Screening strategies and social determinants of health among people with high risk of anal cancer

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Abstract: The incidence of anal cancer has almost doubled during the past decades, along with increased advanced disease and mortality. Persistent high-risk human papillomavirus (hrHPV) infection leads to anal high-grade squamous intraepithelial lesion (aHSIL), the precursor for anal cancer. Anal cancer risk is also exceptionally high among certain groups: people living with HIV, men having sex with men (MSM), and women with lower high-grade anogenital tract diseases. Health disparity further contributes to this high rate, as minorities, such as Black MSM, have a significantly higher rate of aHSIL and cancer. Thus, early detection of aHSIL, particularly among high-risk minorities, is crucial to reduce cancer incidence and disease burden. However, the current recommendation for aHSIL screening is based on expert opinions, and research on high-risk minorities is scarce. Thereby, we propose this large multisite study to investigate potential screening markers for aHSIL, with a specific focus on high-risk minorities. Furthermore, only a small portion of those diagnosed with aHSIL will develop cancer, yet the treatment recommendation is for all aHSIL, resulting in significant over- treatment, leading to unnecessary side effects and increased cost. It is crucial to develop reliable markers to stratify risks of aHSIL progression and regression. Given the importance of local DNA methylation and the immune environment to viral stimulus and carcinogenesis, hence, we will examine DNA methylation and immunological profiles to identify markers for cancer risk stratification after aHSIL. Examining local immune responses may also shed light on targeted immunotherapeutic approaches and for better outcomes. Additionally, given the disparities in anal cancer incidence and outcomes and the increasingly recognized impact of social determinants on health, including in HIV care, HPV infection, and cancer screening, we will examine whether social determinants play a pivotal role in aHSIL prevalence and clearance. We will recruit 500 minority men and women at high risk for anal cancer from Emory University and the University of Miami, where we have a large portion of diverse populations, including US born Blacks, Caribbean Blacks, Latinx, and MSM. We will follow them yearly for up to two years. Overall, the proposed study provides a unique opportunity to examine the much-needed evidence on early aHSIL screening among high-risk minorities. The methylation results will be crucial to stratify risks of screen-detected aHSIL and could be translated to screening. The immune and inflammatory profile will identify alterations associated with neoplastic progression and subsequently inform targeted immune interventions for better outcomes. Documenting the importance of social determinants will provide invaluable recommendations to reduce health disparities, improve screening outcomes, and decrease the incidence of anal cancer among high-risk minorities.