Grant Number:	1R37CA299472-01 Interpret this number
Primary Investigator:	Kresovich, Jacob
Organization:	H. Lee Moffitt Cancer Ctr & Res Inst
Project Title:	Aging, DNA Methylation, and Incident Cardiovascular Disease in Breast Cancer Survivors
Fiscal Year:	2025

PROJECT SUMMARY/ABSTRACT There are nearly four million breast cancer survivors in the U.S., with projections that this figure will exceed five million by 2030. As the number of breast cancer survivors increases, addressing the health issues women face after their initial breast cancer diagnosis is becoming more important. Breast cancer survivors face higher rates of cardiovascular disease (CVD) incidence and mortality than women in the general population, primarily due to cardiotoxic cancer therapies and shared disease risk factors. Identifying high-risk CVD patients before treatment initiation will be critical for reducing CVD morbidity and mortality as it can inform cardiac surveillance and cancer treatment decisions. However, most CVD risk models used in oncology clinics were developed for the general population and underperform in breast cancer patients. It is unclear if existing CVD risk models can be adapted to breast cancer patients by incorporating novel CVD-associated biomarkers specific to this population. DNA methylation biomarkers are emerging as critical components of medical tests (e.g., Cologuard®), and those representing biological aging (e.g., epigenetic clocks, leukocyte composition) are associated with breast cancer and CVD, independent of known risk factors. DNA methylation biomarkers may, therefore, provide novel insights into CVD etiology and enhance risk prediction of breast cancer patients. A key barrier to research on aging, DNA methylation, and incident CVD in breast cancer survivors is the limited number of prospective cohort studies with baseline DNA methylation data and CVD events. This barrier will be addressed by generating new blood DNA methylation data in the Pathways Study, a prospective cohort study of 4,504 women diagnosed with invasive breast cancer between 2005 and 2013. 4,034 (90%) participants provided blood samples in the time immediately following their cancer diagnosis. Data on cancer treatments, CVD risk factors, lifestyle, and CVD events have been collected in the years since enrollment. Using these resources, we propose three specific aims to evaluate our central hypothesis that biological aging metrics can improve our understanding of CVD etiology and enhance CVD risk prediction in breast cancer patients: Aim 1) Using causal inference techniques, estimate biological aging associations with CVD and mortality risk in breast cancer patients; Aim 2) Assess the influence of patient and treatment characteristics and blood collection timing on biological aging associations with CVD/mortality risk; and Aim 3) Test whether existing CVD risk models can be modified to improve performance in breast cancer patients. Findings can improve breast cancer outcomes by providing vital information at diagnosis that guides cardiac surveillance and cancer treatment decisions. Critically, because blood DNA methylation can be quickly and accurately profiled in medical settings, DNA methylation can be easily integrated into existing clinical prediction tools, thereby having an immediate impact on breast cancer survivors’ cardiovascular health.





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