title: Type I receptor tyrosine kinases are associated with hormone escape in prostate cancer.
abstract: Relapse during androgen withdrawal therapy is a significant cause of morbidity and mortality from prostate cancer. Androgen receptor mutations (6-10%) and amplifications (20-30%) may explain relapse in some patients, but in approximately 70% of cases, alternative mechanisms must be invoked and preliminary evidence suggests that type I receptor tyrosine kinases play a role in mediating hormone escape. In this study, EGFR and HER2 gene amplification and expression were analysed by fluorescence in situ hybridization and immunohistochemistry, respectively, in a cohort of matched tumour pairs (one taken before and one after hormone relapse) from 49 prostate cancer patients. No EGFR amplification and low-level, heterogeneous HER2 amplification were observed (6.5%). No significant correlation between EGFR/HER2 gene copy and protein expression was found. Almost one quarter of the cases (12/49, 24.5%) showed increased HER2 or EGFR expression at hormone relapse; this was associated with a significant reduction in time from hormone relapse to death (p = 0.0003). EGFR and HER2 amplification do not play a significant role in prostate cancer, but increased expression of HER2 or EGFR may influence progression to androgen independence in about a quarter of cases as a rise in EGFR/HER2 expression at hormone relapse is associated with a significant reduction in time to death. These findings support the development of EGFR/HER2 targeted therapies in androgen-independent prostate cancer and demonstrate, using a carefully characterized patient cohort, that the EGFR/HER2 pathway may represent one of a number of independent routes to hormone escape in prostate cancer.
authors.affiliation: Division of Cancer Sciences and Molecular Pathology, University Department of Surgery, Level II Queen Elizabeth Building, Glasgow Royal Infirmary, Glasgow, G31 2ER, UK. J.M.Bartlett@clinmed.gla.ac.uk
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
authors.forename: Daniella
authors.initials: D
authors.lastname: Brawley
authors.forename: Ken
authors.initials: K
authors.lastname: Grigor
authors.forename: Alison F
authors.initials: AF
authors.lastname: Munro
authors.forename: Barbara
authors.initials: B
authors.lastname: Dunne
authors.forename: Joanne
authors.initials: J
authors.lastname: Edwards
mesh_terms: D000728:Androgens / Q000502:physiology; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D005784:Gene Amplification; D018815:Genes, erbB / Q000235:genetics*; D018773:Genes, erbB-1 / Q000235:genetics; D018734:Genes, erbB-2 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D016019:Survival Analysis
chemical_list: D000728:Androgens; D020794:Receptor Protein-Tyrosine Kinases