title: Ki-67 in endometrial cancer: scoring optimization and prognostic relevance for window studies.
abstract: Ki-67, a marker of cellular proliferation, is increasingly being used in pre-surgical window studies in endometrial cancer as a primary outcome measure. Unlike in breast cancer, however, there are no guidelines standardizing its measurement and its clinical relevance as a response biomarker is undetermined. It is, therefore, imperative that Ki-67 scoring protocols are optimized and its association with patient survival rigorously evaluated, in order to be able to clinically interpret the results of these studies. Using the International Ki-67 in Breast Cancer Working Group guidelines as a basis, whole slide, hot spot and invasive edge scoring protocols were evaluated using endometrial biopsies and hysterectomy specimens from 179 women. Whole sections and tissue microarrays, manual and semi-automated scoring using Definiens Developer software were additionally compared. Ki-67 scores were related to clinicopathological variables and cancer-specific survival in uni- and multivariate analysis. Against criteria of time efficiency, intra- and inter-observer variability and consistency, semi-automated hot spot scoring was the preferred method. Ki-67 scores positively correlated with grade, stage and depth of myometrial invasion (P-values all <0.03). By univariate analysis, higher Ki-67 scores were associated with a significant reduction in cancer-specific survival (P≤0.05); however, this effect was substantially attenuated in the multivariate model. In conclusion, hot spot scoring of whole sections using Definiens is an optimal method to quantify Ki-67 in endometrial cancer window study specimens. Measured this way, it is a clinically relevant marker, though further work is required to determine whether reductions in Ki-67 in neoadjuvant intervention studies translate into improved patient outcome.
authors.affiliation: Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK.|Department of Obstetrics and Gynaecology, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kitson
authors.affiliation: Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK.|Department of Obstetrics and Gynaecology, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Vanitha N
authors.initials: VN
authors.lastname: Sivalingam
authors.affiliation: Department of Histopathology, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: James
authors.initials: J
authors.lastname: Bolton
authors.affiliation: Department of Histopathology, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Rhona
authors.initials: R
authors.lastname: McVey
authors.affiliation: Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK.|Department of Obstetrics and Gynaecology, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Mashid
authors.initials: M
authors.lastname: Nickkho-Amiry
authors.affiliation: Department of Clinical Oncology, Barts Health NHS Trust, London, UK.
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Powell
authors.affiliation: INSERM U981 and Department of Medicine, Gynecology Unit, Gustave Roussy, Villejuif, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Leary
authors.affiliation: Department of Gynecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Remi A
authors.initials: RA
authors.lastname: Nout
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tjalling
authors.initials: T
authors.lastname: Bosse
authors.affiliation: Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Renehan
authors.affiliation: Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Kitchener
authors.affiliation: Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK.|Department of Obstetrics and Gynaecology, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Edmondson
authors.affiliation: Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK.|Department of Obstetrics and Gynaecology, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Emma J
authors.identifier: 0000-0003-0284-8630
authors.initials: EJ
authors.lastname: Crosbie
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D018269:Carcinoma, Endometrioid / Q000378:metabolism / Q000473:pathology*; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism*; D015588:Observer Variation; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen