Prospective evaluation of circulating plasma thyroid hormones concentrations and breast cancer risk in the EPIC cohort

Abstract

Background Hyperthyroidism has been associated with increased risk of breast cancer and in vitro studies have shown that thyroid hormones may influence breast tumorigenesis. We aimed to study associations between pre-diagnostic circulating thyroid hormone concentrations and breast cancer risk. Methods We evaluated associations between breast cancer risk and circulating concentrations of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), fT3/fT4 ratio, and anti-thyroid peroxidase antibody (TPO-Ab) positivity, in plasma samples from 1518 invasive breast cancer cases (diagnosed between 2 and 14 years after blood collection) and 1518 matched controls from a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort using validated immunoassays. Conditional logistic regression models were used to evaluate associations with breast cancer, with adjustment for established breast cancer risk factors. Findings In fully adjusted models, fT3 (ORper standard deviation (SD) (95% CI) = 1.16 (1.05-1.29)) and fT4 (ORper SD = 1.11 (1.01-1.22)) concentrations were positively associated with breast cancer risk. For fT3, the association was stronger for HER2-positive tumours (HER2+: ORper SD = 1.59 (1.20-2.11); HER2-: ORper SD = 1.10 (0.98-1.23)) compared to other tumour types (P-heterogeneity = 0.01). TSH concentrations, fT3/fT4 ratio, and TPO-Ab positivity were not associated with breast cancer risk. Interpretation In this large-scale study, higher prediagnostic circulating fT3 and fT4 concentrations were associated with increased breast cancer risk, particularly for HER2-positive tumours. Confirming these findings is critical to achieving a better understanding of the associations between thyroid function and breast cancer risk, which may inform personalised prevention. Funding This work was funded by the French National Cancer Institute (grant number 2018-118). Copyright (c) 2025 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND IGO license (http://creativecommons.org/licenses/by-nc-nd/3.0/igo/).