Abstract
BackgroundBreast 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 methodsIn 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.ResultsMedian 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.ConclusionsAge-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.
Highlights
Triple-negative breast cancer (TNBC; defined by ER, PR, and HER2/ERBB2-negativity) is a clinically defined subgroup of breast cancer, constituting approximately 10– 15% of cancers in Western countries
Age was not associated with invasive disease-free survival or overall survival after adjuvant chemotherapy
Age at diagnosis alone does not appear to provide an additional layer of biological complexity above that of proposed genetic and transcriptional phenotypes of triple-negative breast cancer (TNBC)
Summary
Triple-negative breast cancer (TNBC; defined by ER, PR, and HER2/ERBB2-negativity) is a clinically defined subgroup of breast cancer, constituting approximately 10– 15% of cancers in Western countries. Results concerning specific molecular traits or patterns associated with age at diagnosis appear heterogeneous This may in part be due to inconsistent age group definitions between studies and that highly selected cohorts have often been used for molecular analyses. As an example of the latter, an initial study by Anders et al [21] reported transcriptional differences in breast cancer associated with patient age that subsequently disappeared when later correcting for clinical and proposed molecular subtypes [17] Considering these common confounding factors, a more complete understanding of whether age at diagnosis in breast cancer is intrinsically linked to specific genetic, epigenetic, and transcriptional differences requires studies to be performed in representative population-based cohorts that account for the relevant underlying genetic and transcriptional phenotypes of TNBC. 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
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