Refining prognostic tools for luminal breast cancer: genetic insights and comprehensive analysis

Background: Luminal breast cancer (BC) is generally associated with a lower risk of recurrence compared with other subtypes. However, patients with luminal BC can still experience recurrence, which remains a significant concern and contributes to BC-related mortality. Current clinical practice for recurrence risk prognosis relies on prognostic tests based on tumor gene expression profiles. Materials and methods: In this study, we aimed to investigate the association between different genetic alterations with the likelihood of recurrence and gene expression prognostic prediction (Oncotype DX®, MammaPrint®, and PAM50-ROR) in luminal BC patients. We constructed three transcriptome-based predictive models, based on these widely used clinical tests, to evaluate the recurrence risk of patients with luminal BC, using RNA-seq data from 1527 samples across 11 datasets. We further classified 1780 patients from the TCGA and METABRIC datasets into risk groups and detected distinct recurrence risk patterns. Results: Our analysis revealed that low-risk groups had higher frequencies of mutations in PIK3CA, MAP3K1, CDH1, KMT2C, and CBFB, as well as co-mutations in PIK3CA-MAP3K1, PIK3CA-CBFB, and KMT2C-MAP3K1. In contrast, high-risk groups showed enrichment of TP53, RB1, and PTPN22 mutations compared with the whole cohort, with notable co-mutations in TP53-PIK3CA and TP53-KMT2C. Furthermore, mutations in TP53 and BRCA2, and deletions in the 7p22.3 region were at least threefold more frequent in high-risk patients compared with low-risk patients. Using an independent dataset, we validated our finding of higher frequency of BRCA2 mutations in Oncotype DX® high-risk patients. Notably, PIK3CA mutations had an unexpected negative impact on recurrence and survival among high-risk patients. Conclusion: Our study reveals key genetic factors associated with recurrence risk in luminal BC. Identifying these mutations and copy number alterations provides a basis for refined prognostic models and suggests avenues for further research, potentially improving treatment strategies and follow-up care for patients with luminal BC.