Association between cumulative lifetime exposure to reproductive hormones and tumor-infiltrating lymphocytes, CD4 +, and CD8 + T cells among women with breast cancer.

backgroundReproductive hormones may influence immune responses to tumors. Tumor-infiltrating lymphocytes (TILs), CD4 +, and CD8 + T cell densities are markers of immune activity and breast cancer prognosis. We examined associations between lifetime reproductive hormone exposure, tumor immune infiltration, and survival among women with breast cancer.

methodsThe study included invasive breast cancer cases in the Women's Circle of Health Study and the Women's Circle of Health Follow-up Study. Lifetime endogenous hormone exposure (LHEendo) was defined as reproductive years plus pregnancy duration minus breastfeeding duration; lifetime exogenous hormone exposure (LHEexo) was defined as the combined cumulative duration of oral contraceptive and hormone replacement therapy use. TILs were scored as ordered percentage values from 0 to 100% stromal area; CD4 + /CD8 + T cell densities were quantified by immunohistochemistry. TILs were modeled using ordinal logistic regression, and CD4 + /CD8 + T cell densities were modeled using gamma generalized linear models among participants with positive density values, with covariates selected by directed acyclic graphs. Overall survival was assessed using Cox proportional hazards models, and breast cancer-specific survival was assessed using Fine-Gray competing-risk models.

resultsAmong 1195 women with valid TILs measurements, 553 and 610 had CD4 + and CD8 + T cell density data, respectively. Across all tumor molecular subtypes, a 1-year increment of LHEendo was associated with a 2.85% decrease in CD8 + T cell density (95% CI - 5.14%, - 0.61%). LHEendo was associated with lower odds of being in a higher TIL level among women with hormone receptor (HR) + /HER2- tumors (OR = 0.977, 95% CI 0.957, 0.997), although the interaction by molecular subtype was not statistically significant. LHEexo was associated with lower risk of all-cause mortality (HR = 0.979, 95% CI 0.960, 0.998). TIL-stratified analyses suggested that this association may be more apparent among women with TILs ≥ 50% (HR = 0.90, 95% CI = 0.82, 0.99; P-interaction = 0.10).

conclusionsLifetime endogenous hormone exposure was associated with lower CD8 + T cell density overall, with exploratory findings of lower TIL levels among women with HR + /HER2- tumors. Lifetime exogenous hormone exposure was associated with a lower risk of all-cause mortality, with possible variation by TIL levels.