Molecular analyses of triple-negative breast cancer in the young and elderly

Abstract

Background Breast cancer in young adults has been implicated with a worse outcome. Analyses of genomic traits associated with age have been heterogenous, likely because of an incomplete accounting for underlying molecular subtypes. We aimed to resolve whether triple-negative breast cancer (TNBC) in younger versus older patients represent similar or different molecular diseases in the context of genetic and transcriptional subtypes and immune cell infiltration. Patients and methods In total, 237 patients from a reported population-based south Swedish TNBC cohort profiled by RNA sequencing and whole-genome sequencing (WGS) were included. Patients were binned in 10-year intervals. Complimentary PD-L1 and CD20 immunohistochemistry and estimation of tumor-infiltrating lymphocytes (TILs) were performed. Cases were analyzed for differences in patient outcome, genomic, transcriptional, and immune landscape features versus age at diagnosis. Additionally, 560 public WGS breast cancer profiles were used for validation. Results Median age at diagnosis was 62 years (range 26–91). Age was not associated with invasive disease-free survival or overall survival after adjuvant chemotherapy. Among the BRCA1-deficient cases (82/237), 90% were diagnosed before the age of 70 and were predominantly of the basal-like subtype. In the full TNBC cohort, reported associations of patient age with changes in Ki67 expression, PIK3CA mutations, and a luminal androgen receptor subtype were confirmed. Within DNA repair deficiency or gene expression defined molecular subgroups, age-related alterations in, e.g., overall gene expression, immune cell marker gene expression, genetic mutational and rearrangement signatures, amount of copy number alterations, and tumor mutational burden did, however, not appear distinct. Similar non-significant associations for genetic alterations with age were obtained for other breast cancer subgroups in public WGS data. Consistent with age-related immunosenescence, TIL counts decreased linearly with patient age across different genetic TNBC subtypes. Conclusions Age-related alterations in TNBC, as well as breast cancer in general, need to be viewed in the context of underlying genomic phenotypes. Based on this notion, age at diagnosis alone does not appear to provide an additional layer of biological complexity above that of proposed genetic and transcriptional phenotypes of TNBC. Consequently, treatment decisions should be less influenced by age and more driven by tumor biology.

Prognostic Value of Stromal Tumor-Infiltrating Lymphocytes in Young, Node-Negative, Triple-Negative Breast Cancer Patients Who Did Not Receive (neo)Adjuvant Systemic Therapy

“…Recent studies showed that younger patients with TNBC more often have high sTILs tumors when compared with older patients and that there is an inverse correlation between sTILs levels and the number of positive lymph nodes. 12,23 Moreover, the sTILs distribution in our study was in line with the sTILs distribution in the young patient subgroup of the study reported by Aine et al 23 One explanation might be the changing composition and function of immune cells with age. 24 Further research is needed to increase our understanding of the interaction between the immune system, the hormonal system, age, and breast cancer.…”

Clinicopathological characteristics of young versus older patients with breast cancer

“…Further sub-analysis of ER receptor status of our cohort showed a significant correlation between the ER negative status with young age ( p =0.0001), larger tumor size ( p <0.0001), high grade tumor ( p <0.0001), and high Ki67 expression ( p <0.0001). A similar observation of high Ki67 expression by immunohistochemistry and mRNA expression in young patients by Aine et al 33 from Lund University, Sweden.…”

Triple Negative Breast Cancer: An Analysis of the Subtypes and the Effects of Menopausal Status on Invasive Breast Cancer

“…TNBC is commonly seen in women 50 years of age and younger and the other breast cancer subtypes tend to occur more often in women aged 60 or older. One study reported [3] that there was no correlation between age and invasive disease-free survival (DFS) or overall survival (OS) after adjuvant chemotherapy. However, a different study [4] reported that shorter survival times, distant DFS, and breast cancer-specific survival were found in the older age group with TNBC.…”