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. 2022 Nov 9;14(22):5500.
doi: 10.3390/cancers14225500.

Prognostic Impact of Caspase-8, CDK9 and Phospho-CDK9 (Thr 186) Expression in Patients with Uterine Cervical Cancer Treated with Definitive Chemoradiation and Brachytherapy

Maximilian Fleischmann  1   2 , Ranadip Mandal  3 , Izabela Kostova  3 , Monika Raab  3 , Mourad Sanhaji  3 , Stephanie Hehlgans  1 , Markus Diefenhardt  1   2 , Claus Rödel  1   2   4   5 , Emmanouil Fokas  1   2   4   5 , Klaus Strebhardt  3   4   5 , Franz Rödel  1   2   4   5
Affiliations

Prognostic Impact of Caspase-8, CDK9 and Phospho-CDK9 (Thr 186) Expression in Patients with Uterine Cervical Cancer Treated with Definitive Chemoradiation and Brachytherapy

Maximilian Fleischmann et al. Cancers (Basel). .

Abstract

Introduction: After primary platinum-based chemoradiation of locally advanced uterine cervical cancer, a substantial proportion of women present with persistent, recurrent or metastatic disease, indicating an unmet need for biomarker development. Methods: We evaluated the clinical records of 69 cervical cancer patients (Federation of Gynecology and Obstetrics, FIGO Stage > IB3) who were subjected to definitive CRT. Immunohistochemical scoring of caspase-8, cyclin dependent kinase 9 (CDK9) and phosphorylated (phospho-)CDK9 (threonine (Thr) 186) was performed on pretreatment samples and correlated with the histopathological and clinical endpoints, including relapse-free survival (RFS), distant metastasis-free survival (DMFS), cancer-specific survival (CSS) and overall survival (OS). Results: Lower levels of caspase-8 were more prevalent in patients with a higher T-stage (p = 0.002) and a higher FIGO stage (p = 0.003), and were significantly correlated with CDK9 expression (p = 0.018) and inversely with pCDK9 detection (p = 0.014). Increased caspase-8 levels corresponded to improved RFS (p = 0.005), DMFS (p = 0.038) and CSS (p = 0.017) in the univariate analyses. Low CDK9 expression was associated with worse RFS (p = 0.008), CSS (p = 0.015) and OS (p = 0.007), but not DMFS (p = 0.083), and remained a significant prognosticator for RFS (p = 0.003) and CSS (p = 0.009) in the multivariate analyses. Furthermore, low pCDK9 staining was significantly associated with superior RFS (p = 0.004) and DMFS (p = 0.001), and increased CSS (p = 0.022), and remained significant for these endpoints in the multivariate analyses. Conclusion: Increased caspase-8 and CDK9 levels correlate with improved disease-related outcomes in cervical cancer patients treated with CRT, whereas elevated pCDK9 levels predict worse survival in this patient population.

Keywords: CDK9; caspase-8; cervical cancer; phospho-CDK9 (Thr 186); prognosis; radiochemotherapy.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analysis or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Examples of cervix cancer biopsies with immunohistochemical detection of high (A) and low (B) caspase-8, CDK9 and pCDK9 (Thr 186). Original magnification, 50×; scale bar, 100 μm. Casp 8, caspase 8; CDK9, cyclin-dependent kinase 9; pCDK9, phosphorylated (Thr 186) CDK9.
Figure 2
Figure 2
Overall survival (A), cancer-specific survival (B), relapse-free survival (C) and distant metastasis-free survival (D) according to caspase-8 expression (low: individual weighted score (WS) ≤ 6; high: individual WS > 6) in patients with cervical carcinoma treated with definitive CRT and BT.
Figure 3
Figure 3
Overall survival (A), cancer-specific survival (B), relapse-free survival (C) and distant metastasis-free survival (D), according to cyclin-dependent kinase 9 (CDK9) expression (low: individual weighted score (WS) ≤ 6; high: individual WS > 6) in patients with cervical carcinoma cancer treated with definitive CRT and BT.
Figure 4
Figure 4
Overall survival (A), cancer-specific survival (B), relapse-free survival (C) and distant metastasis-free survival (D) according to phosphorylated (Thr 186) CDK9 (pCDK9) expression (low: ≤ median of 6; high: >median) in patients with cervical carcinoma treated with definitive CRT and BT.
See this image and copyright information in PMC

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