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Her-2/neu-triggered intracellular tyrosine kinase activation: in vivo relevance of ligand-independent activation mechanisms and impact upon the efficacy of trastuzumab-based treatment.

Hudelist G, Köstler WJ, Attems J, Czerwenka K, Müller R, Manavi M, Steger GG, Kubista E, Zielinski CC, Singer CF - Br. J. Cancer (2003)

Bottom Line: Serum ECD levels were significantly higher in 15 (24%) patients with tumours exhibiting activated Her-2/neu as compared to those without detectable Her-2/neu phosphorylation (median 148.2 vs 28.5 ng ml(-1), P=0.010).Whereas response rate only showed a trend to be higher in patients with Her-2/neu-phosphorylated breast cancer (47 vs 34%, P=0.197), both uni- and multivariate analyses revealed that the median progression-free survival under trastuzumab-based treatment was significantly longer in patients with Her-2/neu-phosphorylated breast cancer-11.7 (95% CI 5.2-18.3) months-when compared to the progression-free survival of 4.5 (95% CI 3.4-5.6) months observed in patients with tumours lacking phosphorylated Her-2/neu (P=0.001).Proteolytic cleavage of the ECD represents a biologically relevant ligand-independent mechanism of Her-2/neu activation in vivo.

View Article: PubMed Central - PubMed

Affiliation: Clinical Division of Special Gynaecology, Department of Obstetrics and Gynaecology, University Hospital, Vienna, Austria.

ABSTRACT
Proteolytic cleavage of the Her-2/neu extracellular domain (ECD) has been shown to initiate receptor phosphorylation representing Her-2/neu activation in vitro. The present investigation was performed to evaluate the clinical relevance of ECD cleavage for Her-2/neu activation and the consequences of active intracellular Her-2/neu signalling reflected by tyrosine kinase phosphorylation in patients treated with the anti-Her-2/neu antibody trastuzumab. Sera from 62 patients receiving trastuzumab-based treatment for Her-2/neu overexpressing metastatic breast cancer were assessed for pretreatment ECD levels using an enzyme-linked immunosorbent assay. In parallel, Her-2/neu activation status of tumour specimens was assessed by immunohistochemistry using a Her-2/neu phosphorylation state specific antibody (PN2A) and correlated with the patients' ECD levels and clinical course of disease. Serum ECD levels were significantly higher in 15 (24%) patients with tumours exhibiting activated Her-2/neu as compared to those without detectable Her-2/neu phosphorylation (median 148.2 vs 28.5 ng ml(-1), P=0.010). Whereas response rate only showed a trend to be higher in patients with Her-2/neu-phosphorylated breast cancer (47 vs 34%, P=0.197), both uni- and multivariate analyses revealed that the median progression-free survival under trastuzumab-based treatment was significantly longer in patients with Her-2/neu-phosphorylated breast cancer-11.7 (95% CI 5.2-18.3) months-when compared to the progression-free survival of 4.5 (95% CI 3.4-5.6) months observed in patients with tumours lacking phosphorylated Her-2/neu (P=0.001). Proteolytic cleavage of the ECD represents a biologically relevant ligand-independent mechanism of Her-2/neu activation in vivo. The influence of Her-2/neu activation status upon the outcome of trastuzumab-based therapies merits further investigation in larger prospective trials.

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Serum Her-2/neu ECD levels are depicted in accordance to Her-2/neu overexpression (grade 2+ vs 3+) and Her-2/neu phosphorylation status of tumours (extreme outliers not depicted).
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fig3: Serum Her-2/neu ECD levels are depicted in accordance to Her-2/neu overexpression (grade 2+ vs 3+) and Her-2/neu phosphorylation status of tumours (extreme outliers not depicted).

Mentions: Patients with Her-2/neu phosphorylation presented with significantly higher serum Her-2/neu ECD levels before initiation of trastuzumab-based treatment (median 148.2, range 6.1–510.0 ng ml−1) as compared to patients without Her-2/neu phosphorylation (median 28.5, range 5.2–6076.2 ng ml−1; Mann–Whitney test: P=0.010, Figure 3Figure 3


Her-2/neu-triggered intracellular tyrosine kinase activation: in vivo relevance of ligand-independent activation mechanisms and impact upon the efficacy of trastuzumab-based treatment.

