Abstract
Higher overall leukocyte counts in women may be associated with increased risk of breast cancer, but the association of specific leukocyte subtypes with breast cancer risk remains unknown. To determine associations between circulating leukocyte subtypes and risk of breast cancer. Between 2003 and 2009, the Sister Study enrolled 50 884 women who had a sister previously diagnosed with breast cancer but were themselves breast cancer free. A case-cohort subsample was selected in July 2014 from the full Sister Study cohort. Blood samples were obtained at baseline, and women were followed up through October 2016. Data analysis was performed in April 2019. The main outcome was the development of breast cancer in women. Whole-blood DNA methylation was measured, and methylation values were deconvoluted using the Houseman method to estimate proportions of 6 leukocyte subtypes (B cells, natural killer cells, CD8+ and CD4+ T cells, monocytes, and granulocytes). Leukocyte subtype proportions were dichotomized at their population median value, and Cox proportional hazard models were used to estimate associations with breast cancer. Among 2774 non-Hispanic white women included in the analysis (mean [SD] age at enrollment, 56.6 [8.8] years), 1295 women were randomly selected from the full cohort (of whom 91 developed breast cancer) along with an additional 1479 women who developed breast cancer during follow-up (mean [SD] time to diagnosis, 3.9 [2.2] years). Circulating proportions of B cells were positively associated with later breast cancer (hazard ratio [HR], 1.17; 95% CI, 1.01-1.36; P = .04). Among women who were premenopausal at blood collection, the association between B cells and breast cancer was significant (HR, 1.38; 95% CI, 1.05-1.82; P = .02), and an inverse association for circulating proportions of monocytes was found (HR, 0.75; 95% CI, 0.57-0.99; P = .05). Among all women, associations between leukocyte subtypes and breast cancer were time dependent: higher monocyte proportions were associated with decreased near-term risk (within 1 year of blood collection, HR, 0.62; 95% CI, 0.43-0.89; P = .01), whereas higher B cell proportions were associated with increased risk 4 or more years after blood collection (HR, 1.38; 95% CI, 1.15-1.67; P = .001). Circulating leukocyte profiles may be altered before clinical diagnoses of breast cancer and may be time-dependent markers for breast cancer risk, particularly among premenopausal women.
Highlights
The immune system plays conflicting roles in cancer development and progression
Circulating proportions of B cells were positively associated with later breast cancer
Among women who were premenopausal at blood collection, the association between B cells and breast cancer was significant (HR, 1.38; 95% CI, 1.05-1.82; P = .02), and an inverse association for circulating proportions of monocytes was found (HR, 0.75; 95% CI, 0.57-0.99; P = .05)
Summary
The immune system plays conflicting roles in cancer development and progression. immunosurveillance provides an important first defense against neoplastic cells, immune responses can be associated with tumor growth by altering tissue microenvironments and selecting more-virulent cells through immunoediting.[1,2] Local immune cell responses to breast tumors are well characterized and are associated with cancer progression and survival.[3,4,5,6,7] Peripheral blood leukocyte profiles measured after diagnosis may be associated with prognosis,[8,9,10] but whether leukocyte subtypes are altered before diagnosis remains largely unexplored.Prospective epidemiologic studies[11,12,13] suggest that women with higher overall leukocyte counts, or certain autoimmune disorders, may be at increased risk of breast cancer. Leukocytes are diverse and can be broadly defined by their cell lineage (myeloid and lymphoid); these subtypes may be differentially associated with breast cancer. Increasing proportions of myeloid-lineage subtypes have been reported to contribute to tumor development.[14,15,16] Few largescale studies have assessed immune cell profiles; isolation of leukocyte subtypes in peripheral blood has traditionally required flow cytometry, which is an expensive and time-consuming assay that requires fresh blood samples.[17] studies of breast cancer and leukocyte subtypes have been limited to small case-control studies[18,19,20] using case samples obtained at diagnosis
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