The purpose of this Ruth L. Kirschstein National Research Service Award (NRSA) Individual Pre-Doctoral Fellowship in Nursing Research (F31) application is to provide research training for Ms. Vasbinder, a second year doctoral student at the University of Washington, and prepare her for a post-doctoral position. The long- term goal of this training is for this applicant to develop into an independent researcher in an intensive academic setting with a program of research focused on translational research to integrate biomarkers in bio-behavioral interventions to reduce and ameliorate symptoms in breast cancer survivors, particularly fatigue. Due to improvements in cancer treatments, survival rates have improved and, as such, there are an estimated 3.5 million breast cancer survivors as of 2016. Fatigue is one of the most commonly reported symptoms in cancer survivors. Radiation, a major contributor of fatigue, produces fatigue in 80% of survivors acutely and 33% of survivors long-term. Radiation is hypothesized to cause fatigue through pathways of inflammation; however, the mechanisms driving long-term fatigue (LTF) after treatment has ceased, is less clear. For breast cancer survivors, radiation can also cause reductions in heart function, which can produce LTF. Evidence also supports the role of oxidative stress in LTF. Given multiple pathways are likely involved in LTF in patients receiving radiation, biomarkers targeting different mechanisms may provide greater insight into the mechanisms leading to LTF and future interventions. Purpose: The purpose of this study is to explore biomarkers of oxidative stress (8-OH-dG), cardiac damage (cystatin-C), and inflammation (IL-6, CRP) in the development of LTF in cancer survivors diagnosed with breast cancer treated with radiation using the National Institutes of Health Symptom Science Model (NIH-SSM). Methods: We propose to leverage a matched, case-control design using serum samples from the Women?s Health Initiative (WHI) Life and Longevity After Cancer (LILAC). Women will be eligible if they meet the following criteria: 1) enrolled in LILAC, 2) have serum samples available at both WHI baseline and year 3, 3) breast cancer diagnosis and treatment between the two serum sample collection time points, and 4) fatigue measured at least 6 months from cancer treatment completion end date. Fatigue will be defined as scoring < 50 and ?non-fatigued? defined as scoring 50 measured using the Short-Form 36 Vitality subscale (SF-36). We anticipate having 150 fatigue cases and 150 non-fatigued controls. Serum biomarkers (cystatin-C, 8-OH-dG, IL-6, and CRP) will be measured using enzyme-linked immunosorbent assay (ELISA) at WHI baseline and year 3 of the WHI. Weighted sampling logistic regression models and mediation analyses will be used to test study aims.
Fatigue is one of the most commonly reported symptoms experienced by breast cancer survivors, with radiation treatment being a substantial contributor. While inflammatory biomarkers are most often cited as associated with fatigue, biomarkers of oxidative stress and cardiac damage may be especially crucial to consider in breast cancer survivors treated with radiation given the proximity to the heart and physiologic effects of radiation. A better understanding of the physiologic underpinnings of fatigue in breast cancer survivors can lead reductions in fatigue through better prediction models and the development of interventions to target the specific physiologic pathways.