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.