Abstract PS18-04: Tumor intrinsic and extrinsic characteristics of invasive lobular carcinomas

Abstract Background: It is now well-established that invasive lobular carcinoma (ILC) is a distinct disease with higher risk of distant recurrence after 10 years compared to invasive ductal carcinoma (IDC) (Pestalozzi et al. J Clin Oncol 2008). However, little is known about the underlying mechanisms of relapse in ILC cases. Additionally, recent large landmark studies have revealed heterogeneity at the morphological, molecular, and microenvironmental levels (Ciriello et al. Cell 2015, Michaut et al. Sci Rep 2016, Desmedt et al. J Clin Oncol 2016) suggesting that the overarching category of ILC may encompass several distinct subgroups. A more detailed understanding of the underlying genomic drivers, mechanisms of immune evasion, and evolution may inform more effective and personalized treatment. Previously, across histological types, we established a genome-driven breast cancer classification scheme that defines 11 integrative subgroups (ICs) of disease with distinct copy number aberrations (CNAs), transcriptional profiles, and clinical outcomes. Specifically, we identified four subgroups of ER+ disease (IC1, IC2, IC6, IC9) with a persistent risk of lethal distant relapse up to two decades after diagnosis, each with focal copy number drivers and two distinct subgroups of triple-negative disease (Curtis et al. Nature 2012; Rueda et al. Nature 2019). These findings nominate new therapeutic strategies, however, it is not known how mutational processes and genomic architecture differ between IDC and ILC in this context to sculpt the evolution of disease, nor how their microenvironments differ. Methods: To interrogate the genomic and immune landscape of invasive lobular carcinomas, we collected a meta-cohort of 401 primary invasive breast tumors, including 254 with whole-genome or whole-exome sequencing, 350 with whole-transcriptome sequencing, and 203 with both modalities. This meta-cohort includes the clinically curated METABRIC dataset with 20 years of clinical follow-up. Additionally, we established a single-cell spatially resolved transcriptomic meta-cohort of 54 primary ILCs, including 7 metastatic ILCs with primary and matched metastatic lesion(s). Results: Analysis of this large clinically curated dataset reveals a distinct pattern of relapse for patients with ILC tumors. Patients with ILC exhibited a higher 5 year recurrence risk (39% vs. 30%) and modestly higher cumulative recurrence risk (62% vs. 54% at 20 years) in the ER+ High-risk group, while this difference was even more striking amongst ER+ Typical-risk tumors, where ILC cases exhibited higher rates of late recurrence than IDC (55% vs. 37% at 20 years). Paradoxically, ILC tumors are enriched for the genomic stable ER+ Typical-risk subgroup that displays quiet genomes compared to other IC subgroups. In particular, ER+ High-risk and HER2+ tumors are associated with focal amplifications, extrachromosomal DNA, and coincident structural variants, whereas triple-negative tumors are characterized by global genomic instability and tandem duplications. Consistent with their quiet genomes and higher proportion of CDH1 mutations, ILC tumors demonstrated a lower proportion of whole-genome doubling, lower ploidy, lower fraction of copy number aberrations, lower proportion of TP53 mutations and replication stress compared to IDC. Moreover, the ILC ER+ Typical-risk tumors were enriched for immune-depleted and fibrotic TMEs compared to ER+ Typical-risk IDCs tumors. Spatial transcriptomic profiling suggests an overall lower level of interaction and cell-cell communication between tumor, immune and stromal cells in ILC compared to IDC. Conclusion: Taken together, our data uncover tumor-intrinsic molecular characteristics of ILC and implicate tumor-extrinsic factors in disease aggression. Citation Format: Lise Mangiante, Kathleen Houlahan, Cristina Sotomayor Vivas, Alvina Adimoelja, Seongyeol Park, Sophia Pribus, Brennan Simon, Zhicheng Ma, Aziz Khan, Jennifer Caswell-Jin, Christina Curtis. Tumor intrinsic and extrinsic characteristics of invasive lobular carcinomas [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS18-04.