TY  - JOUR
A1  - Fleischmann, Maximilian
A1  - Martin, Daniel
A1  - Peña-Llopis, Samuel
A1  - Oppermann, Julius
A1  - Müller-von der Grün, Jens
A1  - Diefenhardt, Markus
A1  - Chatzikonstantinou, Georgios
A1  - Fokas, Emmanouil
A1  - Rödel, Claus
A1  - Strebhardt, Klaus
A1  - Becker, Sven
A1  - Rödel, Franz
A1  - Tselis, Nikolaos
T1  - 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
T2  - Frontiers in oncology
N2  - 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.
KW  - cervical cancer
KW  - polo-like kinase 3
KW  - caspase 8
KW  - chemoradiotherapy
KW  - local control
KW  - cancer-specific survival
KW  - overall survival
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/51281
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-512818
SN  - 2234-943X
N1  - 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.
VL  - 9
IS  - Art. 742
SP  - 1
EP  - 10
PB  - Frontiers Media
CY  - Lausanne
ER  -