Cell cycle traverse rate predicts long-term outcomes in a multi-institutional cohort of patients with triple-negative breast cancer
Abstract Background Ki67 index (KI) and mitotic index (MI) are proliferation markers with established prognostic value in breast carcinomas. While KI is evaluated immunohistochemically and reported as a percentage, MI is determined visually and reflects total mitotic cells in 10 high-power fields. O...
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Nature Portfolio
2024-11-01
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| Series: | BJC Reports |
| Online Access: | https://doi.org/10.1038/s44276-024-00097-z |
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| author | Shristi Bhattarai Manali Rupji Hsueh-ping Chao Qi Xu Geetanjali Saini Padmashree Rida Mohammed A. Aleskandarany Andrew R. Green Ian O. Ellis Emiel A. Janssen Kristin Jonsdottir Emad Rakha Jeanne Kowalski Ritu Aneja |
| author_facet | Shristi Bhattarai Manali Rupji Hsueh-ping Chao Qi Xu Geetanjali Saini Padmashree Rida Mohammed A. Aleskandarany Andrew R. Green Ian O. Ellis Emiel A. Janssen Kristin Jonsdottir Emad Rakha Jeanne Kowalski Ritu Aneja |
| author_sort | Shristi Bhattarai |
| collection | DOAJ |
| description | Abstract Background Ki67 index (KI) and mitotic index (MI) are proliferation markers with established prognostic value in breast carcinomas. While KI is evaluated immunohistochemically and reported as a percentage, MI is determined visually and reflects total mitotic cells in 10 high-power fields. Our objective was to integrate KI and MI into a novel metric; the cell cycle traverse rate (CCTR). Given the lack of prognostic and predictive biomarkers in TNBC, we sought to assess the potential of CCTR as a risk-stratification tool for chemotherapy-treated TNBC patients from two independent cohorts: the Nottingham group (n = 124) and the Norway group (n = 71). Methods We evaluated the ability of CCTR to predict survival after adjuvant chemotherapy for TNBC patients (n = 195) in two independent cohorts. Using immunohistochemistry and RNA sequencing, we determined the differences in immunohistochemical biomarkers, gene ontologies, molecular pathways and immune cell fractions based on CCTR. Results TNBC shows a significantly lower median CCTR compared to luminal A (p < 0.01), luminal B (p < 0.01), and HER2+ samples (p < 0.01). CCTR outperformed both KI and MI in effectively risk-stratifying TNBC patients suggesting that combining KI and MI into a single metric, namely CCTR, could serve as a superior prognostic marker for Breast Cancer Specific Survival (BCSS) (p = 0.041). CCTR-high group exhibited enriched expression of various oncogenic signatures, including angiogenesis, epithelial-to-mesenchymal transition (EMT), Hedgehog signaling, hypoxia, Notch signaling, PI3K-AKT-mTOR signaling, TGFβ signaling, p53 signaling, and TNFα signaling via NFκB. These findings suggest the potential involvement of these pathways in the aggressiveness and clinical outcomes of TNBC patients. Conclusions Collectively, these findings suggest that CCTR offers superior predictive information compared to KI and MI alone with respect to long-term outcomes from adjuvant chemotherapy in patients with TNBC that may guide treatment decision making. |
| format | Article |
| id | doaj-art-8feb79c71f7142a48c824535a1a38430 |
| institution | Kabale University |
| issn | 2731-9377 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | BJC Reports |
| spelling | doaj-art-8feb79c71f7142a48c824535a1a384302024-11-17T12:13:21ZengNature PortfolioBJC Reports2731-93772024-11-012111010.1038/s44276-024-00097-zCell cycle traverse rate predicts long-term outcomes in a multi-institutional cohort of patients with triple-negative breast cancerShristi Bhattarai0Manali Rupji1Hsueh-ping Chao2Qi Xu3Geetanjali Saini4Padmashree Rida5Mohammed A. Aleskandarany6Andrew R. Green7Ian O. Ellis8Emiel A. Janssen9Kristin Jonsdottir10Emad Rakha11Jeanne Kowalski12Ritu Aneja13Department of Molecular and Cellular Biology, Kennesaw State UniversityBiostatistics Shared Resource, Winship Cancer Institute, Emory UniversityDepartment of Oncology and Livestrong Cancer Institutes, The University of Texas at AustinDepartment of Oncology and Livestrong Cancer Institutes, The University of Texas at