Hudelist G, Köstler WJ, Attems J, Czerwenka K, Müller R, Manavi M, Steger GG, Kubista E, Zielinski CC, Singer CF - Br. J. Cancer (2003)

Serum Her-2/neu ECD levels are depicted in accordance to Her-2/neu overexpression (grade 2+ vs 3+) and Her-2/neu phosphorylation status of tumours (extreme outliers not depicted).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376939&req=5

fig3: Serum Her-2/neu ECD levels are depicted in accordance to Her-2/neu overexpression (grade 2+ vs 3+) and Her-2/neu phosphorylation status of tumours (extreme outliers not depicted).
Mentions: Patients with Her-2/neu phosphorylation presented with significantly higher serum Her-2/neu ECD levels before initiation of trastuzumab-based treatment (median 148.2, range 6.1–510.0 ng ml−1) as compared to patients without Her-2/neu phosphorylation (median 28.5, range 5.2–6076.2 ng ml−1; Mann–Whitney test: P=0.010, Figure 3Figure 3

Bottom Line: Serum ECD levels were significantly higher in 15 (24%) patients with tumours exhibiting activated Her-2/neu as compared to those without detectable Her-2/neu phosphorylation (median 148.2 vs 28.5 ng ml(-1), P=0.010).Whereas response rate only showed a trend to be higher in patients with Her-2/neu-phosphorylated breast cancer (47 vs 34%, P=0.197), both uni- and multivariate analyses revealed that the median progression-free survival under trastuzumab-based treatment was significantly longer in patients with Her-2/neu-phosphorylated breast cancer-11.7 (95% CI 5.2-18.3) months-when compared to the progression-free survival of 4.5 (95% CI 3.4-5.6) months observed in patients with tumours lacking phosphorylated Her-2/neu (P=0.001).Proteolytic cleavage of the ECD represents a biologically relevant ligand-independent mechanism of Her-2/neu activation in vivo.

View Article: PubMed Central - PubMed

Affiliation: Clinical Division of Special Gynaecology, Department of Obstetrics and Gynaecology, University Hospital, Vienna, Austria.

ABSTRACT
Proteolytic cleavage of the Her-2/neu extracellular domain (ECD) has been shown to initiate receptor phosphorylation representing Her-2/neu activation in vitro. The present investigation was performed to evaluate the clinical relevance of ECD cleavage for Her-2/neu activation and the consequences of active intracellular Her-2/neu signalling reflected by tyrosine kinase phosphorylation in patients treated with the anti-Her-2/neu antibody trastuzumab. Sera from 62 patients receiving trastuzumab-based treatment for Her-2/neu overexpressing metastatic breast cancer were assessed for pretreatment ECD levels using an enzyme-linked immunosorbent assay. In parallel, Her-2/neu activation status of tumour specimens was assessed by immunohistochemistry using a Her-2/neu phosphorylation state specific antibody (PN2A) and correlated with the patients' ECD levels and clinical course of disease. Serum ECD levels were significantly higher in 15 (24%) patients with tumours exhibiting activated Her-2/neu as compared to those without detectable Her-2/neu phosphorylation (median 148.2 vs 28.5 ng ml(-1), P=0.010). Whereas response rate only showed a trend to be higher in patients with Her-2/neu-phosphorylated breast cancer (47 vs 34%, P=0.197), both uni- and multivariate analyses revealed that the median progression-free survival under trastuzumab-based treatment was significantly longer in patients with Her-2/neu-phosphorylated breast cancer-11.7 (95% CI 5.2-18.3) months-when compared to the progression-free survival of 4.5 (95% CI 3.4-5.6) months observed in patients with tumours lacking phosphorylated Her-2/neu (P=0.001). Proteolytic cleavage of the ECD represents a biologically relevant ligand-independent mechanism of Her-2/neu activation in vivo. The influence of Her-2/neu activation status upon the outcome of trastuzumab-based therapies merits further investigation in larger prospective trials.

Show MeSH
Related in: MedlinePlus