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

Abstract

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 (>5cm), lymph nodes 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 (TNBC), 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 non-metastatic 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 (RPA) 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.

CNA Landscape of HER2-Negative Breast Cancer in Anthracycline-Based Neoadjuvant Chemotherapy Regimens

“…Представлены результаты интегрированного мультиомного профилирования высокодифференцированного HER2-негативного РМЖ. Идентификация кандидатов-драйверов метастатического поражения в опухолях стадии III ER+HER2− на основе первичных (n= 270) и метастатических заболеваний после лечения (n =243) выявила амплификацию локусов 8q24.13 и 8q24.21 в 44.5% случаев метастазирования [16]. Нами проведен поиск потенциальных предиктивных CNA-маркеров объективного ответа на НХТ и маркеров возникновения гематогенного метастазирования.…”

“…he results of an integrated multi-omics profiling of high-grade HER2− BC were presented. Identification of metastatic candidate driver events in stage III ER+HER2− tumors based on primary ( n = 270) and metastatic diseases after treatment ( n = 243) revealed amplification of 8q24.13 and 8q24.21 in 44.5% of metastatic cases [ 16 ].…”

Palazestrant (OP-1250), A Complete Estrogen Receptor Antagonist, Inhibits Wild-type and Mutant ER-positive Breast Cancer Models as Monotherapy and in Combination

“…Mutations in ESR1 that confer constitutive activity of the ER are a known resistance mechanism to endocrine therapy ( 13, 50 ) and are present more frequently in high-grade ( 51 ) and metastatic tumors ( 16 ). Therefore, efficacy against ESR1 -mutant tumors is critical for antiestrogens in clinical development to treat advanced breast cancer.…”