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Expression of truncated human epidermal growth factor receptor 2 on circulating tumor cells of breast cancer patients.

Kallergi G, Agelaki S, Papadaki MA, Nasias D, Matikas A, Mavroudis D, Georgoulias V - Breast Cancer Res. (2015)

Bottom Line: Trastuzumab reduced the percentage of patients with full-length HER2-positive CTCs from 70 % at baseline to 50 % (p = 0.035) after treatment while increased the percentage of patients with p95HER2-positive CTCs from 40 % to 63 %.Moreover, the overall survival of metastatic patients with p95HER2-positive CTCs was significantly decreased (p = 0.03). p95HER2-positive CTCs can be detected in both early and metastatic breast cancer patients.Their incidence is increased in the metastatic setting and their presence is associated with poor survival.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Τumor Cell Biology, School of Medicine, University of Crete, Voutes, 71110, Heraklion, Crete, Greece. kalergi@med.uoc.gr.

ABSTRACT

Introduction: The truncated form of human epidermal growth factor receptor 2 (p95HER2) lacks the HER2 extracellular domain and has been associated with poor prognosis and resistance to trastuzumab. In the present study, the expression of p95HER2 was investigated on circulating tumor cells (CTCs) from breast cancer patients.

Methods: Triple-staining immunofluorescent experiments were performed on peripheral blood mononuclear cells' (PBMCs) cytospins obtained from patients with early (n = 24) and metastatic (n = 37) breast cancer. Cells were stained with the pancytokeratin (A45-B/B3) antibody coupled with antibodies against the extracellular (ECD) and the intracellular (ICD) domains of HER2. Slides were analyzed with either confocal laser scanning microscopy or with the Ariol system.

Results: HER2-positive CTCs were identified in 55.6 % of early and 65.2 % of metastatic CTC-positive breast cancer patients. p95HER2-positive CTCs were identified in 11.1 % of early and 39.1 % of metastatic breast cancer patients (p = 0.047). In 14 patients with metastatic HER2-positive breast cancer, CTCs were also analyzed before and after first-line trastuzumab therapy. Trastuzumab reduced the percentage of patients with full-length HER2-positive CTCs from 70 % at baseline to 50 % (p = 0.035) after treatment while increased the percentage of patients with p95HER2-positive CTCs from 40 % to 63 %. Moreover, the overall survival of metastatic patients with p95HER2-positive CTCs was significantly decreased (p = 0.03).

Conclusions: p95HER2-positive CTCs can be detected in both early and metastatic breast cancer patients. Their incidence is increased in the metastatic setting and their presence is associated with poor survival. Longitudinal studies during anti-HER2 treatment are required to determine the clinical relevance of p95HER2-expressing CTCs.

No MeSH data available.


Related in: MedlinePlus

HER2 full-length and truncated HER2 expression on CTCs of breast cancer patients. Representative Ariol system images from one metastatic patient expressing both (a) CTCs with truncated HER2 receptor after triple-staining with HER2 (ICD), HER2 (ECD) and pancytokeratin (A45-B/B3) antibodies and (b) CTCs with full length receptor. CTCs circulating tumor cells, ECD extracellular domain, HER2 human epidermal growth factor receptor 2, ICD intracellular domain
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Fig3: HER2 full-length and truncated HER2 expression on CTCs of breast cancer patients. Representative Ariol system images from one metastatic patient expressing both (a) CTCs with truncated HER2 receptor after triple-staining with HER2 (ICD), HER2 (ECD) and pancytokeratin (A45-B/B3) antibodies and (b) CTCs with full length receptor. CTCs circulating tumor cells, ECD extracellular domain, HER2 human epidermal growth factor receptor 2, ICD intracellular domain

Mentions: Ιn two patients with early (Table 2; patient number 6 and number 13) and in four (Table 2; patient number 7, number 11, number 20 and number 22) with metastatic disease, two distinct subpopulations of CTCs, according to the expression status of HER2, could be identified: CTCs expressing the full-length HER2 receptor as well as CTCs expressing the p95HER2 receptor. Figure 3 demonstrates the intracellular distribution of HER2 in one patient with the two phenotypically distinct subpopulations of CTCs. Particularly, in panel A, the cell lacks the extracellular domain and the distribution of HER2 is mainly cytoplasmic, while in panel B, HER2 extracellular domain is evident along with a mostly membrane localization of its intracellular domain.Table 2


Expression of truncated human epidermal growth factor receptor 2 on circulating tumor cells of breast cancer patients.

