Abstract 3931: Breast cancer genomic architecture contributes to immune escape across metastasis

Abstract Clinically, breast tumors are stratified based on the expression of three receptors - estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). Breast cancer is a highly heterogeneous disease, and a more detailed understanding of its genomic drivers, mechanisms of immune evasion, and evolution may inform more effective and personalized treatment. Previously, 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 identify 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 across the ICs to sculpt the development and evolution of disease, nor how their microenvironments differ. To interrogate the genomic and immune landscape of breast cancer throughout the disease continuum, we established a meta-cohort of 2, 873 breast tumors spanning pre-invasive (ductal carcinoma in situ), primary invasive, and metastatic breast cancer, including 1, 865 with whole-genome sequencing, 1, 738 with whole-transcriptome sequencing, and 730 with both modalities. We developed a fully containerized bioinformatic workflow to interrogate copy number alterations, complex classes of structural variation, and neoantigens. Analysis of this large clinically curated compendium identifies highly concordant mutational signatures and higher order genomic features in high-risk ER+ (IC1, 2, 6, 9) and HER2+ (IC5) tumors, including distinct patterns of structural variation. In contrast, triple-negative tumors (predominantly IC10) were characterized by global genomic instability and tandem duplications, whilst a third group is largely genomically stable. These distinct genomic architectures were associated with specific tumor microenvironments. As expected, triple-negative tumors were immune-enriched. In contrast high-risk ER+ and HER2+ tumors demonstrated immune-depleted profiles, as compared to typical risk ER+ tumors. These microenvironment classifications were maintained from primary tumors to metastatic lesions, except triple-negative tumors that exhibited increased immune depletion during metastasis. Taken together, our data demonstrate that complex structural alterations established early in breast cancer contribute to immune evasion, and persist throughout the life history of the tumor through metastasis. Citation Format: Lise Mangiante, Kathleen Houlahan, Cristina Sotomayor Vivas, Alvina Adimoelja, Seongyeol Park, Aziz Khan, Sophie Pribus, Zhicheng Ma, Jennifer Caswell-Jin, Christina Curtis. Breast cancer genomic architecture contributes to immune escape across metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3931.