title: Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of Ki67 assay according to histology: prognostic relevance for resected early stage 'pure' and 'mixed' lobular breast cancer.
abstract: BACKGROUND
  The aim of this analysis was to investigate the potential impact of Ki67 assay in a series of patients affected by early stage invasive lobular carcinoma (ILC) undergone surgery.
  
  
  METHODS
  Clinical-pathological data were correlated with disease-free and overall survival (DFS/OS). The maximally selected Log-Rank statistics analysis was applied to the Ki67 continuous variable to estimate appropriate cut-offs. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed to assess the interaction between 'pure' or 'mixed' histology ILC and Ki67.
  
  
  RESULTS
  At a median follow-up of 67 months, 10-years DFS and OS of 405 patients were 67.8 and 79.8%, respectively. Standardized Log-Rank statistics identified 2 optimal cut-offs (6 and 21%); 10-years DFS and OS were 75.1, 66.5, and 30.2% (p = 0.01) and 84.3, 76.4 and 59% (p = 0.003), for patients with a Ki67 < 6%, between 6 and 21%, and >21%, respectively. Ki67 and lymph-node status were independent predictor for longer DFS and OS at the multivariate analysis, with radiotherapy (for DFS) and age (for OS). Ki67 highly replicated at the internal cross-validation analysis (DFS 85%, OS 100%). The STEPP analysis showed that DFS rate decreases as Ki67 increases and those patients with 'pure' ILC performed worse than 'mixed' histology.
  
  
  CONCLUSIONS
  Despite the retrospective and exploratory nature of the study, Ki67 was able to significantly discriminate the prognosis of patients with ILC, and the effect was more pronounced for patients with 'pure' ILC.
authors.affiliation: Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, P.le L.A. Scuro 10, 37124, Verona, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Carbognin
authors.affiliation: Biostatistics, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: Department of Pathology and Diagnostic, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Brunelli
authors.affiliation: Department of Pathology and Diagnostic, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Marcolini
authors.affiliation: Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, P.le L.A. Scuro 10, 37124, Verona, Italy.
authors.forename: Rolando
authors.initials: R
authors.lastname: Nortilli
authors.affiliation: Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, P.le L.A. Scuro 10, 37124, Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pilotto
authors.affiliation: Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, P.le L.A. Scuro 10, 37124, Verona, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Zampiva
authors.affiliation: Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, P.le L.A. Scuro 10, 37124, Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Merler
authors.affiliation: Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, P.le L.A. Scuro 10, 37124, Verona, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Fiorio
authors.affiliation: Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, P.le L.A. Scuro 10, 37124, Verona, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Filippi
authors.affiliation: Biostatistics, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Erminia
authors.initials: E
authors.lastname: Manfrin
authors.affiliation: Chirurgia 'A', Department of Surgery and Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pellini
authors.affiliation: Biostatistics, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Bonetti
authors.affiliation: Department of Pathology and Diagnostic, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Giovanni Paolo
authors.initials: GP
authors.lastname: Pollini
authors.affiliation: Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, P.le L.A. Scuro 10, 37124, Verona, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
authors.affiliation: Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, P.le L.A. Scuro 10, 37124, Verona, Italy. emilio.bria@univr.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology* / Q000601:surgery*; D018275:Carcinoma, Lobular; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D019394:Ki-67 Antigen
keywords: Breast cancer; Ki67; Lobular