Association of polo-like kinase 3 and PhosphoT273 caspase 8 levels with disease-related outcomes among cervical squamous cell carcinoma patients treated with chemoradiation and brachytherapy

  • Introduction: Definitive chemoradiation (CRT) followed by high-dose-rate (HDR) brachytherapy (BT) represents state-of-the-art treatment for locally-advanced cervical cancer. Despite use of this treatment paradigm, disease-related outcomes have stagnated in recent years, indicating the need for biomarker development and improved patient stratification. Here, we report the association of Polo-like kinase (PLK) 3 expression and Caspase 8 T273 phosphorylation levels with survival among patients with cervical squamous cell carcinoma (CSCC) treated with CRT plus BT. Methods: We identified 74 patients with FIGO Stage Ib to IVb cervix squamous cell carcinoma. Baseline immunohistochemical scoring of PLK3 and pT273 Caspase 8 levels was performed on pre-treatment samples. Correlation was then assessed between marker expression and clinical endpoints, including cumulative incidences of local and distant failure, cancer-specific survival (CSS) and overall survival (OS). Data were then validated using The Cancer Genome Atlas (TCGA) dataset. Results: PLK3 expression levels were associated with pT273 Caspase 8 levels (p = 0.009), as well as N stage (p = 0.046), M stage (p = 0.026), and FIGO stage (p = 0.001). By the same token, pT273 Caspase 8 levels were associated with T stage (p = 0.031). Increased PLK3 levels corresponded to a lower risk of distant relapse (p = 0.009), improved CSS (p = 0.001), and OS (p = 0.003). Phospho T273 Caspase 8 similarly corresponded to decreased risk of distant failure (p = 0.021), and increased CSS (p < 0.001) and OS (p < 0.001) and remained a significant predictor for OS on multivariate analysis. TCGA data confirmed the association of low PLK3 expression with resistance to radiotherapy and BT (p < 0.05), as well as increased propensity for metastasis (p = 0.019). Finally, a combined PLK3 and pT273 Caspase 8 score predicted for decreased distant relapse (p = 0.005), and both improved CSS (p < 0.001) and OS (p < 0.001); this combined score independently predicted distant failure (p = 0.041) and CSS (p = 0.003) on multivariate analyses. Conclusion: Increased pre-treatment tumor levels of PLK3 and pT273 Caspase 8 correspond to improved disease-related outcomes among cervical cancer patients treated with CRT plus BT, representing a potential biomarker in this context.

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Author:Max Fleischmann, Daniel MartinORCiD, Samuel Peña-Llopis, Julius Oppermann, Jens Müller-von der GrünORCiDGND, Markus Diefenhardt, Georgios Chatzikonstantinou, Emmanouil FokasORCiDGND, Claus RödelORCiDGND, Klaus StrebhardtORCiD, Sven BeckerGND, Franz RödelORCiDGND, Nikolaos Tselis
Pubmed Id:
Parent Title (English):Frontiers in oncology
Publisher:Frontiers Media
Place of publication:Lausanne
Contributor(s):William, Jr. Small
Document Type:Article
Year of Completion:2019
Date of first Publication:2019/08/14
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/10/10
Tag:cancer-specific survival; caspase 8; cervical cancer; chemoradiotherapy; local control; overall survival; polo-like kinase 3
Issue:Art. 742
Page Number:10
First Page:1
Last Page:10
Copyright © 2019 Fleischmann, Martin, Peña-Llopis, Oppermann, von der Grün, Diefenhardt, Chatzikonstantinou, Fokas, Rödel, Strebhardt, Becker, Rödel and Tselis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0