PROJECT SUMMARY/ABSTRACT The psychological symptom cluster is a common problem that impacts women receiving breast cancer treatment and is associated with several negative outcomes, including reduced functional status and quality of life. Unfortunately, the mechanism(s) that underlie this cluster are unknown which limits the development of targeted interventions. Mounting evidence suggests that individual (e.g., age, education) and community-level determinants of health (e.g., neighborhood deprivation, pollution) increase psychological symptoms in women with breast cancer. While exercise can improve psychological symptoms in women with breast cancer, it is unknown if individual or community-level factors impact this relationship. Given that exercise, individual, and community-level factors can alter DNA methylation, evaluation of epigenetic regulation may provide new mechanistic insights. Investigation into the epigenomic, individual, and community-level factors associated with a psychological symptom cluster in women with breast cancer within the context of a randomized clinical trial for a moderate-intensity aerobic exercise intervention will clarify these relationships and inform the development of targeted interventions. The overarching goal of this research is to alleviate symptoms in cancer patients, which is a research priority of the NCI’s Division of Cancer Prevention. The aims of the K99 study are to (1) test the hypotheses that epigenomic, individual, and community-level factors are associated with psychological symptom cluster severity profiles in women with breast cancer prior to the start of aromatase inhibitor therapy; and (2) test the hypotheses that epigenomic, individual, and community-level factors are associated with worsening psychological symptom cluster severity profiles following six months of aromatase inhibitor therapy in women with breast cancer, while exercise and epigenomic factors mitigate this effect. The candidate will extend this line of research to immunotherapy, which is rapidly emerging as an adjuvant therapy for breast cancer. The detailed training plan, exceptional team of mentors, and research-intensive environment of the University of Pittsburgh will provide the candidate with the mentored training, support, and research experience needed to conduct this research. Through this training plan, the candidate will develop: proficiency in epigenomics; competency in analysis and bioinformatics of longitudinal epigenomic data; proficiency in the evaluation of social determinants of health in symptom science; expertise in the mechanisms of immunotherapy-related symptoms; and knowledge and skills for professional career development. The aims of the R00 study are to: (1) identify symptom cluster profiles of women with breast cancer receiving immunotherapy over time; and (2) evaluate for epigenomic, individual, interpersonal, community, and societal- level factors associated with symptom cluster severity profiles of women with breast cancer receiving immunotherapy over time. Findings from these projects will provide new knowledge to guide clinical assessment and the development of targeted interventions to mitigate the severity common symptom clusters.

PROJECT NARRATIVE The psychological symptom cluster is a common and significant problem that impacts women receiving breast cancer treatment and is associated with several negative outcomes, including reduced functional status and quality of life. Unfortunately, the social, environmental, and molecular mechanism(s) that drive the development and persistence of this cluster are unknown which limits the development of effective prevention strategies and targeted interventions. This project will examine the role of multiple social determinants of health and epigenomic factors in the development and severity of a psychological symptom cluster in women receiving breast cancer treatment which will provide new knowledge to guide clinical assessment and the development of targeted interventions to mitigate the severity of this cluster.