Abstract P3-06-15: Young breast cancer patients demonstrate worse survival associated with aggressive oncogene expression but not with mutation load, tumor heterogeneity or pro-tumor immune cell infiltrations
Authors: Young JS , Asaoka M , Katsuta E , Kawaguchi T , Qi Q , Liu S , Yan L , Takabe K 
Published: May 2019

Abstract
INTRODUCTION: Young breast cancer patients have more aggressive subtypes and higher mortality rates. This study investigates the biologic, immunologic, and oncogenic differences between Young (≤40 yo) and Non-Young (&gt;40 yo) patients with breast cancer.
MATERIALS/METHODS: The Cancer Genome Atlas (TCGA; n=1095) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n=1894) were used for analysis. Gene Set Enrichment Analysis (GSEA) was performed on breast cancer patients in TCGA. We calculated mutation load using both TCGA and METABRIC. We also calculated the Cytolytic Activity Score (CYT), Mutant-Allele Tumor Heterogeneity (MATH), T-Cell Receptor (TCR)-Richness, and Ki67 mRNA expression in TCGA.
RESULTS: There were 97 and 116 Young patients and 994 and 1788 Non-Young patients in the TCGA and METABRIC databases respectively. Young patients had a lower DFS (p=0.012) in TCGA. Young patients had a lower DSS (p&lt;0.001) in METABRIC. There were less Stage I (13.5% vs 17.3%) and II (54.2% vs 58.3%) patients and more Stage III (31.2% vs 22.4%) patients in the Young group. There were more basal-like subtypes in the Young in TCGA (17.8% vs 16.1%) and METABRIC (28.4% vs 9.3%). Mutation load in TCGA was lower in the Young (p=0.030), but not significantly different in the METABRIC database. MATH, which reflects tumor heterogeneity, was not significantly different between the groups. These results were unexpected since Young patients have a higher proportion of basal-like subtype which is known to be rich in mutations and more immunogenic. In TCGA, Young patients were found to have higher amounts of activated dendritic cells (p=0.049). In METABRIC, Young patients had higher amounts of Plasma cells (p=0.016), CD4 memory-activated T-cells (p&lt;0.001), NK resting cells (p=0.015), and M1 Macrophages (p=0.002). We also found that regulatory T-cells (p=0.029), activated NK cells (p=0.016), M2 Macrophages (p&lt;0.001), and resting Mast cells (p=0.006) were lower in the Young. This unexpectedly showed that anti-tumor immune cells were more enriched in Young patients. Indeed, the CYT, which reflects tumor killing activity, and TCR-Richness, which reflects T-cell function, were both significantly higher in Young patients (p=0.034, p=0.004, respectively), which was opposite from what we expected due to its biological aggressiveness. GSEA was then used to analyze the TCGA database to clarify gene sets that are enriched in Young patients. Of the 50 Hallmark gene sets analyzed, 4 gene sets were found to be enriched in Young patients; G2M Checkpoint (p=0.002), Hallmark MYC Targets V1 (p=0.004), HALLMARK E2F Targets (p=0.035), and Hallmark Unfolded Protein Response (p=0.038). Ki67 which reflects cell proliferation was significantly higher in Young vs Non-Young patients (p=0.004).
CONCLUSIONS: Both TCGA and METABRIC cohorts demonstrated that Young patients have more basal-like subtype and significantly worse survival. Our results support the notion that Young patients have more aggressive cancer not because of mutations, tumor heterogeneity or immune cell infiltrations, but because of aggressive oncogene expressions.
Citation Format: Young JS, Asaoka M, Katsuta E, Kawaguchi T, Qi Q, Liu S, Yan L, Takabe K. Young breast cancer patients demonstrate worse survival associated with aggressive oncogene expression but not with mutation load, tumor heterogeneity or pro-tumor immune cell infiltrations [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-15.