Abstract Bladder cancer is one of the top ten most common cancers in the U.S., and one of the most expensive to treat. Most cases (75%) are non-muscle-invasive bladder cancer (NMIBC) with high rates of recurrence (70%) and progression (25%). While prognostic factors remain largely unknown, the success of Bacillus Calmette-Guerin (BCG), an intravesical immunotherapy as the most effective therapy for NMIBC for over four decades, highlights the potential of the inflammatory and immune environments in determining treatment response and prognosis. Given the median age of bladder cancer diagnosis is 73 years, patients are commonly faced with age-related loss of muscle mass (sarcopenia), increase of fat accumulation (obesity), or both (sarcopenic obesity), which are all characterized by chronic inflammation and altered immune responses. These body composition phenotypes are associated with tumor progression and increased mortality. Thus, we hypothesize that body composition at diagnosis may shape the host inflammatory and immune milieu and impact bladder cancer prognosis. This hypothesis will be tested in the Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well; R01 CA172855, MPI: Kwan/Tang/Kushi) of newly diagnosed NMIBC patients from 2015-2019 at Kaiser Permanente, one of the largest prospective cohort studies of NMIBC, with 1,472 patients enrolled with rich patient, clinical, and biospecimen data to examine genetic and lifestyle factors in prognosis and survival. We propose to conduct a full investigation of body composition, inflammation, and immunity in bladder cancer outcomes in Be-Well to determine how adiposity, muscle, and inflammatory and immune biomarkers at diagnosis can identify NMIBC patients at high risk for treatment failure and/or disease recurrence and progression. Our aims are: 1) to determine the association of computed tomography (CT)-derived body composition phenotypes (sarcopenia, adiposity, myosteatosis) with NMIBC recurrence (first and multiple) and progression; 2) to determine the association of body composition with BCG immunotherapy outcomes including adverse events and treatment failure; 3) to examine the association of circulating inflammatory and immune biomarkers with body composition and BCG outcomes and NMIBC prognosis; 4) explore if the addition of body composition measures and inflammatory and immune biomarkers improves the performance of current risk stratification models for NMIBC patients. Given the common clinical use of CT, body composition measures could be readily incorporated into the current clinicopathological factor- based risk stratification system to improve the clinical care of NMIBC.

Project Narrative Bladder cancer is one of the top ten most common cancers in the U.S., with 75% diagnosed with non-muscle invasive disease (NMIBC) and up to 70% of which experience recurrence, making it one of the most expensive cancers to treat per patient. Body composition, which is the amount of fat and muscle tissue, affects the inflammatory and immune environments, and thus can possibly influence treatment response and disease prognosis in NMIBC patients. In a prospective study of 1,472 NMIBC patients, we will conduct a comprehensive study of body composition, inflammation, and immunity to evaluate their impact on treatment and prognosis outcomes over eight years of follow-up.