title: Heterogeneous HER2 gene amplification: impact on patient outcome and a clinically relevant definition.
abstract: Heterogeneous expression or amplification is a challenge to HER2 diagnostics. A guideline defines heterogeneity as the presence of between 5% and 50% cells with HER2/CEP17 ratios of more than 2.20. We audited the frequency of such cells and their clinical impact in the results from 2 pathology laboratories combined with data from the TEAM [Tamoxifen vs Exemestane Adjuvant Multicentre] pathology study. HER2 reports were scanned and the percentages of amplified cells reported. Of 6,461 eligible cases, 754 (11.7%) exhibited 50% or more cells with ratios of more than 2.20, which is "amplified" by College of American Pathologists guidelines. Of the cases, 2,166 (33.5%) exhibited more than 5% but less than 50% of cells with HER2/CEP17 ratios of more than 2.20, or "heterogeneous amplification." No prognostic impact was observed when fewer than 30% of cells exhibited ratios of more than 2.20. All amplified cases with 30% to 50% of cells with ratios more than 2.20 were identified as such by United Kingdom guidelines. The percentage of tumor cells with HER2/CEP17 ratios more than 2.20 does not identify cases with heterogeneous amplification or poor outcome. A modified approach for identification of true heterogeneous amplification is suggested.
authors.affiliation: Endocrine Cancer Group, Edinburgh University, Edinburgh, Scotland.
authors.forename: Alastair I
authors.initials: AI
authors.lastname: Bartlett
authors.forename: Jane
authors.initials: J
authors.lastname: Starcyznski
authors.forename: Tammy
authors.initials: T
authors.lastname: Robson
authors.forename: Alex
authors.initials: A
authors.lastname: Maclellan
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Campbell
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: Annette
authors.initials: A
authors.lastname: Hasenburg
authors.forename: Christos
authors.initials: C
authors.lastname: Markopoulos
authors.forename: Caroline
authors.initials: C
authors.lastname: Seynaeve
authors.forename: Daniel
authors.initials: D
authors.lastname: Rea
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
mesh_terms: D000730:Androstadienes / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005784:Gene Amplification / Q000235:genetics*; D018734:Genes, erbB-2 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D015337:Multicenter Studies as Topic; D017410:Practice Guidelines as Topic; D011379:Prognosis; D013629:Tamoxifen / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D013629:Tamoxifen; C056516:exemestane