Molecular Prognostic Factors for Distant Metastases in Premenopausal Patients with HR+/HER2- Early Breast Cancer

Molecular factors that drive metastasis in premenopausal patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), early breast cancer (EBC) are largely unknown. To identify markers/signatures contributing to metastasis, we analyzed molecular changes in tumors from premenopausal patients who developed metastasis (M1) and who did not (M0). Ninety-seven premenopausal patients with HR+/HER2- EBC were included (M1, n = 48, median distant metastasis-free survival (DMFS): 54 (7-184) months; M0, n = 49, median follow-up: 149 (121-191) months). Gene expression profiling on tumor RNA (Breast Cancer 360^TM panel, Nanostring) was performed, followed by comprehensive bioinformatic and statistical analyses. Significantly enhanced ROR (risk of recurrence) scores and reduced signature scores of PGR (progesterone receptor), claudin-low, and mammary stemness were determined in M1. These differences were significantly associated with shorter DMFS in univariate survival analyses. Gene set enrichment analysis showed an enriched mTORC1 pathway in M1. Moreover, a metastasis signature of 19 differentially expressed genes (DEGs) that were DMFS-related was defined. Multivariate analysis including the four signatures, 19 DEGs, pN, and pT status, identified LRP2, IBSP, and SCUBE2 as independent prognostic factors. We identified prognostic gene signatures and single-gene markers for distant metastasis in premenopausal HR+/HER2- EBC potentially applicable in future clinical practice.