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Cyclin A as a Predictive Factor for Chemotherapy Response in Advanced Head and Neck Cancer

¹ Molecular Pathology Program at the Spanish National Cancer Centre (CNIO), Madrid; ² Pathology and ³ Oncology Departments at the Hospital 12 de Octubre, Madrid; ⁴ Statistics Department at the Universidad Autonoma, Madrid; ⁵ Immunohistochemistry and Histology Unit at the Spanish National Cancer Centre (CNIO), Madrid; and ⁶ Pathology Department at the Hospital del Mar, Barcelona, Spain.

Purpose: Overall survival of head and neck squamous cell cancer (HNSCC) patients has not improved despite advances in our understanding of the biology and molecular features of this disease. In particular, patients with advanced HNSCC have the poorest prognosis. To understand more about the contribution of cell cycle alterations to HNSCC development and their possible value in predicting prognosis and response to chemotherapy, we evaluated the levels of proteins involved in cell cycle control in patients diagnosed with advanced HNSCC.

Experimental Design: A tissue microarray was made with 122 HNSCC specimens obtained from biopsy material. Protein expression was evaluated by immunohistochemistry and correlated with clinical and pathological characteristics.

Results: Multiple alterations at various checkpoints of cell cycle progression were observed. Loss of P16 protein was less common in oropharyngeal tumors than at other HNSCC locations (P = 0.02). Evaluation of the simultaneous expression of different proteins highlighted direct correlations (P < 0.05) such as that of the cyclin-dependent kinases with their cyclin-partners, and the Ki-67 protein with cyclin-dependent kinases 1, cyclin A (CA) and cyclin B1. Median overall survival and time-to-progression were longer in patients with CA-expressing tumors (not reached versus 34.4 months, P = 0.02) and (47.3 versus 14.6 months, P = 0.006), respectively. Moreover, expression of CA in tumors predicted a better response to chemotherapy. Positive expression of cyclin E in tumors was also associated with an increased median time-to-progression (14.6 versus 25.8 months, P = 0.04). Finally, patients with cyclin D1-expressing tumors had shorter median overall survival (29.6 months versus not reached, P = 0.05) and shorter median time-to-progression (21.5 months versus not reached, P = 0.06). However, in a multivariate analysis a CA-negative–expressing tumor was the only independent poor prognostic factor in the entire cohort of HNSCC patients [odds ratio, 2.3; 95% confidence interval (CI) = 1.2–4.5; P = 0.01].

Conclusions: Our results provide detailed information on the molecular profile of cell cycle components in HNSCCs and identify CA-negative–expressing tumors as an independent marker of tumor progression and poor response to chemotherapy in patients diagnosed with advanced HNSCC.

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