title: Low Ki67/high ATM protein expression in malignant tumors predicts favorable prognosis in a retrospective study of early stage hormone receptor positive breast cancer.
abstract: BACKGROUND
  This study was designed to investigate the combined influence of ATM and Ki67 on clinical outcome in early stage hormone receptor positive breast cancer (ES-HPBC), particularly in patients with smaller tumors (< 4 cm) and fewer than four positive lymph nodes.
  
  
  METHODS
  532 formalin-fixed paraffin-embedded specimens of resected primary breast tumors were used to construct a tissue microarray. Samples from 297 patients were suitable for final statistical analysis. We detected ATM and Ki67 proteins using fluorescence and brightfield immunohistochemistry respectively, and quantified their expression with digital image analysis. Data on expression levels were subsequently correlated with clinical outcome.
  
  
  RESULTS
  Remarkably, ATM expression was useful to stratify the low Ki67 group into subgroups with better or poorer prognosis. Specifically, in the low Ki67 subgroup defined as having smaller tumors and no positive nodes, patients with high ATM expression showed better outcome than those with low ATM, with estimated survival rates of 96% and 89% respectively at 15 years follow up (p = 0.04). Similarly, low-Ki67 patients with smaller tumors, 1-3 positive nodes and high ATM also had significantly better outcomes than their low ATM counterparts, with estimated survival rates of 88% and 46% respectively (p = 0.03) at 15 years follow up. Multivariable analysis indicated that the combination of high ATM and low Ki67 is prognostic of improved survival, independent of tumor size, grade, and lymph node status (p = 0.02).
  
  
  CONCLUSIONS
  These data suggest that the prognostic value of Ki67 can be improved by analyzing ATM expression in ES-HPBC.
authors.affiliation: Department of Oncology, BC Cancer Agency-Vancouver Island Center, Victoria, British Columbia, Canada.|Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.|Department of Oncology, Tom Baker Cancer Centre and University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Oncology, Tom Baker Cancer Centre and University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada.|Department of Community Health Science, TRW Building, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Haocheng
authors.initials: H
authors.lastname: Li
authors.affiliation: Functional Tissue Imaging Unit, Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada.|Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Elizabeth N
authors.initials: EN
authors.lastname: Kornaga
authors.affiliation: Functional Tissue Imaging Unit, Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada.|Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Dean
authors.affiliation: Department of Biochemistry and Molecular Biology, Health Science Building, University of Calgary, Alberta, Canada.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Lees-Miller
authors.affiliation: Department of Biochemistry and Molecular Biology, Health Science Building, University of Calgary, Alberta, Canada.
authors.forename: Karl
authors.initials: K
authors.lastname: Riabowol
authors.affiliation: Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Magliocco
authors.affiliation: Department of Oncology, Tom Baker Cancer Centre and University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada.|Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Don
authors.initials: D
authors.lastname: Morris
authors.affiliation: Department of Pathology, BC Cancer Agency-Vancouver Island Center, Victoria, British Columbia, Canada.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Watson
authors.affiliation: Functional Tissue Imaging Unit, Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada.|Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Emeka K
authors.initials: EK
authors.lastname: Enwere
authors.affiliation: Department of Oncology, Tom Baker Cancer Centre and University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada.|Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Gwyn
authors.initials: G
authors.lastname: Bebb
authors.affiliation: Department of Oncology, Tom Baker Cancer Centre and University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Paterson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis*; D008875:Middle Aged; D011379:Prognosis; D011960:Receptors, Estrogen / Q000032:analysis*; D011980:Receptors, Progesterone / Q000032:analysis*; D012189:Retrospective Studies
chemical_list: D019394:Ki-67 Antigen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; Ki67; automated quantitative immunofluorescence analysis; disease specific overall survival; early stage hormone receptor positive breast cancer