title: Comparing the prognostic value of PTEN and Akt expression with the Mitotic Activity Index in adjuvant chemotherapy-treated node-negative breast cancer patients aged <55 years.
abstract: BACKGROUND
  The prognostic value of the PI3K/Akt/mTOR pathway and PTEN in invasive breast cancer (IBC) is controversial. Cell proliferation, especially the Mitotic Activity Index (MAI), is strongly prognostic in lymph node-negative (LNneg) invasive breast cancer. However, its prognostic value has not been compared with the value of Akt and PTEN expression.
  
  
  METHODS
  Prognostic comparison of Her2Neu, p110alpha (PIK3CA), Akt, mTOR, PTEN, MAI and cell-cycle regulators in 125 LNneg patients aged <55 years with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)-based adjuvant systemic chemotherapy.
  
  
  RESULTS
  Twenty-one (17%) patients developed distant metastases=DMs (median follow-up: 134 months). p110alpha correlated (p=0.01) with pAkt but only in PTEN-negatives; pAkt correlated (p=0.02) with mTOR. PTEN-negativity correlated with high MAI, high grade and ER-negativity (p=0.009). The MAI was the strongest prognosticator (Hazard Ratio=HR=2.9, p=0.01). Her2Neu/p110alpha/Akt/mTOR features have no additional prognostic value to the MAI. PTEN had additional value but only in MAI<3 (39/125=31%; 8% DMs). 19/39=49% of the MAI<3 patients have combined MAI<3 / PTEN+ with 0% DMs, contrasting 15% DMs in MAI<3 / PTEN- (p=0.03).
  
  
  CONCLUSIONS
  In T(1-3)N(0)M(0) adjuvant CMF-treated breast cancer patients aged <55 years, MAI was the strongest survival predictor. The PI3K/Akt/mTOR pathway and cell-cycle regulator characteristics had no additional prognostic value, but PTEN has. Patients with combined MAI<3 & PTEN-positivity had 100% survival. The small subgroup of MAI<3 patients that died were PTEN-negative.
authors.affiliation: Department of Pathology, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Emiel A M
authors.initials: EA
authors.lastname: Janssen
authors.forename: Håvard
authors.initials: H
authors.lastname: Søiland
authors.forename: Ivar
authors.initials: I
authors.lastname: Skaland
authors.forename: Einar
authors.initials: E
authors.lastname: Gudlaugson
authors.forename: Kjell H
authors.initials: KH
authors.lastname: Kjellevold
authors.forename: Arne
authors.initials: A
authors.lastname: Nysted
authors.forename: Jon-Arne
authors.initials: JA
authors.lastname: Søreide
authors.forename: Jan P A
authors.initials: JP
authors.lastname: Baak
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant / Q000379:methods; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human