The Role of 27-hydroxycholesterol in Breast Cancer: A Population-Based Multiethnic Study

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Abstract This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-20-037. The median survival of breast cancer has improved steadily so that over 90% of patients will now survive at least 5 years after their initial diagnosis. As the number of older breast cancer survivors continues to increase, attention has now shifted to the occurrence of new comorbidities, symptoms, and complications after the initial breast cancer diagnosis, and the combined impact of aging and the consequences of breast cancer and its treatment in older women. Multimorbidities (MM) defined as the occurrence of two or more chronic conditions (or morbidities) in an individual may be a proxy measure of multisystem failures and progressive loss of resilience and functional reserve with increasing age. This supplement application aims to investigate the relationship between the accumulation of MM and risk of select aging phenotypes among women with incident breast cancer using the long-standing Multiethnic Cohort (MEC) study. Specifically, we will examine the relationships between MM patterns (MMP; number, type, clusters of MM, duration of MM and treatment) and three well-established metrics of physical function associated with aging: activities of daily living (ADL), instrumental activities of daily living (IADL), and mobility. This supplement proposal will build upon the parent MEC R01 study “The Role of 27-hydroxycholesterol in Breast Cancer: A Population-Based Multiethnic Study” (MPI: L. Loo/I. Cheng) by studying breast cancer survivorship in relation to MMP, as well as specific clusters of MMP such as cardiovascular disease and dyslipidemia that are directly relevant to the 27- hydroxycholesterol pathway. We propose the following aims: Aim 1: To characterize the relationship of MMP (number, type, and clusters of MM, duration of MM and treatment) among 9121 women with incident breast cancer in the MEC. We will assess MMP using baseline and follow-up questionnaires and Medicare claims data among incident breast cancer cases to examine the associations of pre- and post- cancer diagnosis MMP with demographic factors (age, race/ethnicity, marital status, education), lifestyle and health behaviors (body weight, dietary patterns, physical activity, smoking) as well as social and contextual factors (neighborhood socioeconomic status, ethnic enclaves). We will assess the association of MMP over time with breast cancer incidence among all women and by racial/ethnic groups. Aim 2. To investigate the risk of physical function disabilities associated with MMP among 3358 women with incident breast cancer in the MEC. We will use three aging metrics of physical function disabilities (ADL, IADL, and mobility) assessed in follow-up questionnaire. We will evaluate the associations of a history of MMP over time with the outcomes ADL, IADL, and mobility separately as well as a combined index among breast cancer cases. Aim 3: To assess the impact of MMP and physical function disabilities on overall mortality among 3358 women with incident breast cancer in the MEC. In a prospective analysis of breast cancer cases, we will investigate whether breast cancer survival is associated with (a) pre- and post-diagnostic MMP; (b) physical function disabilities (ADL, IADL, and mobility) separately and as a combined index; and (c) pre- and post-diagnostic MMP and physical function disabilities in a joint model