Integrated molecular profiling of young and elderly patients with triple‐negative breast cancer indicates different biological bases and clinical management strategies

Background Age at the time of breast cancer diagnosis not only predicts clinical outcome but also indicates distinct molecular characteristics that provide the rationale for appropriate treatment strategies. However, to the authors' knowledge, little is known regarding the molecular profile and biological basis of triple‐negative breast cancers (TNBCs) occurring in young and elderly patients. Methods Using the study institution's largest, single‐center, multiomics TNBC data set, the authors analyzed the clinical and genomic features of young (aged ≤39 years) and elderly (aged ≥65 years) patients with TNBC. Results In the current study, a total of 50 patients, 354 patients, and 69 patients, respectively, were grouped as young, intermediate, and elderly patients with TNBC. Young patients with TNBC had worse short‐term survival, upregulation of DNA repair, cell cycle and RNA metabolism gene sets, frequent pathogenic germline variants, and predominant homologous recombination deficiency‐related mutational signatures. Several copy number alterations also were found to be enriched in young patients with TNBC. Nearly one‐half of the TNBC cases in elderly patients were of the luminal androgen receptor subtype. TNBC in elderly patients was identified as being associated with severe fibrosis; a lower Ki‐67 index; and somatic mutations in PIK3CA, KMT2D, ERBB2, ERBB3, and their corresponding pathways. Elderly patients with TNBC also were more likely to harbor targetable mutations. Conclusions The findings of the current study indicated that young patients with TNBC had an enhanced cell cycle, which may have helped to explain their inferior short‐term survival, whereas the homologous recombination deficiency and enriched pathogenic germline variants observed among young patients with TNBC suggested the need for genetic counseling and testing, as well as the potential use of DNA damage agents and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors. Molecular characteristics of elderly patients with TNBC, although suggesting less response to chemotherapy, provided a rationale for the routine detection of actionable somatic mutations. Triple‐negative breast cancer (TNBC) diagnosed in young women is characterized by a higher incidence of early metastasis or disease recurrence, upregulated DNA repair, cell cycle and RNA metabolism gene sets, frequent pathogenic germline variants, a homologous recombination deficiency‐related mutational signature, and several foc