Abstract P5-05-02: Thyroid hormone replacement therapy shortens survival in hormone receptor positive early stage breast cancers
Authors: Wahdan-Alaswad RS , Edgerton SM , Salem HS , Liu B , Thor AD 
Published: May 2019

Abstract
Purpose
A majority of breast cancer (BC) patients have clinical or subclinical thyroid disease as compared to a minority of unaffected women. This comorbidity has been recognized for over a century. We hypothesized that thyroid hormone (TH) promotes breast carcinogenesis and growth, and may reduce survival for patients on long term TH replacement therapy (THRT). We sought to validate these findings in a study of BC patients and investigate mechanisms of hormonal interaction using model systems.
Methods
Over 800 consecutively diagnosed lymph node (LN) negative, mostly chemo-naïve invasive BC patients from 1976 to 1993 at were evaluated. Clinical and outcomes data were derived from medical records (10.2 year median follow up). Primary tumors from surgery (typically mastectomy with node dissection) were analyzed for receptors and biomarkers. Univariate and multivariate statistical methods were used. In vivo and in vitro studies were performed using immortalized human BC cell lines and patient derived xenograft(PDX) models.
Results
LN- THRTvs. non-THRT BC patients showed nosignificantdifferencesinclinical,histologic or prognosticdata. THRT was significantly associated with a higher relativerisk(RR)ofrecurrence2.376fold(p&lt;0.0001)anddisease specific survival (DSS), 2.02fold (p=0.0183). Subset analyses showed only steroid receptor (SR) positive patients had a deleterious interaction with THRT (mean RFS 68mo.,RR3.431,p&lt;0.0001), mean disease specific survival (DSS)81mo.,RR3.960,p=0.0001)ascomparedtonon-THRTpatients(mean RFS206mo.,meanDSS223mo.). Tamoxifen (Tam) treated patients on THRT had an especially poor outcome, DFS p=0.0004. Usinginvitromethods we showedpotent induction of cell proliferation by estrogen (E2)and/or thyroidhormone (TH) acrossawiderange of concentrations in SR+, but not SR- BC (P&lt;0.0001). Fulvestrant (ICI) significantly inhibited these interactions, whereas Tam failed to provide an equivalent antagonistic effect. In some SR+ cells, Tam further increased cell proliferation. In vivo studies showed co-localization of ER and THRα were upregulated by co-administration of E2 + TH. Tam further induced co-localization, whereas ICI lowered receptor expression and co-localization. ER+ PDXtumors in mice with continuous E2 showed enhanced tumorigenesis with TH (tumorgrowth(p&lt;0.0001),tumorweight(mg)(p=0.0052)and Ki67labeling(p=0.001)). Mice on E2 + TH with PDX tumors treated with Tam showed enhanced tumor growth and proliferation (p&lt;0.0001), whereas ICI inhibited and in some cases eliminated tumors. RNA-seq data performed on our ER+ PDX tumors treated with hormone combinations +/- Tam show that E2 + TH potently upregulates numerous cell cycle and hormone regulated genes.
Conclusion
We show statistically significant interactions between THRT at the time of BC diagnosis, early relapse and shortened survival in SR+ (but not SR-) Stage I BC patients. In vitro and in vivo BC models confirm these deleterious interactions. Mechanistically we observe co-localization of the cognate receptors and activation of ER, with downstream upregulation of cell cycle and hormone regulated genes. These interactions are blocked by ICI, whereas Tam fails to block and may in fact enhance tumorigenesis.
Citation Format: Wahdan-Alaswad RS, Edgerton SM, Salem HS, Liu B, Thor AD. Thyroid hormone replacement therapy shortens survival in hormone receptor positive early stage breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-02.