Cell Cycle Traverse Rate Predicts Long-term Outcomes in a Multi-institutional Cohort of Patients with Triple-negative Breast Cancer

Overview

Journal BJC Rep

Publisher Nature Portfolio

Date 2024 Nov 13

PMID 39537757

Authors

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

Affiliations

Soon will be listed here.

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.

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