Abstract PS1-09-30: Clinical and Genomic Associations of Atypical Metastases in Invasive Lobular Carcinoma (ILC)

Abstract Background: ILC exhibits a distinct pattern of metastatic spread compared to invasive carcinoma of no special type (NST), related to loss of E-cadherin function. Sites more commonly involved in ILC vs NST include the serosa, meninges, skin, and ovaries. However, the genomic and clinicopathological characteristics of patients at highest risk of developing these ‘atypical’ metastases remain unclear. Using a single-center cohort of patients with metastatic ILC, we sought to define features associated with atypical metastases and determine their impact on outcomes. Methods: Patients diagnosed from 2002-2022 with stage IV ILC were identified by histology on early-stage biopsy/pathology and/or CDH1 mutation on a metastatic site biopsy. Patients were required to have MSK-IMPACT somatic next generation sequencing and metastatic site data available. Metastatic sites were recorded based on imaging and/or biopsies at the time of metastatic diagnosis and were characterized as serosal (peritoneum, pleura, pericardium) vs non-serosal, and atypical (serosal, skin, non-liver gastrointestinal GI, gynecologic GYN, meninges, bone marrow, orbit, genitourinary GU, endocrine) vs typical. Genomic analyses were performed on tissue biopsies obtained within 2 months of metastatic diagnosis. Pearson’s Chi-squared, Fisher’s exact, and Wilcoxon rank sum test were used to compare characteristics between groups. Overall survival (OS) was estimated using the Kaplan-Meier estimate and compared between groups using the log rank test in univariate analyses. Results: 651 patients were included. Median age at metastatic diagnosis was 61 years (IQR 54-68). 520 (86%) patients had hormone receptor-positive (HR+), 56 (9.5%) had HER2-positive, and 65 (11%) had triple negative (TN) disease. 261 (40%) had bone-only metastases. 50 (7.7%) had peritoneal, 31 (4.8%) had pleural, 48 (7.4%) had non-liver GI, 47 (7.2%) had GYN, and 3 (0.5%) had meningeal involvement. 75 (12%) patients had serosal and 194 (30%) had atypical site involvement. 139 (45%) patients had classic, 65 (21%) had pleomorphic, and 103 (34%) had other subtype ILC; subtype information was unknown for 344 patients. ILC subtype was not associated with serosal/atypical site involvement. More patients with serosal and/or atypical metastases were premenopausal at early-stage diagnosis than those without (61% vs 40%, p=0.005 and 51% vs 39%, p=0.013, respectively). More patients with serosal involvement had HR+ disease (94% vs 85%, p=0.028) and fewer had TN disease (2.7% vs 12%, p=0.019). Patients with atypical metastases were more likely to have progesterone receptor positive disease (59% vs 41%, p0.001). ESR1 mutation was more common in those with serosal/atypical metastases (20% vs 7.5%, p=0.003 and 15% vs 6.6%, p=0.007, respectively), whereas ERBB2 mutation was less common (3.8% vs 14%, p=0.048 and 7.3% vs 15%, p=0.041, respectively). GATA3 mutation was more common in those with serosal metastases (13% vs 4.5%, p=0.019). Presence of serosal metastases was associated with worse OS (median 3.5 vs 4.5 years, p=0.003). OS did not significantly differ among patients with atypical vs typical metastases (4.1 vs 4.5 years, p=0.12). Conclusions: Serosal/atypical metastases were associated with early-stage premenopausal status, HR+ disease, and ESR1/GATA3 mutation. Serosal involvement at metastatic diagnosis was associated with worse OS which will be further examined in this cohort in multivariate analyses accounting for prior treatment as a variable, among others. Prevalence of serosal and/or atypical metastases may be underestimated given the limitations of traditional imaging modalities in ILC; confirmation of these findings in other cohorts is warranted. Citation Format: J. J. Chen, C. White, Y. Chen, F. Pareja, A. Safonov, P. Razavi, C. Dang, K. L. Jhaveri, S. Shen. Clinical and Genomic Associations of Atypical Metastases in Invasive Lobular Carcinoma (ILC) 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 PS1-09-30.