Project Summary Abstract In 2020, about 1 million female patients in the US will be living with pelvic cancers, and roughly half of them will have received radiation during their course of treatment. The importance of optimizing cancer-directed and supportive therapies to minimize the adverse effects of radiation and improve quality of life is increasingly recognized. Among the many aspects of quality of life adversely impacted by cancer treatment is the ability to continue engaging in pleasurable sexual behaviors, an essential human function throughout the lifespan, and a clinical problem long overlooked in female cancer survivors. Current classifications of toxicity and normal tissues in radiation oncology account only poorly for the anatomy and critical function of female erectile tissues (arousal and orgasm) with respect to such patients' capacities to engage in pleasurable sexual behaviors. In addition, it has yet to be tested whether observed alterations of vaginal and stool microbiome ecology after radiotherapy contribute to increased susceptibility to radiation-induced vaginal toxicity and sexual dysfunction, as has been explored recently in the context of radiation-induced gastrointestinal toxicity. Because roughly 70% of women with pelvic malignancies now survive at least 5 years, it is imperative to identify predictors and mechanisms of long-term female sexual dysfunction to improve quality of life given the significant role of sexual activity in overall well-being. To accelerate advances in mitigating or preventing pelvic radiotherapy-associated female sexual dysfunction, my proposed research aims to 1) establish a functional anatomic-domain (dermatologic, vaginal, erectile) classification of long-term radiation-related sexual dysfunction in a multi-center, longitudinal cohort of female patients undergoing pelvic radiotherapy; 2) define and/or validate novel dosimetric predictors of sexual dysfunction in each anatomic domain; and, 3) identify quantitative imaging and microbiome biomarker indices of radiation damage to specific sexual organs. My proposed study will be the first to analyze the effects of radiotherapy on the erectile anatomic organs in females, and will thereby both elucidate the anatomic bases of adverse sexual function outcomes, especially those related to arousal and orgasm, and advance overall understanding of radiation effects for all female sexual anatomic domains. These advances will enable redesign of radiotherapy protocols to improve such outcomes and identification of imaging biomarkers to assess dose- volume response and the effectiveness of such interventions. In addition, we will be the first to test the hypothesis that observed alterations of vaginal and stool microbiome ecology contribute to increased susceptibility to radiation-induced vaginal toxicity and sexual dysfunction. I aim to pioneer key discoveries in these underrepresented scientific areas to provide an innovative, tailored approaches to preven...