Abstract PO-059: The genomic landscape of the in situ to invasive ductal breast carcinoma transition shaped by the immune system

Abstract

Abstract Background: The transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) is an evolutionary bottleneck where progression occurs only in 30% of patients. Whilst the genetic drivers of this transition remain poorly understood, we have previously shown that immune escape is a key event. In this study, we profile the evolutionary trajectory of matched pure DCIS and IDC in the context of the immune microenvironment. Methods: We have evaluated changes in copy number profiles, mutational profiles, expression and neoantigen load in 6 cases of matched pure DCIS and IDC using exome and RNA sequencing. We have integrated this information with topologic assessment of H&E images and cyclic immunofluorescence. Results: We provide evidence for an evolutionary bottleneck during DCIS to IDC in matched patient samples, showing that copy number aberrations are early events, but low overlap in mutational profiles. Variation in immune composition and spatial orientation can arise as early as in DCIS and are subtype specific. Tumor-specific copy number changes including loss of MHC-I presentation machinery or changes at cytokine rich loci specifically in ER− tumors could contribute to a more immunosuppressive environment in IDC. Oncogenic hotspot mutations can present as neoantigens yet are paradoxically conserved during the DCIS-to-IDC transition. We suggest these mutations have a secondary immune-modulatory function or may be present in normal tissue, escaping immune surveillance as early as in DCIS. Conclusions: We show both genomic and microenvironmental differences in matched pure DCIS and recurrent IDC, highlighting that progression is shaped by both tumor and immune system at this evolutionary bottleneck. Citation Format: Anne Trinh, Carlos R. Gil Del Alcazar, Sachet A. Shukla, Koei Chin, Young Hwan Chen, Guillaume Thibault, Jennifer Eng, Bojana Jovanovic, C. Marcelo Aldaz, So Yeon Park, Joon Jong, Catherine Wu, Joe Gray, Kornelia Polyak. The genomic landscape of the in situ to invasive ductal breast carcinoma transition shaped by the immune system [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-059.