title: Basal biomarkers nestin and INPP4b identify intrinsic subtypes accurately in breast cancers that are weakly positive for oestrogen receptor.
abstract: OBJECTIVE
  Recent evidence indicates that weakly positive immunohistochemical staining of oestrogen receptor (ER) is not associated reliably with a luminal subtype, with the majority reclassified as basal-like by gene expression profile. In this study we assessed the capacity of recently identified immunohistochemical markers of basal-like subtype not dependent upon ER status - positive expression of nestin or loss of inositol polyphosphate-4-phosphatase (INPP4b) - to discriminate intrinsic subtypes, focusing on clinically problematic cases with weak ER positivity.
  
  
  RESULTS
  Formalin-fixed paraffin-embedded blocks, enriched for large proportions of ER-negative and ER weakly positive breast cancers, were selected from two previous studies conducted in the period 2008-13 and used for (i) RNA extraction for 50-gene subtype predictor (PAM50) intrinsic subtyping and (ii) tissue microarray construction for immunohistochemical assessment of nestin and INPP4b. Fifty-eight cases were weakly positive for ER (Allred 3-5), among which 28 (48%) were assigned as basal-like by PAM50 gene expression. In these 58 cases, the nestin/INPP4b panel identified 23 basal-like cases with a positive predictive value of 87% [95% confidence interval (CI) 78-95%] and excluded luminal subtype with a negative predictive value of 95% (95% CI 88-100%). Weakly positive ER patients assigned as basal-like by nestin/INPP4b definition demonstrated a median survival time of 45.8 months, significantly lower than 65 months among other ER weakly positive cases (P = 0.012).
  
  
  CONCLUSIONS
  Immunohistochemical assessment of nestin and INPP4b provides an accurate, accessible and inexpensive tool to identify basal-like breast cancer subtype in the clinically problematic setting of weak ER positivity. This panel identifies poor prognosis patients who might need strong considerations for non-endocrine-based therapies.
authors.affiliation: Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Karama
authors.initials: K
authors.lastname: Asleh-Aburaya
authors.affiliation: Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Sheffield
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Ottawa and The Ottawa Hospital, Ottawa, ON, Canada.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Kos
authors.affiliation: Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, Canadian Immunohistochemistry Quality Control (CIQC), University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Won
authors.affiliation: Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Xiu Q
authors.initials: XQ
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Dongxia
authors.initials: D
authors.lastname: Gao
authors.affiliation: Department of Pathology and Laboratory Medicine, Lions Gate Hospital, North Vancouver, BC, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Wolber
authors.affiliation: Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, Canadian Immunohistochemistry Quality Control (CIQC), University of British Columbia, Vancouver, BC, Canada.
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.affiliation: Department of Pathology, University of Utah/Health Sciences, Salt Lake City, UT, USA.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Bernard
authors.affiliation: Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Stephen K L
authors.initials: SK
authors.lastname: Chia
authors.affiliation: Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000145:classification* / Q000401:mortality; D018270:Carcinoma, Ductal, Breast / Q000145:classification* / Q000401:mortality; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D064231:Nestin / Q000032:analysis / Q000096:biosynthesis*; D010744:Phosphoric Monoester Hydrolases / Q000032:analysis / Q000096:biosynthesis*; D011379:Prognosis; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000096:biosynthesis; D046888:Tissue Array Analysis; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; C577484:NES protein, human; D064231:Nestin; D011960:Receptors, Estrogen; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase
keywords: ER; INPP4b; PAM50; breast cancer; nestin; weakly positive