Abstract PD9-01: Comprehensive Genomic Landscape of Invasive Lobular Carcinoma Reveals Distinct Molecular Subtypes

Abstract Introduction: Invasive lobular carcinoma (ILC) represents a distinct subtype of breast cancer with unique clinical and molecular features compared to invasive ductal carcinoma (IDC). A hallmark of ILC is the loss of E-cadherin due to CDH1 alterations, yet large-scale genomic profiling of this histology, which is predominantly hormone receptor-positive (HR+)/HER2-negative, remains limited. Here, we comprehensively characterized the somatic mutational landscape of HR+/HER2-negative ILC and explored associations with clinical outcomes using real-world data. Methods: Whole-exome sequencing (WES) was performed as part of the SignateraTM (Natera, Inc.) workflow. WES-derived somatic variants from 1,451 patients with HR+/HER2- ILC in Natera’s large real-world database. Variants were annotated using the Ensembl Variant Effect Predictor (VEP), and only non-synonymous mutations with variant allele frequency (VAF) ≥ 5% were included in the prevalence analysis. Mutational signatures were assessed by comparing 96-trinucleotide mutation contexts with COSMIC single base substitution (SBS) signatures (v3.3). Event dates, including curative-intent surgery and distant relapse, together with treatment information, were sourced from claims data. Subtype was inferred based on treatment received. Associations between gene-level mutation and distant relapse-free survival (DRFS) were evaluated. Results: Among 1,451 HR+/HER2- ILC cases, CDH1 mutations were observed in 68%, with truncating variants accounting for 91% of these alterations. The most frequent CDH1 variants were p.Q23* (6.2%), p.I650Yfs13 (1.03%), p.Q129 (1.03%), and p.Q610* (1.03%). Comparative analysis with HR+/HER2- IDC revealed differential mutation frequencies in key genes, including PIK3CA, TBX3, TP53, and ERBB2 (47.3% vs 37.33%, 11.8% vs 4.0%,6.9% vs 25.2%, and 5.8% vs 2.2% P0.001 for all), in addition to CDH1 (68% vs 2.6%, P0.001). Despite its prevalence, CDH1-truncated tumors were not associated with worse clinical outcomes when compared to wild-type or non-truncating counterparts. In contrast, mutations in TP53, ERBB2, and RYR1 were significantly associated with inferior DRFS in ILC (HR(95% CI), p-val); 2.2 (1.2-3.9), P=0.006; 2.4(1.2-4.6), P=0.009; 2.4(1.2,4.9), P=0.018). Mutational signature analysis revealed enrichment of age-related, APOBEC-mediated, and mismatch repair (MMR)-associated processes. Tumors harboring the APOBEC signature exhibited the highest tumor mutational burden (TMB), with a mean TMB of 7.1 Muts/MB (vs. 1.31 Muts/MB, p-val 0.001). Co-mutation analysis showed significant co-occurrence of CDH1 and PIK3CA mutations (P0.01), while PIK3CA and AKT1 mutations were mutually exclusive (P0.01). VAF analysis suggested that CDH1 mutations generally precede PIK3CA alterations, indicating CDH1 loss as an early event in ILC tumorigenesis. Conclusions: This study provides one of the largest genomic profiling studies of HR+/HER2- ILC, highlighting the central role of CDH1 loss and its likely function as an early initiating event. CDH1 mutations alone did not portend worse outcomes, mutations in TP53, ERBB2, and RYR1 were associated with significantly poorer DRFS and may serve as clinically relevant prognostic markers. The presence of APOBEC-driven mutational signatures and the co-occurrence of PIK3CA and CDH1 mutations further underscore the molecular heterogeneity within ILC. These insights enhance our understanding of ILC biology and may guide future therapeutic stratification and biomarker development in this histologic subtype. Citation Format: S. Oesterreich, S. Rivero-Hinojosa, V. N. Aushev, S. Satta, E. Kalashnikova, R. Green, A. Ramu, A. Rodriguez, M. C. Liu, J. Foldi, M. Balic, A. V. Lee. Comprehensive Genomic Landscape of Invasive Lobular Carcinoma Reveals Distinct Molecular Subtypes 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 PD9-01.