A breast cancer (BC) diagnosis is a significant life event that can adversely impact health-related quality of life (HRQOL) in BC survivors by inducing major stress associated with diagnosis and treatment over the short-term. Over the long-term, BC survivors can also experience major stress associated with persistent symptoms and treatment-related late effects, as well as related psychological, social, and financial stress that persist long into survivorship, adversely affecting HRQOL in long-term BC survivors. There is growing evidence that in addition to these individual-level stressors, neighborhood-level stressors of the social and built environments also adversely impact cancer survivorship outcomes, including HRQOL. Most prior studies of HRQOL, however, examined individual-level stressors only and were focused on short-term BC survivors, primarily from non- Hispanic White (NHW) populations. There is a significant gap in knowledge about multi-level stressors that adversely impact HRQOL among long-term BC survivors, and it is not known whether key stressors differ among survivors from different racial and ethnic minoritized (REM) and immigrant populations who likely have a greater burden of both individual-level and neighborhood-level stressors. We will conduct the R21 pilot study in the Northern California Breast Cancer Family Registry (NC-BCFR), a prospective population-based cohort enriched with African American, Asian American, and Hispanic women with incident BC diagnosed from 1995-2009 who have been actively followed for 14-28 years since diagnosis. From the 1,116 active long-term BC survivors who completed the latest follow-up (2019-2022), we will select a representative sample of BC survivors who self- identified as African American, Asian American, or Hispanic. We will collect questionnaire data online or by phone interview on HRQOL, individual-level stressors (cancer-specific and social stressors), and updated sociodemographic characteristics for 270 participants (90 African American, 90 Asian American, 90 Hispanic survivors). Using geospatial data from the American Community Survey, we will append census-tract level neighborhood characteristics and derive social neighborhood-level stressors to geocoded addresses. We will collect blood samples for 176 participants and measure C-reactive protein (CRP) and a panel of cytokines to explore associations with multi-level stressors and with HRQOL. In Aim 1, we will explore associations between multi-level stressors and HRQOL and identify key stressors in each racial, ethnic, and nativity group. In Aim 2, we will assess variation in inflammatory biomarkers by multi-level stressors and by HRQOL. The findings from this R21 pilot study will inform the design of a larger study of stress, inflammation, and HRQOL among long-term BC survivors. The identification of specific long-term BC survivor groups with low HRQOL and specific stressor profiles will inform survivorship care and lay the foundation for future targeted multi-level strategies and interventions to reduce multi-level stressors and improve HRQOL in all racial, ethnic, and nativity groups of BC survivors, with the ultimate goal of achieving high HRQOL, improved survival, and health equity for all survivors.

We hypothesize that stress plays a major role in health-related quality of life (HRQOL) among long-term breast cancer (BC) survivors. In this R21 pilot study, we will collect data on both individual-level (cancer-specific and social stressors) and neighborhood-level stressors and HRQOL for 270 long-term BC survivors, and collect blood samples to measure inflammatory biomarkers that may mediate the stressor-HRQOL relationships. The study findings will inform the design of a larger study of stress, inflammation, and HRQOL, as well as the development of targeted interventions to improve HRQOL for the growing number of long-term BC survivors.