Abstract P6-05-03: Exogenous steroid hormone exposure and the biology of lobular breast cancer
Authors: Guenthoer Jamie , Jenkins Isaac C , Thompson Beti , Tang Mei-Tzu C , Davidson Nancy E , Ashley Ryan L , Li Christopher I , Hsu Li , Porter Peggy L 
Published: March 2020

Abstract
Introduction. Invasive lobular carcinoma (ILC) accounts for 10-15% of breast cancer diagnoses and is characterized by a high rate of estrogen and progesterone receptor (ER and PR) expression, low rate of HER2 amplification, and a defining lack of e-cadherin expression. Multiple population-based, observational studies have shown that the risk of ILC is significantly elevated with the intake of combined estrogen/progestin (E+P) hormone replacement therapy (HRT) but not with estrogen-alone (E alone) HRT. In addition, recent studies have revealed that ILCs might respond differently to hormone therapies than IDCs. We sought to understand the influence of exogenous hormone exposure in the form of HRT on biological pathways in ILCs compared to the more common histologic subtype, ER+ invasive ductal carcinoma (IDC).
Specimens and Methods. We assessed 297 ER+/HER2- FFPE breast carcinomas, 165 IDCs and 132 ILCs, previously collected from an epidemiological study of HRT use and breast cancer in post-menopausal women. These tumors were characterized for histopathological features and protein marker expression by immunohistochemistry along with the extensive clinical and demographic data, including HRT use, collected in the parent study. Using the Nanostring nCounter assay, we measured expression of ~1000 genes representing canonical cancer-promoting pathways and steroid hormone-associated pathways to determine the relationship between HRT use and pathway alterations in ER+ breast cancer subtypes.
Results. From the histopathological assessment, we observed that ILCs had lower overall lymphocyte response than IDCs (p=0.005), but HRT use shifted the lymphocyte response higher than what was observed in ILCs from never/former HRT users (p=0.002). In the gene expression analysis, we found that IDCs and ILCs have distinct expression profiles after adjusting for HRT use, including genes in cell cycle, steroid hormone-response pathways, and cytokine/cytokine receptor interactions, with increased signaling seen in the IL6/12-like family. When comparing gene expression between the HRT-use groups, adjusting for histology, we observed that E+P and E alone are both associated with down-regulation of cell cycle and DNA repair genes compared to the never/former use group. When we focused on expression patterns specific to progestin exposure, (i.e., E+P versus all others), we found decreased expression of genes related to DNA replication initiation and G1/S transition and WNT4. Unsupervised hierarchical clustering revealed additional subgroups within each histologic subtype including a group of low-grade, low-proliferating IDCs enriched for E+P exposure, which clusters with the majority of the ILCs. While many gene expression changes with HRT use are shared across the tumors, we observed alterations that are specific to either ILCs or IDCs, suggesting different steroid hormone-responsive pathways between the subtypes.
Conclusions. Our study demonstrates there are potentially specific pathways differentially activated between ILCs and IDCs dependent on the type of hormone exposure. Further, while our study is focused on tumor molecular pathways modulated in response to HRT use, steroid hormone exposure can come from multiple sources, and we propose that the results from this study can provide insight into hormonally-driven breast cancers that develop with excess estrogen and/or progesterone exposure. This could have implications in clinical management of ILCs and IDCs that arise in HRT users.
Citation Format: Jamie Guenthoer, Isaac C Jenkins, Beti Thompson, Mei-Tzu C Tang, Nancy E Davidson, Ryan L Ashley, Christopher I Li, Li Hsu, Peggy L Porter. Exogenous steroid hormone exposure and the biology of lobular breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-05-03.