Abstract P4-06-01: Expression and DNA copy number profiling suggest novel therapeutic approaches for triple negative breast cancer subtypes
Authors: Burstein MD , Tsimelzon A , Hilsenbeck SG , Fuqua SW , Chang JC , Osborne CK , Mills GB , Brown PH , Lau CC 
Published: August 2014

Abstract
The aggressive triple negative breast cancers (TNBCs), which lack ER, PR and HER2, comprise a high-risk subset of human breast cancers which remain poorly characterized and lack effective treatments. While recent meta-analyses indicate the complexity of these tumors, no robust independently validated phenotypes have been defined. We have identified four distinct molecular subtypes through independent non-negative matrix factorization of expression data from 84 Discovery and 114 Validation Set TNBCs profiled at a single institution, with matching CNV data (SNP array). We then classified 485 publically available TNBCs via a centroid signature of only 80 genes. All three sets supported stratification of tumors by cell cycle, DNA repair, and immunological signaling pathways that have significantly different clinical outcomes. The first subtype, composed of intermediate grade tumors, resembles the “Molecular Apocrine” or “Luminal AR” subtype described previously and was defined by enrichment of prolactin, aryl hydrocarbon receptor, and ERBB4 signaling with activated downstream expression patterns of ESR1 signaling. Large deletions of chromosome 6 were specific to this subtype. While focal deletions at 14q21.2 and 12q13.13 were present in &gt;60% of tumors of the other subtypes, the genes at these loci (FOXA1 and ERBB3) were overexpressed in the first subtype. Inhibitors of AR and MUC1, both overexpressed, may prove effective for these tumors. A second subtype defined as “Claudin-Low” or “Mesenchymal Stem-Like” showed overexpression of markers of mesenchymal lineage (ADIPOQ and OGN). Targets responsive to beta-blockers (ADRB2), and targetable molecules associated with platelet and endothelial function (EDNRB, PLA2G2A, PTGER3/4, PTGFR, PTGFRA) were also upregulated. Two basal-like subtypes were found with significant differences in DFS and OS, even after correction for available clinical covariates. The high-risk (31% 5-year DFS), low immune function subtype was regulated by SOX 10, 8, and 6 and had unique copy-number driven expression of FGFR2. The second, low-risk (78% 5-year DFS) basal-like subtype was enriched for overexpression of many immune pathways, regulated by increased STAT1 and activated STAT downstream signaling, as well as exclusive upregulation of CTLA4. This subtype also had the lowest tumor cell fraction as calculated by allele specific copy number analysis of tumors (ASCAT). Both basal-like subtypes expressed TTK, CHEK1, TOP2A, and AURKA. CDK1 was correlated with copy number variation at 10q21.1. We proposed and validated four molecular subtypes of TNBC before applying the resulting gene signature to 7 external expression sets. The described subtypes vary by clinical behavior and inferred biology. Each subtype appears to have specific gene expression regulated by copy number variation and a set of genes targetable by currently available agents. These findings further define the heterogeneity of TNBCs and suggest potential therapeutic targets for each subtype.
This work was supported by a Promise grant from the Susan G. Komen for the Cure Foundation (KG081694).
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-06-01.