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

Purpose: 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. Experimental Design: Levels of Bcl-2, Bcl-X _L, 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-X _L expression and disease-free survival following chemoradiation therapy in a uniformly treated cohort of patients with OPSCC. Results: 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 riskof treatment failure (hazard ratio, 5.99; 95% confidence interval, 1.73-20.8; P = 0.0014). In contrast, endogenous Bcl-X _L 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. Conclusions: 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.