title: MIB1/Ki-67 labelling index can classify grade 2 breast cancer into two clinically distinct subgroups.
abstract: Histological grade is recognized as one of the strongest prognostic factors in operable breast cancer (BC). Although grade 1 and grade 3 tumours are biologically and clinically distinct, grade 2 tumours bear considerable difficulty in outcome prediction and planning therapies. Several attempts such as genomic grade index have been performed to subclassify grade 2 into two subgroups with clinical relevance. Here, we present evidence that the routinely evaluable immunohistochemical MIB1/Ki67 labelling index (MIB-LI) can classify grade 2 tumours into two clinically distinct subgroups. In this study, growth fractions of 1,550 primary operable invasive breast carcinomas were immunohistochemically assayed on full-face tissue sections using the MIB1 clone of Ki-67. Growth fractions were assessed as number of MIB1 positive nuclei in 1,000 tumour nuclei at high-power magnification and expressed as MIB1-LI. Using a 10% cut-point of MIB1-LI, grade 2 BCs were classified into low (49.8%) and high (50.2%) proliferative subgroups. Univariate and multivariate survival analysis revealed statistically significant differences between these subgroups regarding patients' BC specific survival (P < 0.001), and metastasis free survival (P < 0.001) which was independent of the well-established prognostic factors (HR = 2.944, 95% CI = 1.634-5.303, P < 0.001). In conclusion, our results further demonstrate that grade 2 BCs may represent at least two biological or behaviourally different entities. Assay of growth fraction in BC using MIB1/Ki67 immunohistochemistry is a robust cost-effective diagnostic tool that subdivides grade 2 tumours into low and high risk populations providing additional prognostic information in planning therapies and outcome prediction.
authors.affiliation: Division of Pathology, School of Molecular Medical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Aleskandarany
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
authors.forename: R Douglas
authors.initials: RD
authors.lastname: Macmillan
authors.forename: Desmond G
authors.initials: DG
authors.lastname: Powe
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000737:chemistry* / Q000175:diagnosis* / Q000401:mortality; D018797:Cell Cycle Proteins; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis* / Q000276:immunology; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D019394:Ki-67 Antigen