Independent Clinical Validation of the Automated Ki67 Scoring Guideline from the International Ki67 in Breast Cancer Working Group
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patient Cohort
2.2. Immunohistochemical Staining
2.3. Digital Image Analysis
2.4. Statistical Analysis
3. Results
3.1. Patient and Tumor Characteristics
3.2. Reproducibility among Pathologists
3.3. Prognostic Potential of DIA Ki67 Scoring
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
IKWG | International Ki67 in Breast Cancer Working Group |
DIA | Digital image analysis |
ICC | Intraclass correlation coefficient |
WS | Whole-slide section |
HE | Hematoxylin and eosin |
DAB | 3,3’-diaminobenzidine |
CI | Confidence interval |
RFS | Relapse-free survival |
pTNM | Pathological Tumor-Node-Metastasis |
AJCC | American Joint Committee on Cancer |
References
- Sun, X.; Kaufman, P.D. Ki-67: More than a proliferation marker. Chromosoma 2018, 127, 175–186. [Google Scholar] [CrossRef]
- Goldhirsch, A.; Wood, W.C.; Coates, A.S.; Gelber, R.D.; Thürlimann, B.; Senn, H.J. Strategies for subtypes-dealing with the diversity of breast cancer: Highlights of the St Gallen in-ternational expert consensus on the primary therapy of early breast cancer 2011. Ann. Oncol. 2011, 22, 1736–1747. [Google Scholar] [CrossRef]
- Nielsen, T.O.; Leung, S.C.Y.; Rimm, D.L.; Dodson, A.; Acs, B.; Badve, S.; Denkert, C.; Ellis, M.J.; Fineberg, S.; Flowers, M.; et al. Assessment of Ki67 in Breast Cancer: Updated Recommendations from the International Ki67 in Breast Cancer Working Group. J. Natl. Cancer Inst. 2021, 113, 808–819. [Google Scholar] [CrossRef] [PubMed]
- Penault-Llorca, F.; Radosevic-Robin, N. Ki67 assessment in breast cancer: An update. Pathology 2017, 49, 166–171. [Google Scholar] [CrossRef]
- Leung, S.C.Y.; Nielsen, T.O.; Zabaglo, L.A.; Arun, I.; Badve, S.S.; Bane, A.L.; Bartlett, J.M.S.; Borgquist, S.; Chang, M.C.; Dodson, A.; et al. Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: An international multicentre collaboration. Histopathology 2019, 75, 225–235. [Google Scholar] [CrossRef]
- Paik, S.; Kwon, Y.; Lee, M.H.; Kim, J.Y.; Lee, D.K.; Cho, W.J.; Lee, E.Y. Systematic evaluation of scoring methods for Ki67 as a surrogate for 21-gene recurrence score. NPJ Breast Cancer 2021, 7, 1–8. [Google Scholar] [CrossRef] [PubMed]
- Acs, B.; Pelekanou, V.; Bai, Y.; Martinez-Morilla, S.; Toki, M.; Leung, S.C.Y.; Nielsen, T.O.; Rimm, D.L. Ki67 reproducibility using digital image analysis: An inter-platform and inter-operator study. Lab. Investig. 2020, 99, 107–117. [Google Scholar] [CrossRef]
- Acs, B.; Leung, S.C.; Kidwell, K.M.; Arun, I.; Augulis, R.; Badve, S.S.; Bai, Y.; Bane, A.L.; Bartlett, J.M.; Bayani, J.; et al. Abstract P5-02-01: Analytical validation and prognostic potential of an automated digital scoring protocol for Ki67: An international Ki67 working group study. In Proceedings of the 2019 San Antonio Breast Cancer Symposium, San Antonio, TX, USA, 10–14 December 2019. [Google Scholar]
- Robertson, S.; Acs, B.; Lippert, M.; Hartman, J. Prognostic potential of automated Ki67 evaluation in breast cancer: Different hot spot definitions versus true global score. Breast Cancer Res. Treat. 2020, 183, 161–175. [Google Scholar] [CrossRef]
- Stålhammar, G.; Robertson, S.; Wedlund, L.; Lippert, M.; Rantalainen, M.; Bergh, J.; Hartman, J. Digital image analysis of Ki67 in hot spots is superior to both manual Ki67 and mitotic counts in breast cancer. Histopathology 2018, 72, 974–989. [Google Scholar] [CrossRef] [PubMed]
