Hormone Receptor Positive HER2-negative/MammaPrint High-2 Breast Cancers Closely Resemble Triple Negative Breast Cancers

Abstract Purpose: The MammaPrint prognostic assay categorizes breast cancers into high- and low-risk subgroups, and the high-risk group can be further subdivided into high 1 (MP-H1), and very high-risk high-2 (MP/H-2). The aim of this analysis was to assess clinical and molecular differences between the hormone receptor positive/HER2-negative (HR+) MP-H1, -H2, and triple negative (TN) MP-H1 and -H2 cancers. Experimental design: Pre-treatment gene expression data from 742 HER2 negative breast cancers enrolled in the I-SPY2 neoadjuvant trial was used. Prognostic risk categories were assigned using the MammaPrint assay. Transcriptional similarities across the 4 receptor and prognostic groups were assessed using principal component analyses and by identifying differentially expressed genes. We also examined pathologic complete response (pCR) rates and event-free survivals (EFS) by risk group. Results: Principal component analysis showed that HR+/MP-H2 tumors clustered with TN/MP-H2 cancers. Only 125 genes showed differential expression between the HR+/MP-H2 and TN/MP-H2 cancers while 1,465 genes were differentially expressed between HR+/MP-H2 and -H1. Gene set analysis revealed similarly high expression of cell cycle, DNA repair, and immune-infiltration related pathways in HR+/MP-H2 and TN/MP-H2 cancers. HR+/MP-H2 cancers also showed low estrogen receptor (ER)-related gene expression. pCR rates were similarly high in TN/MP-H2 and HR+/MP-H2 cancers (42% vs 30.5%, p=0.11), and MP-H2 cancers with residual cancer had similarly poor EFS regardless of ER status. Conclusions: In conclusion, HR+/MP-H2 cancers closely resemble TN breast cancers in transcriptional and clinical features and benefit from similar treatment strategies.