Molecular profiling of the Basal-like intrinsic molecular subtype in primary ER-positive HER2-negative breast cancer.

BACKGROUND: The clinical management of ER-positive/HER2-negative (ERpHER2n) breast cancer is complicated by a heterogeneous patient population, with some patients exhibiting endocrine resistance and an increased risk of recurrence. Among these high-risk subgroups, ERpHER2n Basal-like (ERpHER2n-Basal) breast cancer, as defined by PAM50 gene expression subtyping, remains poorly characterized due to limited available material. However, understanding the somatic molecular features driving treatment resistance and progression is critical for optimizing therapy. METHODS: To address these challenges, we comprehensively characterized the patient subgroup by comparing it to both ERpHER2n and triple-negative breast cancer (TNBC) patients. We investigated 4474 Swedish patients with primary ERpHER2n tumors (Basal-like = 76, Luminal A = 3049, Luminal B = 1349) with clinical and RNA-sequencing data available, including 16 Basal-like tumors with whole-genome sequencing and matched global DNA methylation data. For TNBC comparisons, we used an additional 228 cases with available WGS, RNA-sequencing, and DNA methylation data. ER-positivity was defined as ≥ 10% of tumor cells being IHC-stained according to Swedish national guidelines. RESULTS: Clinicopathological analyses highlighted ERpHER2n-Basal patients as a small subgroup comprising generally younger patients with high-grade and high-risk tumors. This patient group was associated with worse prognosis than Luminal A/Luminal B subtypes, especially when treated only with endocrine therapy, independent of lymph node status, patient age, tumor size and grade. Molecularly, ERpHER2n-Basal tumors were distinguished by high proliferation and elevated immune response together with low ESR1 mRNA expression and low activity of steroid-response pathways. High proportions of the mutational signatures associated with homologous recombination deficiency in ERpHER2n-Basal tumors suggest potential benefits from platinum or PARP inhibitor treatments. Additionally, their DNA methylation profile closely resembles that of Basal triple-negative breast cancer (TNBC), indicating shared epigenetic regulation despite differences in ER status. Further molecular similarities to TNBC such as high immune infiltration indicate immune checkpoint inhibitors as promising agents for improving patient care. CONCLUSIONS: ERpHER2n-Basal breast cancer represents a clinically high-risk subgroup whose molecular resemblance to TNBC highlights potential therapeutic opportunities, particularly for immunotherapy and DNA repair-targeting treatments.