Abstract PS2-09-27: Patterns of central nervous system (CNS) and leptomeningeal (LM) involvement in advanced breast cancer (BC) with invasive lobular histology: insights from a large multicenter study with a focus on estrogen receptor-positive (ER+)/

Abstract Background: Invasive lobular carcinoma (ILC) is the second most common BC histological subtype and the most frequent among special histological types, accounting for 10-15% of all BCs. While ILC is known to exhibit distinct metastatic patterns compared to carcinoma of no special type (NST, formerly invasive ductal carcinoma), little is known about its specific propensity for CNS and LM involvement, particularly in ER+(>=10%)/HER2- BC. Methods: We leveraged a large multicenter study of 1710 pts with advanced BC. Classification of tumor histology: NST, ILC, other special-types. CNS events: brain-only (parenchymal), LM (sub-classified as isolated-LM: no concurrent parenchymal brain mets; all-LM events: isolated + co-occurring cases). Survival endpoints: CNS-free survival (from BC diagnosis to the first CNS event/last follow up), LM-free survival (from BC diagnosis to LM as first CNS event/last follow up), post-LM survival (from LM as first CNS event to death/last follow up). Fine-Gray competing risk model was used to test the association between histology (ILC vs NST) and the risk of LM as first CNS event, accounting for brain-only as a competing event. Results: Among 1587 pts with known tumor histology, 15.5% (n=245) had ILC and 4.5% (n=72) other special-type histology, with an ER+/HER2- phenotype in 64.5% (n=158) and 41.6% (n=30) of cases, respectively. ILC was significantly enriched in ER+/HER2- tumors compared to triple-negative and HER2+ subtypes (p<0.001). A total of 526 pts developed a CNS event (n=219 in ER+/HER2-), including 466 brain-only (n=181 in ER+/HER2) and 60 LM (n=38 in ER+/HER2-). LM was diagnosed by radiological imaging in 90% of cases, while 10% were diagnosed by CSF cytology, in the absence of radiological evidence. At a median follow up of 16 years, among ER+/HER2- BC pts, those with ILC and NST experienced similar CNS-free survival, both numerically longer than that of other special-type histologies (10-yr CNS-free survival: NST 70.0%; ILC 68.1%; other 34.9%, p=0.083). In contrast, LM-free survival was significantly shorter in ILC compared with NST and other special histologies both when considering all LM events and isolated-LM (all-LM events, 10-yr LM-free survival: NST 95.6%; ILC 89.0%; other 92.3%, p=0.005; isolated-LM, 10-yr LM-free survival: NST 96.0%; ILC 89.9%; other 95.2%, p=0.003). In multivariate Cox models (adjusted for age, histologic grade, % estrogen/progesterone receptor expression, % ki67 and visceral involvement as first site of relapse), ILC was independently associated with worse LM-free survival than NST both when considering all-LM events and isolated-LM (all-LM events: adjusted HR for ILC vs NST [ref] = 5.21 [95%CI 1.54-17.60] p=0.008; isolated-LM; adjusted HR for ILC vs NST [ref.] = 5.36 [95%CI 1.59-18.14] p=0.007). Competing risk analysis confirmed a significantly increased risk of LM involvement as the first CNS event in ER+/HER2- BC pts with ILC compared to NST (HR for ILC vs NST [ref] 2.94 [95%CI 1.56-5.56], p<0.001). Among pts with LM disease, ILC was associated with significantly worse post-LM survival compared to NST (1-yr post-LM survival: NST 30.0% vs ILC 5.9%, p=0.036; HR of ILC vs NST [ref] 2.10 [95%CI 1.04-4.23] p=0.036). Conclusions: In ER+/HER2- advanced BC, compared with NST, ILC was significantly and independently associated with a marked tropism for LM involvement as first CNS event. Moreover, among pts with LM disease, those with ILC experienced particularly poor outcome, with a post-LM survival significantly worse than that of pts with NST-associated LM. These findings underscore the need for closer clinical vigilance and possibly tailored CNS surveillance strategies in pts with ER+/HER2- advanced BC of ILC histology. Citation Format: F. Miglietta, C. Vernieri, T. Giarratano, G. Griguolo, M. Bottosso, A. Vingiani, F. Piacentini, M. Cacciatore, A. Botticelli, G. Fotia, P. Napolitano, G. Landa, G. Vernaci, E. Di Liso, L. Casadei, D. Palleschi, G. Pruneri, A. Dei Tos, V. Guarneri, M. Dieci. Patterns of central nervous system (CNS) and leptomeningeal (LM) involvement in advanced breast cancer (BC) with invasive lobular histology: insights from a large multicenter study with a focus on estrogen receptor-positive (ER+)/HER2- disease [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-09-27.