Abstract LB077: Identifying therapeutic vulnerabilities in lobular breast cancer

Abstract Invasive lobular breast cancer (ILC) is less responsive to chemotherapy and tamoxifen than other breast cancers, leading to a higher risk of recurrence and poor survival for patients with this disease. Loss of CDH1, a key component of adherens junctions, is a defining feature of ILC that manifests as single-file discohesive tumor cells in the stroma and suggests a unique microenvironment signaling network impacts disease course. We hypothesize that identifying key features of the tumor-stroma interface that are prognostic of ILC patient outcomes will provide new targets for suppressing and preventing the progression of this disease. To accomplish this, we have initiated spatial transcriptomic studies to identify the ILC tumor and adjacent stromal transcriptomes by using an in-house generated tissue microarray (TMA) coupled with outcomes data. This robust TMA comprises >100 ILC tumors, adjacent normal stroma, 46 paired metastatic lymph nodes, and at least 8 years of patient outcomes data. To determine if long-archived tissue can provide quality data, we performed a pilot analysis of 2 short-archived and 6 long-archived ILC tumors ranging from 3-28 years. We observed no differences in the normalized expression values between short and long-archived tissues, and principal component analysis of normalized unfiltered gene expression revealed no clear separation of samples based on archival age. We also confirmed decreased CDH1 expression in ILC compared to normal epithelium and increased LOXL1 expression in ILC stroma compared to normal-adjacent stroma, suggesting that prognostic gene expression analyses will not be significantly skewed by variable RNA integrity. We also uncovered enrichment of the Hedgehog signaling (Hh) pathway and the ligand-receptor pair, IHH-BOC, in ILC-adjacent stroma. The Hh pathway is a known poor prognostic indicator in many solid cancers and an emerging therapeutic target in breast cancer. Moreover, IHH is associated with worse outcomes in ILC. Together, these early studies validate the use of long-archived tissue in spatial transcriptomic studies and suggest that Hh inhibition may be a viable strategy for treating ILC. We are currently expanding these studies to include the whole cohort of ILC tumors and paired metastatic lymph nodes to identify essential genes or pathways that are associated with ILC patient survival and can serve as future candidates for therapeutic targeting in this disease. Citation Format: Darcie D. Seachrist, Salendra Singh, Saul Castillo, Najla Fakhruddin, Ruth A. Keri. Identifying therapeutic vulnerabilities in lobular breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB077.