Abstract B53: Genomic redefinition of Her2+ breast shows role of estrogen and androgen signaling

Abstract

Abstract Many breast cancers are driven by amplification and overexpression of the Her2 receptor tyrosine kinase. We searched the TCGA and Metabric genomic datasets to define and better understand the genetic drivers of Her2+ cancer. We defined Her2+ tumors as those with a ploidy-corrected copy number for Her2 of 4 or more, encompassing 12% of breast tumors in both cohorts. This population showed high concordance with Her2 IHC/FISH status, but weak concordance with intrinsic PAM50 subtype: 45% of Her2+ breast tumors were Her2-enriched, 48% luminal A or B, and 7% basal-like. We characterized this transcriptionally heterogeneous Her2+ population using a meta-consensus clustering approach. Her2 amplification--though a driver--had limited impact on the transcriptional profile of each tumor. Her2+ tumors were rather additionally driven by estrogen or androgen signaling, with their transcriptional subtype defined by ER, PR and AR status. In terms of copy number, Her2+ tumors showed biologic selectivity for oncogenes and putative driver genes located in 8 regions outside of the Her2 amplicon that were selectively aberrated in presence of Her2 amplification. We also identified a small population of breast tumors with substantial over-expression of Her2 and neighboring genes that lack amplification but show consistent hypo-methylation. In conclusion, considering the transcriptional profile of Her2+ breast tumors provides combination strategies and viable treatment options for patients who developed resistance to Her2-targeted treatments, with endocrine therapies for Her2+/ER+ tumors, and antiandrogen strategies for Her2+/AR+ tumors. Furthermore, co-ordinated regulation of Her2 and neighboring genes supports the notion that the effect of the Her2 amplicon may be more than through overexpression of Her2. Citation Format: Anneleen Daemen, Jacob Rinaldi, Gerard Manning. Genomic redefinition of Her2+ breast shows role of estrogen and androgen signaling. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B53.