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

Abstract

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. Highthroughput automated scoring of Ki-67 might enable standardization of quantification and definition of clinical cutoff 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.

Tissue microarrey: a potential cost-effective approach for mismatch repair testing in colorectal cancer

“…The classifier had a mean area under the ROC curve of 92% [18]. Other studies used automated digital image analysis of KI67 levels and other proteins in TMA breast cancer tissue cores [31][32][33], these studies show the advantages of TMA as a cost effective and as a standalone technique and further emphasize the advantages in combining it with automated digital image analysis software. Another study by Guy Nir et al used automated digital image analysis to determine the grade of prostate cancer in 333 TMA tissue cores.…”

“…This opens the door for automatic assesssment of slides by computer assisted diagnosis (CAD). Indeed, many studies examined the feasibility of incorporating CAD softwares into the routine pathologic examination [28][29][30][31]. Reports regarding CAD for MMR IHC analysis in TMA blocks are scarce.…”

TMA-Mate: An open-source modular toolkit for constructing tissue microarrays of arbitrary layouts

“…Tissue microarrays (TMAs) can be considered as a high-throughput technique, to process up to hundreds of miniaturized tissue samples simultaneously on a single microscopy slide under identical laboratory conditions, in order to reduce labor, costs, and sample utilization and to increase results comparability (reviewed in [4] , [5] ). Like in conventional histology, TMAs can be subjected to primary and special stainings, enzyme histochemistry [6] , conventional [7] and various specialized immunohistochemical (IHC) methods [8] , [9] , in situ hybridizations of RNA [10] and DNA [11] , as well as mass spectrometry techniques [12] , [13] , digital analysis [10] , [14] , [15] , [16] , [17] and more. TMAs are powerful and valuable with a wide range of applications in clinical routine diagnostics [5] , [18] tumor marker research [19] , [20] , [21] , drug discovery [10] , [22] , deep-learning [23] , biobanking [24] , [25] , quality control [5] and education [26] .…”

Tissue Microarrey: A potential cost-effective approach for mismatch repair testing in colorectal cancer

“…This opens the door for automatic assesssment of slides by computer assisted diagnosis (CAD). Indeed, many studies examined the feasibility of incorporating CAD softwares into the routine pathologic examination [28][29][30][31].…”

“…The classi er had a mean area under the ROC curve of 92% [18]. Other studies used automated image analysis of KI67 levels and other proteins in TMA breast cancer tissue cores [31][32][33], these studies show the advantages of TMA as a cost effective and as a standalone technique and further emphasize the advantages in combining it with automated digital image analysis software. Another study by Guy Nir et al used automated digital image analysis to determine the grade of prostate cancer in 333 TMA tissue cores.…”