Digital Image Analysis of Ki-67 Stained Tissue Microarrays and Recurrence in Tamoxifen-Treated Breast Cancer Patients

• Type of Material: Article
• Authors: Nina Gran Egeland, Stavanger University Hospital; Kristin Jonsdottir, Stavanger University Hospital; Kristina Lystlund Lauridsen, Aarhus University Hospital; Ivar Skaland, Stavanger University Hospital; Catherine F. Hjorth, Aarhus University Hospital; Einar G. Gudlaugsson, Stavanger University Hospital; Stephen Hamilton-Dutoit, Aarhus University Hospital; Timothy Lash, Emory University; Deidre Cronin-Fenton, Aarhus University Hospital; Emiel A. M. Janssen, Stavanger University Hospital
• Language: English
• Date: 2020-01-01
• Publisher: Dove Medical Press Ltd.
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Egeland et al.
• License: Creative Commons Attribution-Noncommercial 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.2147/CLEP.S248167
• Title of Journal or Parent Work: Clinical Epidemiology
• Volume: 12
• Start Page: 771
• End Page: 781
• Grant/Funding Information: This project was additionally supported by funding from the National Cancer Institute (R01 CA118708 and R01 CA166825) awarded to Timothy Lash, the Danish Cancer Society (DP06117) awarded to Stephen Hamilton-Dutoit; the Lundbeck Foundation (R167-2013-15861) and the Danish Cancer Research Foundation awarded to Deirdre Cronin-Fenton, and the Danish Medical Research Council (DOK 1158869) awarded to Timothy Lash.; This work was supported by multiple agency grants; Kristin Jonsdottir and Nina Gran Egeland obtained grants from Folke Hermansen Foundation (2013, 2014, and 2019), Norway.
• Keywords: Index; tamoxifen; Public, Environmental & Occupational Health; Science & Technology; Phosphohistone H3; Resistance; Proliferation; proliferation; TMA; Prognostic marker; Ki-67; digital image analysis; recurrence risk; Women; Predictive value; tissue microarray; DIA; Life Sciences & Biomedicine; breast cancer; KI67 expression; Endocrine therapy; Adjuvant tamofixen
• Research Categories: Health Sciences, Pathology; Health Sciences, Epidemiology; Chemistry, Biochemistry; Health Sciences, Rehabilitation and Therapy; Health Sciences, Oncology

Abstract

Purpose The proliferation marker Ki-67 has been used as a prognostic marker to separate low- and high-risk breast cancer subtypes and guide treatment decisions for adjuvant chemotherapy. The association of Ki-67 with response to tamoxifen therapy is unclear. High-throughput automated scoring of Ki-67 might enable standardization of quantification and definition of clinical cut-off values. We hypothesized that digital image analysis (DIA) of Ki-67 can be used to evaluate proliferation in breast cancer tumors, and that Ki-67 may be associated with tamoxifen resistance in early-stage breast cancer. Patients and Methods Here, we apply DIA technology from Visiopharm using a custom designed algorithm for quantifying the expression of Ki-67, in a case–control study nested in the Danish Breast Cancer Group clinical database, consisting of stages I, II, or III breast cancer patients of 35–69 years of age, diagnosed during 1985–2001, in the Jutland peninsula, Denmark. We assessed DIA-Ki-67 score on tissue microarrays (TMAs) from breast cancer patients in a case–control study including 541 ER-positive and 300 ER-negative recurrent cases and their non-recurrent controls, matched on ER-status, cancer stage, menopausal status, year of diagnosis, and county of residence. We used logistic regression to estimate odds ratios and associated 95% confidence intervals to determine the association of Ki-67 expression with recurrence risk, adjusting for matching factors, chemotherapy, type of surgery, receipt of radiation therapy, age category, and comorbidity. Results Ki-67 was not associated with increased risk of recurrence in tamoxifen-treated patients (ORadj =0.72, 95% CI 0.54, 0.96) or ER-negative patients (ORadj =0.85, 95% CI 0.54, 1.34). Conclusion Our findings suggest that Ki-67 digital image analysis in TMAs is not associated with increased risk of recurrence among tamoxifen-treated ER-positive breast cancer or ER-negative breast cancer patients. Overall, our findings do not support an increased risk of recurrence associated with Ki-67 expression.