P16INK4A, P53, EGFR Expression and KRAS Mutation Status in Squamous Cell Cancers of the Anus: Correlation with Outcomes Following Chemo-radiotherapy

Background And Purpose: Squamous 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.

Methods: Tumours from 153 patients treated with radical chemo-radiotherapy (50.4 Gy in 28# with concurrent Mitomycin and 5-Fluorouracil between 2004 and 2009) were retrieved and immunohistochemistry performed for p16(INK4A), p53 and EGFR and correlated with outcome. Primary and relapsed samples were analysed for mutations in KRAS.

Results: 137/153 (89.5%) stained moderately or strongly for p16(INK4A). p16(INK4A) correlated strongly with outcome. 37/137 patients demonstrating moderate/strong p16(INK4A) 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. p16(INK4A) negative tumours were more frequent in men. p16(INK4A) negative patients had significantly worse overall survival (p<0.001). No mutations in KRAS were identified in primary tumours or relapses following treatment.

Conclusions: p16(INK4A) 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.