Abstract 3613: Association between cumulative lifetime exposure of reproductive hormones and TILs among women with breast cancer
Authors: Yidan Zhang, Rand Akasheh, Bo Qin, Angela Omilian, Nur Zeinomar, Song Yao, Elisa V. Bandera, Christine Ambrosone, Thaer Khoury, Ting-Yuan David Cheng
Journal: Cancer Research (2025)

Abstract Background: Tumor-infiltrating lymphocytes (TILs) within the tumor and its surrounding microenvironment reflect an active immune response and are regarded as a prognostic marker for breast cancer. However, host factors that affect TILs remain less explored. The study investigated the association between lifetime hormone exposure and TILs. Methods: The study included newly diagnosed invasive breast cancer cases in the Women's Circle of Health Study. Lifetime endogenous hormone exposure (LHEendo) was defined as the sum of reproductive years and cumulative pregnancy duration, minus cumulative breastfeeding duration. The reproductive years were defined as the duration between age at menarche and age at diagnosis for premenopausal women, and as the duration between age at menarche and age at menopause for postmenopausal women. Lifetime exogenous hormone exposure (LHEexo) was estimated by summing the years of oral contraceptive (OC) use and hormone replacement therapy (HRT) use. TILs were scored as 0% to 100% of stromal tissue based on established guidelines. Generalized linear models with Gamma distribution and log link function were used to assess the associations between LHEendo or LHEexo and TILs. Directed acyclic graphs (DAGs) were used to select covariates. When assessing the association between LHEendo and TILs, we adjusted for race, family history of breast cancer, and duration of OC use. For the association between LHEexo and TILs, adjustments included race, BMI at enrollment, age at diagnosis, and menopausal status. Results: A total of 1315 patients (920 Black and 395 White women) were included in the study. Overall, we did not observe a significant association between either LHEendo or LHEexo and TILs. However, when analyses were stratified by race, shorter LHEendo or LHEexo was associated with higher TILs among White women (exponentiated (exp) beta=0.98, 95% CI=0.96 to 0.99 for LHEendo, and (exp) beta= 0.98, 95% CI=0.97 to 1.00, respectively; P-interaction=0.042 for LHEexo and 0.15 for LHEendo), but not among Black women. When stratifying the analyses by breast cancer molecular subtype, a shorter LHEendo was associated with higher TILs in hormone receptor (HR)+/HER2- patients ((exp) beta=0.99, 95% CI=0.97 to 1.00), while a shorter LHEexo was associated with higher TILs in HR+/HER2+ patients ((exp) beta=0.97, 95% CI=0.95 to 1.00). The interactions between LHEendo or LHEexo and molecular subtype were not significant (P&amp;gt;0.05). Conclusions: The associations of lifetime endogenous and exogenous hormone exposure with TILs may vary by race and breast cancer molecular subtype. These findings contribute to our understanding of the roles of hormonal factors in the breast tumor microenvironment. Citation Format: Yidan Zhang, Rand Akasheh, Bo Qin, Angela Omilian, Nur Zeinomar, Song Yao, Elisa V. Bandera, Christine Ambrosone, Thaer Khoury, Ting-Yuan David Cheng. Association between cumulative lifetime exposure of reproductive hormones and TILs among women with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3613.