AUTHOR=Fleischmann Max , Martin Daniel , Peña-Llopis Samuel , Oppermann Julius , von der Grün Jens , Diefenhardt Markus , Chatzikonstantinou Georgios , Fokas Emmanouil , Rödel Claus , Strebhardt Klaus , Becker Sven , Rödel Franz , Tselis Nikolaos 

TITLE=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

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.00742

DOI=10.3389/fonc.2019.00742

ISSN=2234-943X

ABSTRACT=<p><bold>Introduction:</bold> 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.</p><p><bold>Methods:</bold> 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.</p><p><bold>Results:</bold> PLK3 expression levels were associated with pT273 Caspase 8 levels (<italic>p</italic> = 0.009), as well as N stage (<italic>p</italic> = 0.046), M stage (<italic>p</italic> = 0.026), and FIGO stage (<italic>p</italic> = 0.001). By the same token, pT273 Caspase 8 levels were associated with T stage (<italic>p</italic> = 0.031). Increased PLK3 levels corresponded to a lower risk of distant relapse (<italic>p</italic> = 0.009), improved CSS (<italic>p</italic> = 0.001), and OS (<italic>p</italic> = 0.003). Phospho T273 Caspase 8 similarly corresponded to decreased risk of distant failure (<italic>p</italic> = 0.021), and increased CSS (<italic>p</italic> &lt; 0.001) and OS (<italic>p</italic> &lt; 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 (<italic>p</italic> &lt; 0.05), as well as increased propensity for metastasis (<italic>p</italic> = 0.019). Finally, a combined PLK3 and pT273 Caspase 8 score predicted for decreased distant relapse (<italic>p</italic> = 0.005), and both improved CSS (<italic>p</italic> &lt; 0.001) and OS (<italic>p</italic> &lt; 0.001); this combined score independently predicted distant failure (<italic>p</italic> = 0.041) and CSS (<italic>p</italic> = 0.003) on multivariate analyses.</p><p><bold>Conclusion:</bold> 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.</p>