic features. Two expression subtypes were observed: (1) luminal with dual epithelial–mesenchymal properties (high ESR1 and VIM/CAV1 expression), and (2) basal-like with proliferative/stem cell-like phenotype (low ESR1 and high MKI67/ALDH1A1 expression). We observed high discordance between ESR1 (40%) and ERRB2 (43%) expression in DTC pools vs. the clinical ER and HER2 status of the corresponding primary tumors, suggesting plasticity of biomarker status during dissemination to the bone marrow. Comparison of expression profiles of DTC pools with available data from circulating tumor cells (CTCs) of metastatic breast cancer patients revealed gene expression signatures in DTCs that were unique from those of CTCs. For example, ALDH1A1, CAV1, and VIM were upregulated in DTC pools relative to CTCs. Taken together, analysis of pooled DTCs revealed molecular heterogeneity, possible genetic divergence from corresponding primary tumor, and two distinct subpopulations. Validation in larger cohorts is needed to confirm the presence of these molecular subtypes and to evaluate their biological and clinical significance.

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Section: Discussionmentioning

confidence: 97%

Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer

et al. 2018

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“…Whole blood from patients and HDs was collected in 10‐mL EDTA vacutainer tubes (Becton Dickinson), and cytospins were prepared as previously described (Rack et al ., ) (for details, see Appendix S1).…”

Section: Methodsmentioning

confidence: 99%

LKB1 pro‐oncogenic activity triggers cell survival in circulating tumor cells

et al. 2017

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During intravasation, circulating tumor cells (CTCs) detach from the epithelium of origin and begin the epithelial‐to‐mesenchymal transition (EMT) process, where they lose epithelial features and pass through the endothelium to enter circulation. Although detachment from the extracellular matrix is a strong source of metabolic stress, which induces anoikis, CTCs can survive. Recently, the tumor suppressor liver kinase B1 (LKB1) has gained attention for its role as a proto‐oncogene in restoring the correct ATP/AMP ratio during metabolic stress. The aim of this study was to assess LKB1 expression in epithelial‐negative CTCs isolated from patients with metastatic breast cancer and to characterize its possible association with EMT and stemness features. Transcriptome analysis of EpCAM‐negative CTCs indicated that over 25% of patients showed enhanced LKB1 levels, while almost 20% of patients showed enhanced levels of an EMT transcription factor known as ZEB1. Transcriptome and immunofluorescence analyses showed that patients with enhanced LKB1 were correspondingly ZEB1 negative, suggesting complementary activity for the two proteins. Only ZEB1 was significantly associated with cancer stem cell (CSC) markers. Neither LKB1 nor ZEB1 upregulation showed a correlation with clinical outcome, while enhanced levels of stemness‐associated CD44 correlated with a lower progression‐free and overall survival. Ex vivo models showed that MDA‐MB‐231, a mesenchymal tumor cell line, grew in suspension only if LKB1 was upregulated, but the MCF‐7 epithelial cell line lost its ability to generate spheroids and colonies when LKB1 was inhibited, supporting the idea that LKB1 might be necessary for CTCs to overcome the absence of the extracellular matrix during the early phases of intravasation. If these preliminary results are confirmed, LKB1 will become a novel therapeutic target for eradicating metastasis‐initiating CTCs from patients with primary breast cancer.

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“…Furthermore, discordant expression of so-called predictive markers on the primary tumor (hormonal and growth factor receptors) and corresponding DTCs has been described. 5,9,10 Whereas therapy decisions are based solely on the expression of these markers on the primary tumor, targets in DTCs might be useful to eliminate minimal residual disease at primary diagnosis. In addition, some DTCs have been identified as cancer stem cells (CSCs) that might have the ability to renew themselves.…”

Section: Introductionmentioning

confidence: 99%

CXCR4 and JUNB double-positive disseminated tumor cells are detected frequently in breast cancer patients at primary diagnosis

et al. 2020

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Background: The chemokine receptor CXCR4 and the transcription factor JUNB, expressed on a variety of tumor cells, seem to play an important role in the metastatic process. Since disseminated tumor cells (DTCs) in the bone marrow (BM) have been associated with worse outcomes, we evaluated the expression of CXCR4 and JUNB in DTCs of primary, nonmetastatic breast cancer (BC) patients before the onset of any systemic treatment. Methods: Bilateral BM (10 ml) aspirations of 39 hormone receptor (HR)-positive, HER2-negative BC patients were assessed for the presence of DTCs using the following combination of antibodies: pan-cytokeratin (A45-B/B3)/CXCR4/JUNB. An expression pattern of the examined proteins was created using confocal laser scanning microscopy, Image J software and BC cell lines. Results: CXCR4 was overexpressed in cancer cells and DTCs, with the following hierarchy of expression: SKBR3 > MCF7 > DTCs > MDA-MB231. Accordingly, the expression pattern of JUNB was: DTCs > MDA-MB231 > SKBR3 > MCF7. The mean intensity of CXCR4 (6411 ± 334) and JUNB (27725.64 ± 470) in DTCs was statistically higher compared with BM hematopoietic cells (2009 ± 456, p = 0.001; and 11112.89 ± 545, p = 0.001, respectively). The (CXCR4+JUNB+CK+) phenotype was the most frequently detected [90% (35/39)], followed by the (CXCR4–JUNB+CK+) phenotype [36% (14/39)]. However, (CXCR4+JUNB–CK+) tumor cells were found in only 5% (3/39) of patients. Those patients harboring DTCs with the (CXCR4+JUNB+CK+) phenotype revealed lower overall survival (Cox regression: p = 0.023). Conclusions: (CXCR4+JUNB+CK+)-expressing DTCs, detected frequently in the BM of BC patients, seem to identify a subgroup of patients at higher risk for relapse that may be considered for close follow up.

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Comparison of HER2 Expression in Primary Tumor and Disseminated Tumor Cells in the Bone Marrow of Breast Cancer Patients

Cited by 17 publications

References 51 publications

Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer

Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer

LKB1 pro‐oncogenic activity triggers cell survival in circulating tumor cells

CXCR4 and JUNB double-positive disseminated tumor cells are detected frequently in breast cancer patients at primary diagnosis

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