- Stålhammar, G.; Martinez, N.F.; Lippert, M.; Tobin, N.P.; Mølholm, I.; Kis, L.; Rosin, G.; Rantalainen, M.; Pedersen, L.; Bergh, J.; et al. Digital image analysis outperforms manual biomarker assessment in breast cancer. Mod. Pathol. 2016, 29, 318–329. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rantalainen, M.; Klevebring, D.; Lindberg, J.; Ivansson, E.; Rosin, G.; Kis, L.; Celebioglu, F.; Fredriksson, I.; Czene, K.; Frisell, J.; et al. Sequencing-based breast cancer diagnostics as an alternative to routine biomarkers. Sci. Rep. 2016, 6, 38037. [Google Scholar] [CrossRef] [Green Version]
- Wang, M.; Klevebring, D.; Lindberg, J.; Czene, K.; Grönberg, H.; Rantalainen, M. Determining breast cancer histological grade from RNA-sequencing data. Breast Cancer Res. 2016, 18, 48. [Google Scholar] [CrossRef] [Green Version]
- Goldhirsch, A.; Winer, E.P.; Coates, A.S.; Gelber, R.D.; Piccart-Gebhart, M.; Thürlimann, B.; Senn, H.-J. Personalizing the treatment of women with early breast cancer: Highlights of the st gallen inter-national expert consensus on the primary therapy of early breast Cancer 2013. Ann. Oncol. 2013, 24, 2206–2223. [Google Scholar] [CrossRef]
- Landis, J.R.; Koch, G.G. The Measurement of Observer Agreement for Categorical Data. Biometrics 1977, 33, 159–174. [Google Scholar] [CrossRef] [Green Version]
- Pinder, S.E.; Wencyk, P.M.S.D.; Sibbering, D.M.; Bell, J.A.; Elston, C.W.; Nicholson, R.; Roberstson, J.F.R.; Blamey, R.W.; Ellis, I.O. Assessment of the new proliferation marker MIB1 in breast carcinoma using image analysis: Associations with other prognostic factors and survival. Br. J. Cancer 1995, 71, 146–149. [Google Scholar] [CrossRef] [Green Version]
- Trihia, H.; Murray, S.; Price, K.; Gelber, R.D.; Golouh, R.; Goldhirsch, A.; Coates, A.S.; Collins, J.; Castiglione-Gertsch, M. Ki-67 expression in breast carcinoma: Its association with grading systems, clinical parameters, and other prognostic factors—A surrogate marker? Cancer 2003, 97, 1321–1331. [Google Scholar] [CrossRef] [PubMed]
- Molino, A.; Micciolo, R.; Turazza, M.; Bonetti, F.; Piubello, Q.; Bonetti, A.; Nortilli, R.; Pelosi, G.; Cetto, G.L. Ki-67 immunostaining in 322 primary breast cancers: Associations with clinical and pathological variables and prognosis. Int. J. Cancer 1997, 74, 433–437. [Google Scholar] [CrossRef]
- Fasching, P.A.; Heusinger, K.; Haeberle, L.; Niklos, M.; Hein, A.; Bayer, C.M.; Rauh, C.; Schulz-Wendtland, R.; Bani, M.R.; Schrauder, M.; et al. Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment. BMC Cancer 2011, 11, 486. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Reinert, T.; de Souza, A.B.A.; Sartori, G.P.; Obst, F.M.; Barrios, C.H. Highlights of the 17th St. Gallen International Breast Cancer Conference 2021: Customising local and systemic therapies. ecancer 2021, 15, 1236. [Google Scholar] [CrossRef]
- Denkert, C.; Budczies, J.; von Minckwitz, G.; Wienert, S.; Loibl, S.; Klauschen, F. Strategies for developing Ki67 as a useful biomarker in breast cancer. Breast 2015, 24, S67–S72. [Google Scholar] [CrossRef]
- Polley, M.-Y.C.; Leung, S.C.Y.; McShane, L.M.; Gao, D.; Hugh, J.C.; Mastropasqua, M.G.; Viale, G.; Zabaglo, L.A.; Penault-Llorca, F.; Bartlett, J.M.; et al. An International Ki67 Reproducibility Study. J. Natl. Cancer Inst. 2013, 105, 1897–1906. [Google Scholar] [CrossRef]
- Acs, B.; Fredriksson, I.; Rönnlund, C.; Hagerling, C.; Ehinger, A.; Kovács, A.; Røge, R.; Bergh, J.; Hartman, J. Variability in Breast Cancer Biomarker Assessment and the Effect on Oncological Treatment Decisions: A Nationwide 5-Year Population-Based Study. Cancers 2021, 13, 1166. [Google Scholar] [CrossRef]
