PROJECT SUMMARY/ABSTRACT We recently reported that SCCA incidence (particularly advanced-stage disease) and mortality rates are increasing rapidly (>3% per year) in the US with notable (>5%/year) increases in women 50 years and older showing that SCCA is one of the fastest accelerating causes of cancer incidence and mortality among all cancer sites. Women with lower genital tract (cervical/vaginal/vulvar) dysplasia or cancer (WLGTN) represent a large population (>200,000 new cases per year) at elevated risk of developing SCCA. We and others have shown that the incidence of SCCA among WLGTN aged 50 years and older is over 20 per 100,000 persons, which is both comparable to the incidence rate among women with HIV (who are the focus of current screening efforts) and is similar to the cervical cancer incidence prior to widespread screening. Furthermore, HPV vaccination is unlikely to decrease SCCA incidence in this population both because WLGTN have already been exposed to oncogenic HPV, and vaccine rates remain low among US women. This highlights an urgent need for studies evaluating possible targeted prevention in the form of anal cancer screening. Our goal is to evaluate the benefits and harms of SCCA screening among WLGTN. Screening for SCCA involves the identification of precancerous anal lesions (high-grade squamous intraepithelial lesions or "aHSILs") using cytologic testing or HPV testing (potentially performed by patients themselves). These lesions (if histologically confirmed) can then be treated, thereby preventing carcinoma development, similar to practices widely endorsed for cervical cancer. To inform guidelines, data regarding screening characteristics, natural history, patient acceptability, the benefits and harms, and cost-effectiveness of screening for SCCA among WLGTN, are urgently needed. We therefore propose a two-site, two-year longitudinal study of 350 HIV uninfected WGLTN aged ≥45 years. The results of this longitudinal study will be used to synthesize a mathematical (simulation) model that will estimate clinical and population-level benefits versus harms and cost-effectiveness associated with different screening approaches. The Specific Aims are: (1A) To evaluate the respective screening test characteristics of anal cytology, clinician-collected and self-collected high-risk HPV (hrHPV) testing, and cytology/hrHPV cotesting compared to the gold standard of high-resolution anoscopy (HRA) exam with biopsy; (1B): To determine baseline anal hrHPV and histologic aHSIL (haHSIL) prevalence and longitudinal risk among WLGTN; (2): To compare patient acceptability and experiences for anal cancer screening strategies among WLGTN; and (3): To develop a mathematical model determining the potential mortality and morbidity benefits, harms, and cost-effectiveness of anal dysplasia screening and/or hrHPV testing in WLGTN. In summary, the proposed multidisciplinary study will generate much-needed data regarding the optimal SCCA screening approa...