74P Transcriptomic profile identifies biological differences in very young women with breast cancer

Breast cancer (BC) mostly occurs in women over 50 years old, however, around 5% of cases are very young women (BCVY) (age ≤35) being associated to poorer prognosis and shorter survival. Age-associated differences in BC remain poorly studied. Understanding biological differences in BCVY may lead to better therapeutic options for these patients. This work aimed to identify molecular differences between breast tumors from BCVY and old women (BCO). The formalin-fixed samples of a retrospective cohort (N = 49) collecting treatment naïve core needle biopsies from 22 BCVY and 27 BCO (age ≥ 50) were analyzed. A preanalytic sample selection was performed to assess the quality before the RNA sequencing (HiSeq X Series, Illumina). Wilcoxon test was used on normalized RNA-seq data to compare the BCVY and BCO groups. All analyses were performed using R software (v 4.0.2). The BCVY cohort included 12 (55%) luminal, and 10 (45%) non-luminal BCs, while the BCO cohort was 17 (63%) luminal and 10 (37%) non-luminal patients. Principal Components Analysis of mRNA-seq data revealed a higher heterogeneity among BCVY. Age-related gene expression differences were confirmed (40 and 13 genes down- and up-regulated [fold change ± 2]). BCVY presented higher chromosomal instability (CIN70, p= 1e-06) and were more immunoreactive tumors presenting significantly higher scores in immune-related gene signatures (inflammation, cytokines, IFN gamma, macrophages, Th2 cells, B cells, DC, and IGG). Moreover, BCVY tumors were more proliferative as confirmed by higher expression of related gene signatures (p= 5.17e-05) and ki67 (IHC, p= 0.021). These findings were particularly significant in luminal BC. Interestingly, despite there were no differences in ER and PR by IHC, lower expression was found at RNA level in luminal BCVY patients (ESR1: p= 0.0027, PGR: p= 0.0476). Our study provides novel findings on the impact of aging on transcriptional landscape in BC. We found age-related gene expression changes not only in cancer cells but also in the tumor microenvironment. These data suggest that luminal BCVY could be more endocrine-resistant and aggressive than BCO. Therefore, this work highlights age as an important factor to be considered in clinical practice.