Abstract P3-08-11: Multi-omics profiling reveals distinct molecular features in young and elderly triple negative breast cancer
Authors: D Ma, Y-Z Jiang, M-D Xie, Y Xiao, S Zhao, Z-M Shao
Journal: Cancer Research (2019)

Abstract Purpose Age at breast cancer diagnosis not only predicts clinical outcome, but also indicates distinct molecular features thus we can choose the most appropriate treatment strategies. Yet little is known about the molecular profile of young and elderly triple negative breast cancers (TNBCs). Methods Clinical, genomic and transcriptome features of young (&amp;lt;40 year-olds) and elderly (≥65 year-olds) TNBC patients were studied in a cohort of 473 TNBCs from Fudan University Shanghai Cancer Center. Results In this study, 50, 354 and 69 patients were &amp;lt;40, 40–64 and ≥65 years of age, respectively. Young TNBCs had more relapse or metastasis within the first 2 years after surgery (P=0.036) which was also significant in the basal-like subgroup (P=0.004), while elderly TNBCs were more likely to be luminal androgen receptor (LAR) subtype (46%) harboring frequent PIK3CA and KMT2C/KMT2D somatic mutations, with more fibrosis or mesenchymal-like (MES) subtype (in the basal-like subgroup) and featured by significantly lower Ki-67 index. Gene set enrichment analyses revealed that young TNBCs showed elevated expression of genes involved in cell cycle, nucleotide metabolism and DNA damage repair. In further discussion on nucleotide metabolism, TYMS, a crucial gene encoding thymidylate synthase while is also the target of fluorouracil and capecitabine, were identified to be enriched in young TNBCs independent of molecular subtype in both our cohort (adjusted P&amp;lt;0.001) and METABRIC (adjusted P=0.027). We next studied DNA damage features and found that while TNBCs of different age groups had comparable somatic mutation load, their mutations had distinct generation mechanism that homologous recombination deficiency (HRD) related signature and Aging related signature tend to be enriched in younger and elder patients, respectively. We also observed higher germline BRCA1 mutation rate in young TNBCs (23%). Interestingly, while germline BRCA2 mutation rate was comparable among the groups, copy number (CN) loss of Chr13q13 (with BRCA2 in the 'peak') was almost exclusively found in young patients (adjusted P&amp;lt;0.05). We also found enriched CN loss at Chr15q13 (with FAN1 in the 'peak') and CN amplification at Chr1p34 (with KDM4A in the 'peak') in young patients. These two events significantly affected the expression levels of FAN1 and KDM4A, respectively, and were both corrected with genomic based HRD indexes. Conclusions TNBCs of different age had distinct clinical and molecular features. We should pay attention to that nearly half of the TNBCs diagnosed at 65 years-old or later were not basal-like cancers but a special group with positive AR staining. Taking together with the higher fibrosis/MES proportion in elderly TNBC, we should reconsider the benefit of specific treatment strategies (like neoadjuvant chemotherapy) in these patients. The young TNBCs were characterized by activated cell cycle, elevated nucleotide metabolism (especially TYMS expression and corresponding pyrimidine metabolism) and enhanced DNA damage (especially HRD). These molecular features supported the aggressive phenotypes of young TNBC, while also provide us with potential therapeutic strategies. Citation Format: Ma D, Jiang Y-Z, Xie M-D, Xiao Y, Zhao S, Shao Z-M. Multi-omics profiling reveals distinct molecular features in young and elderly triple negative breast cancer [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 P3-08-11.