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

Dovile Zilenaite-Petrulaitiene; Allan Rasmusson; Justinas Besusparis; Ruta Barbora Valkiuniene; Renaldas Augulis; Aida Laurinaviciene; Benoit Plancoulaine; Linas Petkevicius; Arvydas Laurinavicius

doi:10.1007/s00428-024-03737-4

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

Virchows Arch. 2024 Jan 13. doi: 10.1007/s00428-024-03737-4. Online ahead of print.

Authors

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 Petkevicius⁷, Arvydas Laurinavicius^{4

5}

Affiliations

¹ Institute of Informatics, Faculty of Mathematics and Informatics, Vilnius University, Naugarduko Str. 24, 03225, Vilnius, Lithuania. dovile.zilenaite@vpc.lt.
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@vpc.lt.
³ National Centre of Pathology, affiliate of Vilnius University Hospital Santaros Klinikos, P. Baublio Str. 5, 08406, Vilnius, Lithuania. dovile.zilenaite@vpc.lt.
⁴ Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, M. K. Ciurlionio Str. 21, 03101, Vilnius, Lithuania.
⁵ National Centre of Pathology, affiliate of Vilnius University Hospital Santaros Klinikos, P. Baublio Str. 5, 08406, Vilnius, Lithuania.
⁶ Path-Image/BioTiCla, University of Caen Normandy, François Baclesse Comprehensive Cancer Center, 3 Av. du Général Harris, 14000, Caen, France.
⁷ Institute of Informatics, Faculty of Mathematics and Informatics, Vilnius University, Naugarduko Str. 24, 03225, Vilnius, Lithuania.

PMID: 38217716
DOI: 10.1007/s00428-024-03737-4

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.