Prognostic biomarkers in squamous cell carcinoma of the anus: a systematic review.

Anal cancer is a disease whose incidence has risen markedly in several parts of the world including Europe and the United States (Rousseau et al, 2005). Of notable concern is the significant impact of this disease on the young male population, with incidence rates of up to 37 per 100 000 in homosexual men (Place et al, 2001). Of men who have sex with men (MSM), 95% are seropositive for the implicated viral pathogen, human papilloma virus (subtypes 16, 18, 32 and 34) (Palefsky et al, 2005). Also, 81% of MSM have anal intraepithelial neoplasia (AIN; premalignant lesion) (Palefsky et al, 2005). HPV is associated with the proteins E6 and E7 that can silence important tumour-suppressor proteins in normal cells (Mammas et al, 2008). These proteins, namely p53 and Rb, normally exert apoptotic cellular effects to prevent disordered cell growth (Mammas et al, 2008). Removal of this growth restriction may lead to malignant transformation (Mammas et al, 2008). At the time of diagnosis, up to 50% of patients have locoregional disease with visceral metastases present in 10% of patients (UKCCCR Anal Cancer Trial Working Party, 1996; Rousseau et al, 2005). The most common sites are the liver and lungs (Rousseau et al, 2005). In the past, the mainstay of treatment for anal carcinoma was abdominoperineal resection with formation of a permanent end colostomy. Over the last two decades, combined chemoradiotherapy pioneered in the 1970s by Nigro et al (1974) has become the standard of care with salvage abdominoperineal resection reserved for a small proportion of cases refractory to chemoradiotherapy (Place et al, 2001). Despite respectable treatment response rates in non-metastatic disease with overall survival rates of 60–75%, only 10% of patients with distant metastases survive 2 years from the time of their diagnosis (Cummings, 2006; Das et al, 2008). Furthermore, it is evident that treatment response shows a degree of heterogeneity between individual patients within a specific stage category, suggesting a spectrum of chemoradiation sensitivity. Furthermore, the acute and long-term toxicity associated with standard chemoradiation schedules are considerable, and therefore predictors of response and novel therapeutic approaches are required to allow treatments to be tailored according to treatment sensitivity. Clinical and pathological factors have been evaluated extensively with regard to outcomes in anal cancer. Clinicopathological parameters have not consistently enabled prediction of response to currently available treatment modalities. This had led to considerable interest in prognostic and predictive biomarkers as putative means to improving patient survival. A prognostic biomarker gives information regarding the patient's overall outcome, irrespective of the therapy received, whereas a predictive biomarker provides information about the effect of a specific therapeutic intervention (Oldenhuis et al, 2008). Molecular analysis may permit the tailoring of treatments to individual patients and help identify new therapeutic targets. Tyrosine kinases (TKs), which have an established role in malignant transformation of human cells, have served as major target in cancer treatment strategies such as imatinib, the BCR-ABL TK inhibitor used in the treatment of chronic myeloid leukaemia and GISTs (Madhusudan and Ganesan, 2004). In recent years, the epidermal growth factor receptor (EGFR – particularly HER-1 and HER-2) has been the most extensively investigated TKs and now forms a significant component of the ongoing research into molecular targeted cancer therapy. In non-small cell lung cancer, mutations in the TK domain of the EGFR have been shown to be associated with a high treatment response rate to the EGFR TK inhibitor erlotinib (Paz-Ares et al, 2006). Randomised trials in metastatic colorectal cancer have demonstrated that use of monoclonal antibodies directed against EGFR (HER-1), namely cetuximab and panitumumab, is associated with favourable outcomes in patients expressing the wild-type form of K-ras proto-oncogene (Siddiqui and Piperdi, 2009). Therefore, a search for putative predictive markers in anal cancer is warranted in order to explore whether these and other targeted treatments should be assessed in the setting of early and/or metastatic anal cancer. The purpose of this systematic review was to evaluate the literature available to-date on biological and molecular prognostic factors in squamous cell carcinoma (SCC) of the anus.