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Bcl-2 blocks cisplatin-induced apoptosis and predicts poor outcome following chemoradiation treatment in advanced oropharyngeal squamous cell carcinoma.

ABSTRACT: This study aimed to test the hypothesis that elevated expression of antiapoptotic Bcl-2 family proteins predicts a poor therapeutic response of oropharyngeal squamous cell carcinoma (OPSCC) to concurrent platinum-based chemoradiation therapy.Levels of Bcl-2, Bcl-XL, and Bcl-w were determined and correlated with resistance to cisplatin in a large panel of cell lines derived from squamous cell carcinoma of the head and neck (HNSCC). Univariate and multivariate analyses were used to evaluate the relationship between Bcl-2 and Bcl-XL expression and disease-free survival following chemoradiation therapy in a uniformly treated cohort of patients with OPSCC.In HNSCC cell lines, high endogenous Bcl-2 expression was associated with increased cisplatin resistance, and experimental overexpression of Bcl-2 promoted cisplatin resistance. In patients, tumors positive for Bcl-2 before treatment had greater risk of treatment failure (hazard ratio, 5.99; 95% confidence interval, 1.73-20.8; P=0.0014). In contrast, endogenous Bcl-XL showed no correlation either with cisplatin sensitivity in the cell line panel in vitro, or with risk of recurrence in vivo (hazard ratio, 1.28; 95% confidence interval, 0.39-4.19; P=0.68). Associations between Bcl-2 expression and other clinical characteristics did not account for the predictive value of Bcl-2.Immunohistochemical assessment of Bcl-2 in pretreatment biopsy specimens can predict response of advanced OPSCC to concurrent platinum-based chemoradiation. As treatments targeting Bcl-2 and its family members become available, this immunohistochemical assessment could help personalize therapy by identifying a subpopulation of patients with a poor prognosis who might benefit from such treatments.

SUBMITTER: Michaud WA

PROVIDER: S-EPMC2745309 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Bcl-2 blocks cisplatin-induced apoptosis and predicts poor outcome following chemoradiation treatment in advanced oropharyngeal squamous cell carcinoma.

Michaud William A WA Nichols Anthony C AC Mroz Edmund A EA Faquin William C WC Clark John R JR Begum Shahnaz S Westra William H WH Wada Hiroshi H Busse Paul M PM Ellisen Leif W LW Rocco James W JW

Clinical cancer research : an official journal of the American Association for Cancer Research 20090224 5

<h4>Purpose</h4>This study aimed to test the hypothesis that elevated expression of antiapoptotic Bcl-2 family proteins predicts a poor therapeutic response of oropharyngeal squamous cell carcinoma (OPSCC) to concurrent platinum-based chemoradiation therapy.<h4>Experimental design</h4>Levels of Bcl-2, Bcl-XL, and Bcl-w were determined and correlated with resistance to cisplatin in a large panel of cell lines derived from squamous cell carcinoma of the head and neck (HNSCC). Univariate and multiv ...[more]

PMID: 19240170

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Project description:Background:p53 isoform ?133p53 is directly transactivated by p53 and antagonizes p53 activities in cancer progression. However, its correlation with prognosis and cancer recurrence in esophageal squamous cell carcinoma (ESCC) is still unclear. Patients and Methods:Expression of ?133p53 and ?133p53/full-length p53 (FLp53) in tissues and serums of 180 ESCC patients was evaluated using qRT-PCR. Patients were divided into high- and low-expression groups according to the cutoff value determined by X-tile 3.6.1 software. Survival analysis was performed by the Kaplan-Meier method. Univariate and multivariate Cox survival analyses were applied to assess the hazard ratios (HRs). Results:Tissue ?133p53 expression and ?133p53/FLp53 ratio were significantly increased in ESCC tissue compared with adjacent normal tissue. Pre-operative ?133p53 expression and ?133p53/FLp53 ratio in tissue or serum samples were positively associated with TNM stage and post-operative recurrence. Kaplan-Meier curve and multivariate cox regression analyses revealed that the tissue and serum ?133p53/FLp53 ratios (cutoff value: 2.9160) were independent prognostic factors for overall survival (OS) and progression-free survival (PFS) in ESCC patients and showed no statistical difference in receiver-operating characteristic curve (ROC) analysis, while serum ?133p53 showed no significant prognostic value. More importantly, the serum ?133p53/FLp53 ratio in ESCC patients was significantly decreased within 72 h post tumor resection and patients with a consistently high serum ?133p53/FLp53 ratio (?2.9160) had higher recurrence rates than those with consistently low ratio values. In addition, dynamic detection in each follow-up timepoint showed that serum ?133p53/FLp53 ratios were higher than 2.9160 upon recurrence, and they even increased prior to radiologic progression. Conclusion:The serum ?133p53/FLp53 ratio can be a novel predictor for survival outcome and may serve as a real-time parameter for monitoring recurrence in ESCC patients after surgery.

Project description:IntroductionMost patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) have an excellent response to chemoradiation, and trials are now investigating de-escalated treatment. However, up to 25% of patients with HPV-positive OPSCC will experience recurrence, and up to 5% will even progress through primary treatment. Currently, there are no molecular markers to identify patients with poor prognosis who would be harmed by de-escalation. Herein we report the clinical and genomic characteristics of persistent HPV-positive OPSCC after definitive platinum-based chemoradiation therapy.MethodsPatients with HPV-positive OPSCC treated with curative intent platinum-based chemoradiation between 2007 and 2017 at two institutions and with a persistent locoregional disease were included. We evaluated clinical characteristics, including smoking status, age, stage, treatment, and overall survival. A subset of five patients had tissue available for targeted exome DNA sequencing and RNA sequencing. Genomic analysis was compared to a previously published cohort of 47 treatment-responsive HPV+ OPSCC tumors after batch correction. Mutational landscape, pathway activation, and OncoGPS tumor states were employed to characterize these tumors.ResultsTen patients met the inclusion criteria. The tumor and nodal stages ranged from T1 to T4 and N1 to N2 by AJCC 8th edition staging. All patients were p16-positive by immunohistochemistry, and eight with available in situ hybridization were confirmed to be HPV-positive. The 1-year overall survival from the time of diagnosis was 57%, and the 2-year overall survival was 17%. TP53 mutations were present in three of five (60%) persistent tumors compared to 2% (one of 47) of treatment-responsive HPV-positive tumors (p = 0.008). Other genes with recurrent mutations in persistent HPV-positive OPSCC tumors were NF1, KMT2D, PIK3C2B, and TFGBR2. Compared to treatment-responsive HPV-positive tumors, persistent tumors demonstrated activation of DNA Repair and p53, EMT, MYC, SRC, and TGF-beta signaling pathways, with post-treatment samples demonstrating significant activation of the PI3K-EMT-Stem pathways compared to pretreatment samples.ConclusionChemoradiation-resistant HPV-positive OPSCC occurs infrequently but portends a poor prognosis. These tumors demonstrate higher rates of p53 mutation and activation of MYC, SRC, and TGF-beta pathways. A comparison of tumors before and after treatment demonstrates PI3K-EMT-Stem pathways post-treatment in HPV-positive tumors with persistent disease after platinum-based chemoradiation.

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Dataset Information

Bcl-2 blocks cisplatin-induced apoptosis and predicts poor outcome following chemoradiation treatment in advanced oropharyngeal squamous cell carcinoma.

Publications

Bcl-2 blocks cisplatin-induced apoptosis and predicts poor outcome following chemoradiation treatment in advanced oropharyngeal squamous cell carcinoma.

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