- Alataki, A.; Zabaglo, L.; Tovey, H.; Dodson, A.; Dowsett, M. A simple digital image analysis system for automated Ki67 assessment in primary breast cancer. Histopathology 2021, 79, 200–209. [Google Scholar] [CrossRef]
- Koopman, T.; Buikema, H.J.; Hollema, H.; de Bock, G.H.; van der Vegt, B. Digital image analysis of Ki67 proliferation index in breast cancer using virtual dual staining on whole tissue sections: Clinical validation and inter-platform agreement. Breast Cancer Res. Treat. 2018, 169, 33–42. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sanchez, M.D.R.T.; Soler-Monsó, T.; Petit, A.; Azcarate, J.; Lasheras, A.; Artal, C.; Gil, M.; Falo, C.; Pla, M.J.; Matias-Guiu, X. Digital quantification of KI-67 in breast cancer. Virchows Archiv 2018, 474, 169–176. [Google Scholar] [CrossRef] [PubMed]
- Rimm, D.L.; Leung, S.C.Y.; McShane, L.M.; Bai, Y.; Bane, A.L.; Bartlett, J.M.S.; Bayani, J.; Chang, M.C.; Dean, M.; Denkert, C.; et al. An international multicenter study to evaluate reproducibility of automated scoring for assessment of Ki67 in breast cancer. Mod. Pathol. 2018, 32, 59–69. [Google Scholar] [CrossRef] [PubMed]
- Focke, C.M.; Bürger, H.; van Diest, P.J.; Finsterbusch, K.; Gläser, D.; Korsching, E.; Decker, T.; Anders, M.; Bollmann, R.; Eiting, F.; et al. Interlaboratory variability of Ki67 staining in breast cancer. Eur. J. Cancer 2017, 84, 219–227. [Google Scholar] [CrossRef]
n | % | |
---|---|---|
Total cases | 157 | 100 |
Patient median age (range) | 59 (28–79) | |
Tumor mean diameter (mm) | 25 | |
Tumor median diameter (mm) | 22 | |
Histological grade * | ||
1 | 27 | 17 |
2 | 84 | 54 |
3 | 46 | 29 |
Tumor size ** | ||
pT1 | 63 | 40 |
pT2 | 86 | 55 |
pT3 | 8 | 5 |
Lymph node status ** | ||
pN0 | 87 | 55 |
pN1 | 51 | 32 |
pN2 | 15 | 10 |
pN3 | 4 | 3 |
Variables | p-Value | HR | 95.0% CI for Exp(B) | |
---|---|---|---|---|
Lower | Upper | |||
HG 1 | 0.623 | |||
HG 2 | 0.703 | 1.348 | 0.291 | 6.249 |
HG 3 | 0.829 | 0.816 | 0.128 | 5.191 |
Tumor size < 20 mm | 0.675 | |||
20–50 mm | 0.434 | 1.448 | 0.573 | 3.655 |
>50 mm | 0.466 | 1.859 | 0.351 | 9.838 |
LN without metastasis | 0.021 | |||
1–3 metastasis in LN | 0.544 | 1.336 | 0.525 | 3.402 |
4–9 metastasis in LN | 0.003 | 4.742 | 1.696 | 13.258 |
≥10 metastasis in LN | 0.151 | 3.947 | 0.607 | 25.649 |
Reference Ki67 | 0.017 | 3.72 | 1.263 | 10.957 |
DIA reader 1 | 0.006 | 4.835 | 1.587 | 14.734 |
DIA reader 2 | 0.018 | 3.597 | 1.246 | 10.386 |
DIA reader 3 | 0.017 | 3.96 | 1.273 | 12.324 |
DIA reader 4 | 0.001 | 8.074 | 2.842 | 22.937 |
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Boyaci, C.; Sun, W.; Robertson, S.; Acs, B.; Hartman, J. Independent Clinical Validation of the Automated Ki67 Scoring Guideline from the International Ki67 in Breast Cancer Working Group. Biomolecules 2021, 11, 1612. https://doi.org/10.3390/biom11111612
Boyaci C, Sun W, Robertson S, Acs B, Hartman J. Independent Clinical Validation of the Automated Ki67 Scoring Guideline from the International Ki67 in Breast Cancer Working Group. Biomolecules. 2021; 11(11):1612. https://doi.org/10.3390/biom11111612
Chicago/Turabian StyleBoyaci, Ceren, Wenwen Sun, Stephanie Robertson, Balazs Acs, and Johan Hartman. 2021. "Independent Clinical Validation of the Automated Ki67 Scoring Guideline from the International Ki67 in Breast Cancer Working Group" Biomolecules 11, no. 11: 1612. https://doi.org/10.3390/biom11111612