Optimization of anal cancer screening for people with HIV using genomic methods

PROJECT SUMMARY Anal cancer represents approximately ~10% of all solid cancers among people with HIV (PWH) and is responsible for ~4% of all mortality in this group, representing a major morbidity burden in this population. Screening for anal precancerous lesions and treating these tumors has been proven to prevent invasive cancer

and offers a clinical opportunity for addressing this emerging disease. However, standard screening tests (anal cytology and high-risk HPV testing) have very poor specificity leading to burdensome and invasive confirmatory testing. To address this we have identified genomic alterations that can identify anal high-grade

squamous intraepithelial lesions (aHSIL), the immediate precursors of invasive cancer, with potentially greater accuracy and at lower cost than standard screening tests. However, the application of this approach for screening has not yet been investigated. The Specific Aims of this research proposal are (1) to compare the

performance of a cytobrush-based, novel genomic test for the detection of aHSIL, to standard of care in a prospective cohort of people with HIV (PWH) at high risk of anal cancer and (2) to identify genomic alterations associated with aggressive aHSIL lesions and to develop a classifier the predicts lesions that are more likely to

recur. To address these Aims, we will enroll a prospective cohort of 250 PWH for anal cancer screening and longitudinal data collection. This project will validate a genomic panel to identify aHSIL and compare it to standard of care screening as well as identify biomarkers associate with aHSIL recurrence. This application will

also support Dr. Richard Silvera's career development into an independent patient-oriented investigator in the field of anal cancer among people with HIV. Dr. Silvera's career goal is to become a leader in developing novel strategies for the identification and prevention of anal cancers among PWH. The proposed career development

plan integrates in-depth mentoring from a team of senior scientists and clinicians, advanced coursework in research design, analysis, cancer genomics, biomarker development, and experiential learning through the conduct of the proposed research in a highly supportive environment. The mentorship team, which includes

independent investigators with extensive expertise in research of cancers among people with HIV as well as the genomics of cancer, will guide the candidate's research and career development. At conclusion of this project Dr. Silvera will be well positioned to become an independent physician-investigator studying biological

and clinical issues related to anal cancers among people with HIV.