AustinDepartment of Nutrition Sciences, School of Health Professions, University of Alabama at BirminghamNovazoi TheranosticsDivision of Biomedical and Forensic Sciences, School of Human Science, University of DerbyNottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine, Biodiscovery Institute, University of NottinghamNottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine, Biodiscovery Institute, University of NottinghamDepartment of Pathology, Stavanger University HospitalDepartment of Pathology, Stavanger University HospitalNottingham Breast Cancer Research Centre, Academic Unit for Translational Medical Sciences, School of Medicine, Biodiscovery Institute, University of NottinghamDepartment of Oncology and Livestrong Cancer Institutes, The University of Texas at AustinDepartment of Biology, Georgia State UniversityAbstract Background Ki67 index (KI) and mitotic index (MI) are proliferation markers with established prognostic value in breast carcinomas. While KI is evaluated immunohistochemically and reported as a percentage, MI is determined visually and reflects total mitotic cells in 10 high-power fields. Our objective was to integrate KI and MI into a novel metric; the cell cycle traverse rate (CCTR). Given the lack of prognostic and predictive biomarkers in TNBC, we sought to assess the potential of CCTR as a risk-stratification tool for chemotherapy-treated TNBC patients from two independent cohorts: the Nottingham group (n = 124) and the Norway group (n = 71). Methods We evaluated the ability of CCTR to predict survival after adjuvant chemotherapy for TNBC patients (n = 195) in two independent cohorts. Using immunohistochemistry and RNA sequencing, we determined the differences in immunohistochemical biomarkers, gene ontologies, molecular pathways and immune cell fractions based on CCTR. Results TNBC shows a significantly lower median CCTR compared to luminal A (p < 0.01), luminal B (p < 0.01), and HER2+ samples (p < 0.01). CCTR outperformed both KI and MI in effectively risk-stratifying TNBC patients suggesting that combining KI and MI into a single metric, namely CCTR, could serve as a superior prognostic marker for Breast Cancer Specific Survival (BCSS) (p = 0.041). CCTR-high group exhibited enriched expression of various oncogenic signatures, including angiogenesis, epithelial-to-mesenchymal transition (EMT), Hedgehog signaling, hypoxia, Notch signaling, PI3K-AKT-mTOR signaling, TGFβ signaling, p53 signaling, and TNFα signaling via NFκB. These findings suggest the potential involvement of these pathways in the aggressiveness and clinical outcomes of TNBC patients. Conclusions Collectively, these findings suggest that CCTR offers superior predictive information compared to KI and MI alone with respect to long-term outcomes from adjuvant chemotherapy in patients with TNBC that may guide treatment decision making.https://doi.org/10.1038/s44276-024-00097-z |
| spellingShingle | Shristi Bhattarai Manali Rupji Hsueh-ping Chao Qi Xu Geetanjali Saini Padmashree Rida Mohammed A. Aleskandarany Andrew R. Green Ian O. Ellis Emiel A. Janssen Kristin Jonsdottir Emad Rakha Jeanne Kowalski Ritu Aneja Cell cycle traverse rate predicts long-term outcomes in a multi-institutional cohort of patients with triple-negative breast cancer BJC Reports |
| title | Cell cycle traverse rate predicts long-term outcomes in a multi-institutional cohort of patients with triple-negative breast cancer |
| title_full | Cell cycle traverse rate predicts long-term outcomes in a multi-institutional cohort of patients with triple-negative breast cancer |
| title_fullStr | Cell cycle traverse rate predicts long-term outcomes in a multi-institutional cohort of patients with triple-negative breast cancer |
| title_full_unstemmed | Cell cycle traverse rate predicts long-term outcomes in a multi-institutional cohort of patients with triple-negative breast cancer |
| title_short | Cell cycle traverse rate predicts long-term outcomes in a multi-institutional cohort of patients with triple-negative breast cancer |
| title_sort | cell cycle traverse rate predicts long term outcomes in a multi institutional cohort of patients with triple negative breast cancer |
| url | https://doi.org/10.1038/s44276-024-00097-z |
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