Integrated multi-omics profiling of high-grade estrogen receptor-positive, HER2-negative breast cancer

Estrogen receptor-positive and human epidermal growth factor receptor 2-negative (ER⁺ HER2^- ) breast cancer accounts for ~ 60-70% of all cases of invasive breast carcinoma. High-grade ER⁺ HER2^- tumors respond poorly to endocrine therapy. In this study, we systematically analyzed clinical and multi-omics data to find potential strategies for personalized therapy of patients with high-grade ER⁺ HER2^- disease. Six different cohorts were analyzed, for which multi-omics data were available. Grade III ER⁺ HER2^- cases harbored higher proportions of large tumor size (> 5 cm), lymph node metastasis, chemotherapy use, and luminal B subtypes defined by PAM50, as compared with grade I/II tumors. DNA methylation (HM450) data and methylation-specific PCR indicated that the cg18629132 locus in the MKI67 promoter was hypermethylated in grade I/II cases and normal tissue, but hypomethylated in grade III cases or triple-negative breast cancer, resulting in higher expression of MKI67. Mutations in ESR1 and TP53 were detected in post-endocrine treatment metastatic samples at a higher rate than in treatment-naive tumors in grade III cases. We identified 42 and 20 focal copy number events in nonmetastatic and metastatic high-grade ER⁺ HER2^- cases, respectively, with either MYC or MDM2 amplification representing an independent prognostic event in grade III cases. Transcriptional profiling within grade III tumors highlighted ER signaling downregulation and upregulation of immune-related pathways in non-luminal-like tumors defined by PAM50. Recursive partitioning analysis was employed to construct a decision tree of an endocrine-resistant subgroup (GATA3-negative and AGR-negative) of two genes that was validated by immunohistochemistry in a Chinese cohort. All together, these data suggest that grade III ER⁺ HER2^- tumors have distinct clinical and molecular characteristics compared with low-grade tumors, particularly in cases with non-luminal-like biology. Due to the dismal prognosis in this group, clinical trials are warranted to test the efficacy of potential novel therapies.