title: PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab.
abstract: BACKGROUND
  This study was conducted to determine the frequency of PIK3CA mutations and human epidermal growth factor receptor-2 (HER2) phosphorylation status (pHER2-Tyr1221/1222) and if PIK3CA, phosphatase and tensin homolog (PTEN), or pHER2 has an impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab.
  
  
  METHODS
  Two hundred and forty HER2-positive early-stage breast cancer patients receiving adjuvant treatment (cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2) before administration of 1 year trastuzumab were assessable. PTEN and pHER2 expression were assessed by immunohistochemistry. PIK3CA mutations (exons 9 and 20) were determined by pyrosequencing.
  
  
  RESULTS
  Five-year overall survival (OS) and invasive disease-free survival were 87.8% and 81.0%, respectively. Twenty-six percent of patients had a PIK3CA mutation, 24% were PTEN low, 45% pHER2 high, and 47% patients had increased PI3K pathway activation (PTEN low and/or PIK3CA mutation). No significant correlations were observed between the clinicopathological variables and PIK3CA, PTEN, and pHER2 status. In both univariate and multivariate analyses, patients with PIK3CA mutations or high PI3K pathway activity had a significant worse OS [multivariate: hazard ratio (HR) 2.14, 95% confidence interval (CI) 1.01-4.51, P=0.046; and HR 2.35, 95% CI 1.10-5.04, P=0.03].
  
  
  CONCLUSIONS
  Patients with PIK3CA mutations or increased PI3K pathway activity had a significantly poorer survival despite adequate treatment with adjuvant chemotherapy and trastuzumab.
authors.affiliation: Department of Oncology, Odense University Hospital, Odense; Institute of Clinical Research, University of Southern Denmark, Odense. Electronic address: jeanette.dupont.jensen@ouh.regionsyddanmark.dk.
authors.forename: J D
authors.initials: JD
authors.lastname: Jensen
authors.affiliation: Department of Oncology, Odense University Hospital, Odense; Institute of Clinical Research, University of Southern Denmark, Odense.
authors.forename: A
authors.initials: A
authors.lastname: Knoop
authors.affiliation: Department of Pathology, Slagelse Hospital, Slagelse.
authors.forename: A V
authors.initials: AV
authors.lastname: Laenkholm
authors.affiliation: Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen.
authors.forename: M
authors.initials: M
authors.lastname: Grauslund
authors.affiliation: Danish Breast Cancer Cooperative Group Data Center, Copenhagen.
authors.forename: M B
authors.initials: MB
authors.lastname: Jensen
authors.affiliation: Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen.
authors.forename: E
authors.initials: E
authors.lastname: Santoni-Rugiu
authors.affiliation: Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Andersson
authors.affiliation: Department of Oncology, Odense University Hospital, Odense; Institute of Clinical Research, University of Southern Denmark, Odense.
authors.forename: M
authors.initials: M
authors.lastname: Ewertz
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D017024:Chemotherapy, Adjuvant; D058534:Class I Phosphatidylinositol 3-Kinases; D003520:Cyclophosphamide / Q000008:administration & dosage; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000378:metabolism; D015996:Survival Rate; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D058534:Class I Phosphatidylinositol 3-Kinases; D003520:Cyclophosphamide; D015251:Epirubicin; D005472:Fluorouracil; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C484760:PIK3CA protein, human; C494929:PTEN protein, human