Digital image analysis of Ki-67 stained tissue microarrays and recurrence in tamoxifen-treated breast cancer patients

Nina Gran Egeland; Kristin Jonsdottir; Kristina Lystlund Lauridsen; Ivar Skaland; Cathrine F. Hjorth; Einar G. Gudlaugsson; Stephen Hamilton-Dutoit; Timothy L. Lash; Deirdre Cronin-Fenton; Emiel A.M. Janssen

doi:10.2147/CLEP.S248167

Digital image analysis of Ki-67 stained tissue microarrays and recurrence in tamoxifen-treated breast cancer patients

Nina Gran Egeland^*, Kristin Jonsdottir, Kristina Lystlund Lauridsen, Ivar Skaland, Cathrine F. Hjorth, Einar G. Gudlaugsson, Stephen Hamilton-Dutoit, Timothy L. Lash, Deirdre Cronin-Fenton, Emiel A.M. Janssen

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

5 Citations (Scopus)

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.

Original language	English
Journal	Clinical Epidemiology
Volume	12
Pages (from-to)	771-781
Number of pages	11
ISSN	1179-1349
DOIs	https://doi.org/10.2147/CLEP.S248167
Publication status	Published - 2020

Keywords

Breast cancer
DIA
Digital image analysis
Ki-67
Proliferation
Recurrence risk
Tamoxifen
Tissue microarray
TMA

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Egeland, N. G., Jonsdottir, K., Lauridsen, K. L., Skaland, I., Hjorth, C. F., Gudlaugsson, E. G., Hamilton-Dutoit, S., Lash, T. L., Cronin-Fenton, D., & Janssen, E. A. M. (2020). Digital image analysis of Ki-67 stained tissue microarrays and recurrence in tamoxifen-treated breast cancer patients. Clinical Epidemiology, 12, 771-781. https://doi.org/10.2147/CLEP.S248167

@article{38ce8d806830409481879a8e2e7e89ab,

title = "Digital image analysis of Ki-67 stained tissue microarrays and recurrence in tamoxifen-treated breast cancer patients",

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.",

keywords = "Breast cancer, DIA, Digital image analysis, Ki-67, Proliferation, Recurrence risk, Tamoxifen, Tissue microarray, TMA",

author = "Egeland, {Nina Gran} and Kristin Jonsdottir and Lauridsen, {Kristina Lystlund} and Ivar Skaland and Hjorth, {Cathrine F.} and Gudlaugsson, {Einar G.} and Stephen Hamilton-Dutoit and Lash, {Timothy L.} and Deirdre Cronin-Fenton and Janssen, {Emiel A.M.}",

year = "2020",

doi = "10.2147/CLEP.S248167",

language = "English",

volume = "12",

pages = "771--781",

journal = "Clinical Epidemiology",

issn = "1179-1349",

publisher = "Dove Medical Press Ltd.",

}

Digital image analysis of Ki-67 stained tissue microarrays and recurrence in tamoxifen-treated breast cancer patients. / Egeland, Nina Gran; Jonsdottir, Kristin; Lauridsen, Kristina Lystlund et al.
In: Clinical Epidemiology, Vol. 12, 2020, p. 771-781.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Digital image analysis of Ki-67 stained tissue microarrays and recurrence in tamoxifen-treated breast cancer patients

AU - Egeland, Nina Gran

AU - Jonsdottir, Kristin

AU - Lauridsen, Kristina Lystlund

AU - Skaland, Ivar

AU - Hjorth, Cathrine F.

AU - Gudlaugsson, Einar G.

AU - Hamilton-Dutoit, Stephen

AU - Lash, Timothy L.

AU - Cronin-Fenton, Deirdre

AU - Janssen, Emiel A.M.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Breast cancer

KW - DIA

KW - Digital image analysis

KW - Ki-67

KW - Proliferation

KW - Recurrence risk

KW - Tamoxifen

KW - Tissue microarray

KW - TMA

UR - http://www.scopus.com/inward/record.url?scp=85088578527&partnerID=8YFLogxK

U2 - 10.2147/CLEP.S248167

DO - 10.2147/CLEP.S248167

M3 - Journal article

C2 - 32801916

AN - SCOPUS:85088578527

SN - 1179-1349

VL - 12

SP - 771

EP - 781

JO - Clinical Epidemiology

JF - Clinical Epidemiology

ER -

Digital image analysis of Ki-67 stained tissue microarrays and recurrence in tamoxifen-treated breast cancer patients

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Keywords

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