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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.

frontiers in oncology

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