title: 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.
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.
authors.affiliation: Clinical Division of Special Gynaecology, Department of Obstetrics and Gynaecology, University Hospital, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Hudelist
authors.forename: W J
authors.initials: WJ
authors.lastname: Köstler
authors.forename: J
authors.initials: J
authors.lastname: Attems
authors.forename: K
authors.initials: K
authors.lastname: Czerwenka
authors.forename: R
authors.initials: R
authors.lastname: Müller
authors.forename: M
authors.initials: M
authors.lastname: Manavi
authors.forename: G G
authors.initials: GG
authors.lastname: Steger
authors.forename: E
authors.initials: E
authors.lastname: Kubista
authors.forename: C C
authors.initials: CC
authors.lastname: Zielinski
authors.forename: C F
authors.initials: CF
authors.lastname: Singer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008024:Ligands; D008875:Middle Aged; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D015996:Survival Rate; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007074:Immunoglobulin G; D008024:Ligands; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D000068878:Trastuzumab