title: The expression and prognostic significance of HER-2 in colorectal cancer and its relationship with clinicopathological parameters.
abstract: The prognostic role of HER-2 has been established in breast cancer but remains controversial in colorectal cancer. In this study, 170 archival specimens of Dukes' B and C colorectal cancer were analysed immunohisto-chemically, using an anti-HER-2 monoclonal antibody HM64.13. Immunostaining was classified as cytoplasmic or membranous, and the intensity of the immunostaining was graded negative, weak or strong. The association between these scores and survival was estimated using Cox survival analyses. Overall, 87% of cases showed cytoplasmic HER-2 staining, with 54% exhibiting strong intensity cytoplasmic immunostaining. Membranous HER-2 was seen in 41% of cases, with most of these being of strong intensity. No correlation with clinical outcome was seen with membranous HER-2. Positive cytoplasmic immunostaining was found to be associated with a significantly better overall survival (HR 0.46, CI95 0.24-0.87) in the Dukes C cancers, but no survival benefit was seen in the Dukes' B cancers. Tumour grade, depth of tumour invasion and positive apical node were also found to be independent prognostic factors in Dukes' C cancers. We conclude that HER-2 over-expression occurs in a significant number of colorectal cancers. Since cytoplasmic HER-2 is incapable of transmitting the strong mitogenic signal via heterodimerization with other members of the Epidermal Growth Factor Receptor (EGFR) family, this may partly explain the correlation between cytoplasmic HER-2 over-expression and a better prognosis in the Dukes' C colorectal cancers. In addition, high levels of membraneous HER-2 in colorectal cancer could make HER-2 a good target for monoclonal antibody-based immunotherapy.
authors.affiliation: Division of Oncology, Postgraduate Medical School, University of Surrey, Guildford, Surrey GU2 7XH, UK. sharadah.essapen@royalsurrey.nhs.uk
authors.forename: Sharadah
authors.initials: S
authors.lastname: Essapen
authors.forename: Hilary
authors.initials: H
authors.lastname: Thomas
authors.forename: Margaret
authors.initials: M
authors.lastname: Green
authors.forename: Corrine
authors.initials: C
authors.lastname: De Vries
authors.forename: Martin G
authors.initials: MG
authors.lastname: Cook
authors.forename: Christopher
authors.initials: C
authors.lastname: Marks
authors.forename: Clare
authors.initials: C
authors.lastname: Topham
authors.forename: Helmout
authors.initials: H
authors.lastname: Modjtahedi
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry; D000918:Antibody Specificity; D002462:Cell Membrane / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D008297:Male; D008934:Mitogens / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D008934:Mitogens; D018719:Erb-b2 Receptor Tyrosine Kinases