FOXA1 Shapes the Chromatin State of ILC and Drives Differential Response to Aromatase Inhibitors and Tamoxifen [WGS]
Invasive lobular breast cancer (ILC) is the second most common histological sub-type of breast cancer. Although the majority of ILC are strongly hormone receptor positive and are of low-intermediate grade, they present a number of clinical challenges. These challenges include limitations in physical exam and breast imaging for early detection, decreased response to chemotherapy and prospective evidence for differences in the benefit from specific adjuvant endocrine treatment regimens when compared to invasive ductal cancer (IDC). In addition to loss of e-cadherin, ILCs possess genetic alterations that are suggestive of a unique estrogen receptor(ER) axis, including an increase in the frequency of FOXA1 mutations and decrease in GATA3 truncating mutations. We performed a randomized Phase II clinical trial, Palbociclib and Endocrine therapy for Lobular breast cancer Preoperative Study (PELOP), in which patients were stratified by histological subtype and found that the magnitude of the difference between the benefit from letrozole compared tamoxifen is significantly higher in ILC versus IDC. To elucidate the mechanism underlying this divergent response we comprehensively studied the ER axis in experimental models of ILC and IDC and clinical samples and show that ILC harbors a unique ER transcriptional axis that stems from increased FOXA1 chromatin binding and an altered chromatin state. These findings provide insights to the unique pattern of response to endocrine treatment in ILC and mechanisms of resistance to endocrine treatment, and offer new treatment strategies to improve outcomes for patients with this breast cancer subtype." Overall design: Whole Genome Sequencing of ductal (MCF7 and T47D) and lobular (MDA134 and SUM44) cells using Illumina HiSeq X.