Kallergi G, Agelaki S, Papadaki MA, Nasias D, Matikas A, Mavroudis D, Georgoulias V - Breast Cancer Res. (2015)

HER2 full-length and truncated HER2 expression on CTCs of breast cancer patients. Representative Ariol system images from one metastatic patient expressing both (a) CTCs with truncated HER2 receptor after triple-staining with HER2 (ICD), HER2 (ECD) and pancytokeratin (A45-B/B3) antibodies and (b) CTCs with full length receptor. CTCs circulating tumor cells, ECD extracellular domain, HER2 human epidermal growth factor receptor 2, ICD intracellular domain
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4541732&req=5

Fig3: HER2 full-length and truncated HER2 expression on CTCs of breast cancer patients. Representative Ariol system images from one metastatic patient expressing both (a) CTCs with truncated HER2 receptor after triple-staining with HER2 (ICD), HER2 (ECD) and pancytokeratin (A45-B/B3) antibodies and (b) CTCs with full length receptor. CTCs circulating tumor cells, ECD extracellular domain, HER2 human epidermal growth factor receptor 2, ICD intracellular domain
Mentions: Ιn two patients with early (Table 2; patient number 6 and number 13) and in four (Table 2; patient number 7, number 11, number 20 and number 22) with metastatic disease, two distinct subpopulations of CTCs, according to the expression status of HER2, could be identified: CTCs expressing the full-length HER2 receptor as well as CTCs expressing the p95HER2 receptor. Figure 3 demonstrates the intracellular distribution of HER2 in one patient with the two phenotypically distinct subpopulations of CTCs. Particularly, in panel A, the cell lacks the extracellular domain and the distribution of HER2 is mainly cytoplasmic, while in panel B, HER2 extracellular domain is evident along with a mostly membrane localization of its intracellular domain.Table 2

Bottom Line: Trastuzumab reduced the percentage of patients with full-length HER2-positive CTCs from 70 % at baseline to 50 % (p = 0.035) after treatment while increased the percentage of patients with p95HER2-positive CTCs from 40 % to 63 %.Moreover, the overall survival of metastatic patients with p95HER2-positive CTCs was significantly decreased (p = 0.03). p95HER2-positive CTCs can be detected in both early and metastatic breast cancer patients.Their incidence is increased in the metastatic setting and their presence is associated with poor survival.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Τumor Cell Biology, School of Medicine, University of Crete, Voutes, 71110, Heraklion, Crete, Greece. kalergi@med.uoc.gr.

ABSTRACT

Introduction: The truncated form of human epidermal growth factor receptor 2 (p95HER2) lacks the HER2 extracellular domain and has been associated with poor prognosis and resistance to trastuzumab. In the present study, the expression of p95HER2 was investigated on circulating tumor cells (CTCs) from breast cancer patients.

Methods: Triple-staining immunofluorescent experiments were performed on peripheral blood mononuclear cells' (PBMCs) cytospins obtained from patients with early (n = 24) and metastatic (n = 37) breast cancer. Cells were stained with the pancytokeratin (A45-B/B3) antibody coupled with antibodies against the extracellular (ECD) and the intracellular (ICD) domains of HER2. Slides were analyzed with either confocal laser scanning microscopy or with the Ariol system.

Results: HER2-positive CTCs were identified in 55.6 % of early and 65.2 % of metastatic CTC-positive breast cancer patients. p95HER2-positive CTCs were identified in 11.1 % of early and 39.1 % of metastatic breast cancer patients (p = 0.047). In 14 patients with metastatic HER2-positive breast cancer, CTCs were also analyzed before and after first-line trastuzumab therapy. Trastuzumab reduced the percentage of patients with full-length HER2-positive CTCs from 70 % at baseline to 50 % (p = 0.035) after treatment while increased the percentage of patients with p95HER2-positive CTCs from 40 % to 63 %. Moreover, the overall survival of metastatic patients with p95HER2-positive CTCs was significantly decreased (p = 0.03).

Conclusions: p95HER2-positive CTCs can be detected in both early and metastatic breast cancer patients. Their incidence is increased in the metastatic setting and their presence is associated with poor survival. Longitudinal studies during anti-HER2 treatment are required to determine the clinical relevance of p95HER2-expressing CTCs.

No MeSH data available.


Related in: MedlinePlus