Abstract PO4-12-08: Changes in peripheral immune cell composition in women who do and do not develop breast cancer
Authors: Kresovich Jacob , O'Brien Katie , Xu Zongli , Weinberg Clarice , Sandler Dale , Taylor Jack 
Published: May 2024

Abstract
Background: Breast cancer survivors have higher age-specific rates of hypertension and other chronic diseases than women without a history of breast cancer. We and others have shown that alterations to the immune system are associated with risk of these conditions in the general population, leading to the hypothesis that the increased chronic disease risk in breast cancer survivors may be driven, in part, by lasting changes in immunity. Peripheral immune cell composition appears to become altered years before a breast cancer diagnosis, but little is currently known about the influence of different breast cancer treatments on subsequent changes to leukocyte composition and the persistence of these associations over time.
Methods: Among 410 women enrolled in the Sister Study, paired blood samples collected an average of 7.6 years apart were analyzed for DNA methylation (DNAm). Deconvolution methods were applied to these DNAm data to estimate circulating percentages of 12 leukocyte subsets. Approximately half the women sampled were diagnosed and treated for breast cancer between the blood draws (n= 185) whereas the other half remained breast cancer-free (n= 225). Breast tumor characteristics and treatment information were abstracted from medical records. Mixed-effect linear regression models were used to estimate changes in leukocyte composition over time comparing women with breast cancer to those who remained breast cancer-free. A case-only analysis of breast cancer survivors was performed to examine the persistence of changes over time and to explore whether changes in leukocyte composition were associated with the types of therapies received (endocrine therapy, radiation therapy, chemotherapy). All models were adjusted for age and self-reported race. In the treatment analysis, because tumor characteristics can guide clinical decisions, tumor estrogen receptor status and stage at diagnosis were additionally included as model covariates.
Results: At baseline, women who developed breast cancer between the blood draws had lower mean circulating percentages of CD8+ cytotoxic T cells than women who remained breast cancer-free (3.8% vs 4.6%; P-diff= 0.04). After accounting for differences in leukocyte composition at baseline, compared to women who remained breast cancer-free, women diagnosed and treated for breast cancer between the blood draws had decreases in total circulating CD4+ helper T cell percentage (adjusted mean difference [β]= -1.50, 95% CI: -2.56, -0.44, P= 0.006) and alterations to both naïve and memory B cell percentages (naïve B cells, β= 0.46, 95% CI: 0.17, 0.75, P= 0.002; memory B cells, β= -0.22, 95% CI: -0.34, -0.09, P= 0.001). Although associations did not vary by tumor characteristics or participant race, the changes in leukocyte composition appeared to persist over time as changes were not associated with time since diagnosis. In the case-only analysis of different breast cancer therapies, radiation was associated with decreases in CD4+ T cells (β= -2.56, 95% CI: -4.26, -0.88, P= 0.003) and chemotherapy was associated with increases in B cells (β= 0.62, 95% CI: 0.07, 1.16, P= 0.03). Surgery and endocrine therapy were not meaningfully associated with changes in leukocyte composition.
Conclusions: Breast cancer survivors have lasting changes in peripheral leukocyte composition that may be related to the types of treatments received. These findings add to our understanding of the biological changes that underlie the long-term health of breast cancer survivors.
Citation Format: Jacob Kresovich, Katie O'Brien, Zongli Xu, Clarice Weinberg, Dale Sandler, Jack Taylor. Changes in peripheral immune cell composition in women who do and do not develop breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-12-08.