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Intratumoral heterogeneity of Ki67 proliferation index outperforms conventional immunohistochemistry prognostic factors in estrogen receptor-positive HER2-negative breast cancer

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Abstract

In breast cancer (BC), pathologists visually score ER, PR, HER2, and Ki67 biomarkers to assess tumor properties and predict patient outcomes. This does not systematically account for intratumoral heterogeneity (ITH) which has been reported to provide prognostic value. This study utilized digital image analysis (DIA) and computational pathology methods to investigate the prognostic value of ITH indicators in ER-positive (ER+) HER2-negative (HER2−) BC patients. Whole slide images (WSIs) of surgically excised specimens stained for ER, PR, Ki67, and HER2 from 254 patients were used. DIA with tumor tissue segmentation and detection of biomarker-positive cells was performed. The DIA-generated data were subsampled by a hexagonal grid to compute Haralick’s texture indicators for ER, PR, and Ki67. Cox regression analyses were performed to assess the prognostic significance of the immunohistochemistry (IHC) and ITH indicators in the context of clinicopathologic variables. In multivariable analysis, the ITH of Ki67-positive cells, measured by Haralick’s texture entropy, emerged as an independent predictor of worse BC-specific survival (BCSS) (hazard ratio (HR) = 2.64, p-value = 0.0049), along with lymph node involvement (HR = 2.26, p-value = 0.0195). Remarkably, the entropy representing the spatial disarrangement of tumor proliferation outperformed the proliferation rate per se established either by pathology reports or DIA. We conclude that the Ki67 entropy indicator enables a more comprehensive risk assessment with regard to BCSS, especially in cases with borderline Ki67 proliferation rates. The study further demonstrates the benefits of high-capacity DIA-generated data for quantifying the essentially subvisual ITH properties.

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Data availability

The dataset analyzed during the current study is available from the corresponding author on reasonable request.

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Funding

This project has received funding from the Research Council of Lithuania (LMTLT), agreement No S-PD-22-86.

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Authors and Affiliations

  1. Institute of Informatics, Faculty of Mathematics and Informatics, Vilnius University, Naugarduko Str. 24, 03225, Vilnius, Lithuania

    Dovile Zilenaite-Petrulaitiene & Linas Petkevicius

  2. Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, M. K. Ciurlionio Str. 21, 03101, Vilnius, Lithuania

    Dovile Zilenaite-Petrulaitiene, Allan Rasmusson, Justinas Besusparis, Ruta Barbora Valkiuniene, Renaldas Augulis, Aida Laurinaviciene, Benoit Plancoulaine & Arvydas Laurinavicius

  3. National Centre of Pathology, affiliate of Vilnius University Hospital Santaros Klinikos, P. Baublio Str. 5, 08406, Vilnius, Lithuania

    Dovile Zilenaite-Petrulaitiene, Allan Rasmusson, Justinas Besusparis, Ruta Barbora Valkiuniene, Renaldas Augulis, Aida Laurinaviciene & Arvydas Laurinavicius

  4. Path-Image/BioTiCla, University of Caen Normandy, François Baclesse Comprehensive Cancer Center, 3 Av. du Général Harris, 14000, Caen, France

    Benoit Plancoulaine

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  1. Dovile Zilenaite-Petrulaitiene
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Contributions

D.Z.P., A.R., J.B., R.B.V., R.A., Ai.L., B.P., L.P., and A.L. participated in the conception and design of the study. D.Z.P. and Ai.L. participated in tumor sample collection and IHC staining. D.Z.P., J.B., and R.B.V. carried out the digital analysis. D.Z.P. performed statistical analyses. D.Z.P., in collaboration with A.R., A.L., and L.P., participated in the interpretation of the results and drafted essential parts of the manuscript. All authors critically revised and approved the final version of the manuscript.

Corresponding author

Correspondence to Dovile Zilenaite-Petrulaitiene.

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Ethics approval and consent to participate

The study was approved by the Lithuanian Bioethics Committee (reference number: 40, updated on 2023-01-10 (Nr. 6B-23-8)). The patient’s consent to participate in the study was obtained before study entry.

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The authors declare no competing interests.

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Zilenaite-Petrulaitiene, D., Rasmusson, A., Besusparis, J. et al. Intratumoral heterogeneity of Ki67 proliferation index outperforms conventional immunohistochemistry prognostic factors in estrogen receptor-positive HER2-negative breast cancer. Virchows Arch (2024). https://doi.org/10.1007/s00428-024-03737-4

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  • DOI: https://doi.org/10.1007/s00428-024-03737-4

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