title: Very high quantitative tumor HER2 content and outcome in early breast cancer.
abstract: BACKGROUND
  It is unknown how a very high tumor total HER2 (human epidermal growth factor receptor-2) content (H2T) influences outcome in early breast cancer treated with adjuvant trastuzumab plus chemotherapy.
  
  
  METHODS
  H2T was measured using a novel quantitative assay (HERmark(®)) from formalin-fixed tumor tissue of 899 women who participated in the FinHer trial (ISRCTN76560285). In a chromogenic in situ hybridization (CISH) test, 197 (21.9%) patients had HER2-positive cancer and were randomly assigned to receive trastuzumab or control.
  
  
  RESULTS
  Cancer H2T levels varied 1808-fold. High H2T levels were correlated with a positive HER2 status by CISH (P < 0.0001). A nonlinear association was present between H2T and the hazard of distant recurrence in a subpopulation treatment effect pattern plot analysis in CISH-positive disease. Patients with very high H2T (defined by ≥22-fold the median of HER2-negative cancers; 13% of CISH-positive cancers) did not benefit from adjuvant trastuzumab [hazard ratio (HR) 1.23; 95% confidence interval (CI) 0.33-4.62; P = 0.75], whereas the rest of the patients with HER2-positive disease by CISH (87%) did benefit (HR 0.52; 95% CI 0.28-1.00; P = 0.050).
  
  
  CONCLUSIONS
  Patients with HER2-positive breast cancer with very high tumor HER2 content may benefit less from adjuvant trastuzumab compared with those whose cancer has more moderate HER2 content.
authors.affiliation: Department of Oncology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland. Electronic address: heikki.joensuu@hus.fi.
authors.forename: H
authors.initials: H
authors.lastname: Joensuu
authors.affiliation: Division of Research and Development, Monogram Biosciences, Inc., South San Francisco, USA.
authors.forename: J
authors.initials: J
authors.lastname: Sperinde
authors.affiliation: 4Pharma, Turku, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Leinonen
authors.affiliation: Division of Clinical Research, Monogram Biosciences, Inc., South San Francisco, USA.
authors.forename: W
authors.initials: W
authors.lastname: Huang
authors.affiliation: Division of Clinical Research, Monogram Biosciences, Inc., South San Francisco, USA.
authors.forename: J
authors.initials: J
authors.lastname: Weidler
authors.affiliation: Department of Oncology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Bono
authors.affiliation: Department of Oncology, Kuopio University Hospital, Kuopio, and Vaasa Central Hospital, Vaasa.
authors.forename: V
authors.initials: V
authors.lastname: Kataja
authors.affiliation: Department of Oncology, Kanta-Häme Central Hospital, Hämeenlinna.
authors.forename: R
authors.initials: R
authors.lastname: Kokko
authors.affiliation: Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu.
authors.forename: T
authors.initials: T
authors.lastname: Turpeenniemi-Hujanen
authors.affiliation: Department of Oncology, Turku University Central Hospital, Turku.
authors.forename: S
authors.initials: S
authors.lastname: Jyrkkiö
authors.affiliation: Laboratory of Cancer Biology, Institute of Medical Technology, University of Tampere and Tampere University Hospital.
authors.forename: J
authors.initials: J
authors.lastname: Isola
authors.affiliation: Department of Oncology, Tampere University Hospital, Tampere, Finland.
authors.forename: P-L
authors.initials: PL
authors.lastname: Kellokumpu-Lehtinen
authors.affiliation: Division of Clinical Research, Monogram Biosciences, Inc., South San Francisco, USA.
authors.forename: A
authors.initials: A
authors.lastname: Paquet
authors.affiliation: Division of Clinical Research, Monogram Biosciences, Inc., South San Francisco, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Lie
authors.affiliation: Division of Clinical Research, Monogram Biosciences, Inc., South San Francisco, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bates
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D000077143:Docetaxel; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D000077143:Docetaxel; D015251:Epirubicin; D005472:Fluorouracil; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; D014747:Vinblastine; D000077235:Vinorelbine; C508053:ERBB2 protein, human