Standardized Ki67 Diagnostics Using Automated Scoring-Clinical Validation in the GeparTrio Breast Cancer Study

被引:82
作者
Klauschen, Frederick [1 ]
Wienert, Stephan [1 ,2 ]
Schmitt, Wolfgang D. [1 ]
Loibl, Sibylle [3 ]
Gerber, Bernd [4 ]
Blohmer, Jens-Uwe [5 ,6 ]
Huober, Jens [7 ]
Ruediger, Thomas [8 ]
Erbstoesser, Erhard [9 ]
Mehta, Keyur [3 ]
Lederer, Bianca
Dietel, Manfred [1 ]
Denkert, Carsten [1 ]
von Minckwitz, Gunter [3 ,10 ]
机构
[1] Charite, Inst Pathol, Berlin, Germany
[2] VMscope GmbH, Berlin, Germany
[3] German Breast Grp, Neu Isenburg, Germany
[4] Univ Womens Hosp Rostock, Rostock, Germany
[5] Charite, Dept Gynecol, Berlin, Germany
[6] Charite, Breast Ctr, Berlin, Germany
[7] Univ Womens Hosp Ulm, Ulm, Germany
[8] Klinikum Karlsruhe, Karlsruhe, Germany
[9] AMEOS Klinikum Halberstadt, Halberstadt, Germany
[10] Univ Womens Hosp Frankfurt, Frankfurt, Germany
关键词
INTERNATIONAL EXPERT CONSENSUS; III RANDOMIZED GEPARTRIO; PRIMARY THERAPY; PROLIFERATION; KI-67; METAANALYSIS; HIGHLIGHTS; MARKER;
D O I
10.1158/1078-0432.CCR-14-1283
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Scoring proliferation through Ki67 immunohistochemistry is an important component in predicting therapy response to chemotherapy in patients with breast cancer. However, recent studies have cast doubt on the reliability of "visual" Ki67 scoring in the multicenter setting, particularly in the lower, yet clinically important, proliferation range. Therefore, an accurate and standardized Ki67 scoring is pivotal both in routine diagnostics and larger multicenter studies. Experimental Design: We validated a novel fully automated Ki67 scoring approach that relies on only minimal a priori knowledge on cell properties and requires no training data for calibration. We applied our approach to 1,082 breast cancer samples from the neoadjuvant GeparTrio trial and compared the performance of automated and manual Ki67 scoring. Results: The three groups of autoKi67 as defined by low (<= 15%), medium (15.1%-35%), and high (>35%) automated scores showed pCR rates of 5.8%, 16.9%, and 29.5%, respectively. AutoKi67 was significantly linked to prognosis with overall and progression-free survival P values P-OS < 0.0001 and P-PFS < 0.0002, compared with P-OS < 0.0005 and P-PFS < 0.0001 for manual Ki67 scoring. Moreover, automated Ki67 scoring was an independent prognosticator in the multivariate analysis with P-OS = 0.002, P-PFS = 0.009 (autoKi67) versus P-OS = 0.007, P-PFS = 0.004 (manual Ki67). Conclusions: The computer-assisted Ki67 scoring approach presented here offers a standardized means of tumor cell proliferation assessment in breast cancer that correlated with clinical endpoints and is deployable in routine diagnostics. It may thus help to solve recently reported reliability concerns in Ki67 diagnostics. (C)2014 AACR.
引用
收藏
页码:3651 / 3657
页数:7
相关论文
共 25 条
[1]   Cutoff Finder: A Comprehensive and Straightforward Web Application Enabling Rapid Biomarker Cutoff Optimization [J].
Budczies, Jan ;
Klauschen, Frederick ;
Sinn, Bruno V. ;
Gyoerffy, Balazs ;
Schmitt, Wolfgang D. ;
Darb-Esfahani, Silvia ;
Denkert, Carsten .
PLOS ONE, 2012, 7 (12)
[2]  
Cass Jamaica D, 2012, Cancers (Basel), V4, P725, DOI 10.3390/cancers4030725
[3]   Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12 155 patients [J].
de Azambuja, E. ;
Cardoso, F. ;
de Castro, G., Jr. ;
Colozza, M. ;
Mano, M. S. ;
Durbecq, V. ;
Sotiriou, C. ;
Larsimont, D. ;
Piccart-Gebhart, M. J. ;
Paesmans, M. .
BRITISH JOURNAL OF CANCER, 2007, 96 (10) :1504-1513
[4]   Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial† [J].
Denkert, C. ;
Loibl, S. ;
Mueller, B. M. ;
Eidtmann, H. ;
Schmitt, W. D. ;
Eiermann, W. ;
Gerber, B. ;
Tesch, H. ;
Hilfrich, J. ;
Huober, J. ;
Fehm, T. ;
Barinoff, J. ;
Jackisch, C. ;
Prinzler, J. ;
Ruediger, T. ;
Erbstoesser, E. ;
Blohmer, J. U. ;
Budczies, J. ;
Mehta, K. M. ;
von Minckwitz, G. .
ANNALS OF ONCOLOGY, 2013, 24 (11) :2786-2793
[5]   PRODUCTION OF A MOUSE MONOCLONAL-ANTIBODY REACTIVE WITH A HUMAN NUCLEAR ANTIGEN ASSOCIATED WITH CELL-PROLIFERATION [J].
GERDES, J ;
SCHWAB, U ;
LEMKE, H ;
STEIN, H .
INTERNATIONAL JOURNAL OF CANCER, 1983, 31 (01) :13-20
[6]   Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011 [J].
Goldhirsch, A. ;
Wood, W. C. ;
Coates, A. S. ;
Gelber, R. D. ;
Thuerlimann, B. ;
Senn, H. -J. .
ANNALS OF ONCOLOGY, 2011, 22 (08) :1736-1747
[7]   Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009 [J].
Goldhirsch, A. ;
Ingle, J. N. ;
Gelber, R. D. ;
Coates, A. S. ;
Thuerlimann, B. ;
Senn, H. -J. .
ANNALS OF ONCOLOGY, 2009, 20 (08) :1319-1329
[8]   Development and evaluation of a virtual microscopy application for automated assessment of Ki-67 expression in breast cancer [J].
Konsti, Juho ;
Lundin, Mikael ;
Joensuu, Heikki ;
Lehtimaki, Tiina ;
Sihto, Harri ;
Holli, Kaija ;
Turpeenniemi-Hujanen, Taina ;
Kataja, Vesa ;
Sailas, Liisa ;
Isola, Jorma ;
Lundin, Johan .
BMC CLINICAL PATHOLOGY, 2011, 11
[9]   Technical note on the validation of a semi-automated image analysis software application for estrogen and progesterone receptor detection in breast cancer [J].
Laszlo Krecsak ;
Tamas Micsik ;
Gabor Kiszler ;
Tibor Krenacs ;
Daniel Szabo ;
Viktor Jonas ;
Gergely Csaszar ;
Laszlo Czuni ;
Peter Gurzo ;
Levente Ficsor ;
Bela Molnar .
DIAGNOSTIC PATHOLOGY, 2011, 6
[10]   Immunohistochemistry profiles of breast ductal carcinoma: factor analysis of digital image analysis data [J].
Laurinavicius, Arvydas ;
Laurinaviciene, Aida ;
Ostapenko, Valerijus ;
Dasevicius, Darius ;
Jarmalaite, Sonata ;
Lazutka, Juozas .
DIAGNOSTIC PATHOLOGY, 2012, 7