Abstract SP068: The unique epigenetic state of invasive lobular breast cancers

Abstract

Abstract Although the majority of invasive lobular breast cancers (ILC) are strongly hormone receptor positive and are rarely high-grade, they present a number of unique clinical problems compared with invasive ductal cancer (IDC). These include challenges for early detection, decreased response to chemotherapy and evidence of relative resistance specifically to adjuvant tamoxifen treatment. In addition to uniform loss of e-cadherin, ILCs possess genetic alterations that are suggestive of a unique estrogen receptor axis, including an increase in the frequency of FOXA1 mutations and decrease in GATA3 mutations. In this study we performed a comprehensive analysis of the estrogen receptor axis in pre-clinical models and clinical samples of ILC and IDC. We found that ILC has a unique chromatin state that stems from gained FOXA1 chromatin binding and leads the remodeling of ER chromatin binding. We demonstrated that FOXA1 recruitment can classify primary hormone receptor positive breast cancers to ILC and IDC histological subtypes. Moreover, we show that gained FOXA1 recruitment leads to the transcription of a gene signature associated with resistance to adjuvant tamoxifen in estrogen receptor positive breast cancers and is a mechanism for the divergent pattern of response to specific endocrine treatments in ILC. Collectively, these studies unveil key insights to the fundamental biology unique to ILC, set the stage for precision endocrine treatment in estrogen receptor positive breast cancer, and offer potential treatment targets to improve outcomes for patients with ILC. Citation Format: R Jeselsohn. The unique epigenetic state of invasive lobular breast cancers [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP068.