Title: Screening and early detection to prevent anal cancer (SEPAC)
Funder: Cancer Research UK

Abstract: Background Anal cancer is rare in the general population, however, the risk is much higher in certain groups, and the incidence is rising. The highest risk group is HIV-positive men-who-have-sex-with-men (MSM) in whom the risk is more than ten times higher. Anal cancer is caused by high risk HPV (HR-HPV)infection (principally HPV16) and mirrors cervical disease in having a pre-cancer stage of intraepithelial neoplasia (AIN). However there is no national screening programme because this would require high resolution anoscopy (HRA) for all, which is not feasible. Biomarkers including HR-HPV and cytology lack specificity and sensitivity. New biomarkers, including DNA methylation status could, in combination, provide a primary screening tool (with confirmation by HRA) that would allow the identification and treatment of early disease, and reduce morbidity and mortality associated with anal cancer. Aims To determine the sensitivity and specificity of a panel of biomarkers to detect high grade AIN lesions in an at-risk population. Methods Patients attending for routine HIV care (n=1000) at up to 5 clinics in London and Brighton, who are MSM or transgender women, aged 40+ with no history of anal cancer. Consenting participants will have an anal canal brush sample collected for liquid based cytology (LBC) and then undergo HRA with directed biopsy of any suspected AIN lesion. Those with high grade squamous intraepithelial lesions (HSIL) on HRA will have repeat examination at 6 months (to confirm persistence of disease). Residual LBC samples will be tested for HR-HPV, HPV16 E2/E6 ratio, and a panel of methylation markers including the host tumour suppressor gene EBP41L3, HPV16 L1 and late region methylation markers of HPV16, 31 and 33. The sensitivity and specificity of the biomarker panel to correctly identify those with initial and persistent HSIL will be determined. The prediction tool will be defined by logistic regression and the best tool selected by the Akaike Information Criterion. Participants with persistent HSIL will be referred to routine clinical care pathways. How the results of this research will be used The development of a predictive tool using specimens collected by non-invasive techniques will allow for practical and feasible primary screening. The tool will allow other essential research questions to be addressed: the natural history of AIN, and the efficacy of treatment. The study will generate a sample repository which can be used to evaluate further biomarkers. The tool will be an essential component of future screening strategies.

Lay abstract: Background Anal cancer is rare in the general population, however, the risk is much higher in certain groups, and the incidence is rising. The highest risk group is HIV-positive men-who-have-sex-with-men (MSM) in whom the risk is more than ten times higher. Anal cancer is caused by high risk HPV (HR-HPV)infection (principally HPV16) and mirrors cervical disease in having a pre-cancer stage of intraepithelial neoplasia (AIN). However there is no national screening programme because this would require high resolution anoscopy (HRA) for all, which is not feasible. Biomarkers including HR-HPV and cytology lack specificity and sensitivity. New biomarkers, including DNA methylation status could, in combination, provide a primary screening tool (with confirmation by HRA) that would allow the identification and treatment of early disease, and reduce morbidity and mortality associated with anal cancer. Aims To determine the sensitivity and specificity of a panel of biomarkers to detect high grade AIN lesions in an at-risk population. Methods Patients attending for routine HIV care (n=1000) at up to 5 clinics in London and Brighton, who are MSM or transgender women, aged 40+ with no history of anal cancer. Consenting participants will have an anal canal brush sample collected for liquid based cytology (LBC) and then undergo HRA with directed biopsy of any suspected AIN lesion. Those with high grade squamous intraepithelial lesions (HSIL) on HRA will have repeat examination at 6 months (to confirm persistence of disease). Residual LBC samples will be tested for HR-HPV, HPV16 E2/E6 ratio, and a panel of methylation markers including the host tumour suppressor gene EBP41L3, HPV16 L1 and late region methylation markers of HPV16, 31 and 33. The sensitivity and specificity of the biomarker panel to correctly identify those with initial and persistent HSIL will be determined. The prediction tool will be defined by logistic regression and the best tool selected by the Akaike Information Criterion. Participants with persistent HSIL will be referred to routine clinical care pathways. How the results of this research will be used The development of a predictive tool using specimens collected by non-invasive techniques will allow for practical and feasible primary screening. The tool will allow other essential research questions to be addressed: the natural history of AIN, and the efficacy of treatment. The study will generate a sample repository which can be used to evaluate further biomarkers. The tool will be an essential component of future screening strategies.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS