P16INK4A, p53, EGFR expression and KRAS mutation status in squamous cell cancers of the anus: Correlation with outcomes following chemo-radiotherapy

Abstract

Background and PurposeSquamous cell carcinomas of the anal canal are associated with infection with Human Papilloma Viruses (HPVs). Chemo-radiotherapy (CRT) gives 70% 3-year relapse-free survival. Improved predictive markers and therapeutic options are required. MethodsTumours from 153 patients treated with radical chemo-radiotherapy (50.4Gy in 28# with concurrent Mitomycin and 5-Fluorouracil between 2004 and 2009) were retrieved and immunohistochemistry performed for p16INK4A, p53 and EGFR and correlated with outcome. Primary and relapsed samples were analysed for mutations in KRAS. Results137/153 (89.5%) stained moderately or strongly for p16INK4A. p16INK4A correlated strongly with outcome. 37/137 patients demonstrating moderate/strong p16INK4A expression relapsed (27.0%), as opposed to 10/16 (62.5%) with absent/weak staining (log rank test p<0.001). p16 and p53 expression were inversely correlated. p16INK4A negative tumours were more frequent in men. p16INK4A negative patients had significantly worse overall survival (p<0.001). No mutations in KRAS were identified in primary tumours or relapses following treatment. Conclusionsp16INK4A is strongly associated with relapse in SCC of the anus and identifies patients with very poor rates of relapse-free and overall survival. Primary and recurrent anal cancer expresses wild type KRAS, unaffected by treatment, supporting trials targeting EGFR in poor risk/recurrent anal cancer.