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. 2025 Feb;486(2):287-298.
doi: 10.1007/s00428-024-03737-4. Epub 2024 Jan 13.

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

Dovile Zilenaite-Petrulaitiene  1   2   3 , Allan Rasmusson  4   5 , Justinas Besusparis  4   5 , Ruta Barbora Valkiuniene  4   5 , Renaldas Augulis  4   5 , Aida Laurinaviciene  4   5 , Benoit Plancoulaine  4   6 , Linas Petkevicius  7 , Arvydas Laurinavicius  4   5
Affiliations

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

Dovile Zilenaite-Petrulaitiene et al. Virchows Arch. 2025 Feb.

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.

Keywords: Breast cancer; Digital image analysis; Haralick’s texture entropy; Immunohistochemistry; Intratumoral heterogeneity; Ki67 proliferation rate.

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Conflict of interest statement

Declarations. 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. Conflict of interest: The authors declare no competing interests.

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References

    1. Arzmi MH, Abdul Majeed A, Muazu Musa R, Mohd Razman MA, Gan HS, Mohd Khairuddin I, Nasir AF (2023) Epidemiology, detection and management of cancer: an overview. In: Deep Learning in Cancer Diagnostics: A Feature-based Transfer Learning Evaluation. Springer Nature Singapore, Singapore, pp 1–7 - DOI
    1. Wilkinson L, Gathani T (2022) Understanding breast cancer as a global health concern. Br J Radiol 95:20211033. https://doi.org/10.1259/bjr.20211033 - DOI - PubMed
    1. Greenwalt I, Zaza N, Das S, Li BD (2020) Precision medicine and targeted therapies in breast cancer. Surg Oncol Clin N Am 29:51–62. https://doi.org/10.1016/j.soc.2019.08.004 - DOI - PubMed
    1. Allison KH, Hammond MEH, Dowsett M, McKernin SE, Carey LA, Fitzgibbons PL, Hayes DF, Lakhani SR, Chavez-MacGregor M, Perlmutter J, Perou CM, Regan MM, Rimm DL, Symmans WF, Torlakovic EE, Varella L, Viale G, Weisberg TF, McShane LM, Wolff AC (2020) Estrogen and progesterone receptor testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists guideline update. Arch Pathol Lab Med 144:545–563. https://doi.org/10.5858/arpa.2019-0904-SA - DOI - PubMed
    1. Wolff AC, Somerfield MR, Dowsett M, Hammond MEH, Hayes DF, McShane LM, Saphner TJ, Spears PA, Allison KH (2023) Human epidermal growth factor receptor 2 testing in breast cancer: ASCO–College of American Pathologists guideline update. J Clin Oncol 41:3867–3872. https://doi.org/10.1200/JCO.22.02864 - DOI - PubMed

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