Integrative molecular profiling identifies a novel cluster of estrogen receptor‐positive breast cancer in very young women

Abstract

Very young breast cancer patients are more common in Asian countries than Western countries and are thought to have worse prognosis than older patients. The aim of the current study was to identify molecular characteristics of young patients with estrogen receptor ( ER )‐positive breast cancer by analyzing mutations and copy number variants ( CNV ), and by applying expression profiling. The whole exome and transcriptome of 47 Korean young breast cancer ( KYBR ) patients (age <35) were analyzed. Genomic profiles were constructed using mutations, CNV and differential gene expression from sequencing data. Pathway analyses were also performed using gene sets to identify biological processes. Our data were compared with young ER + breast cancer patients in The Cancer Genome Atlas ( TCGA ) dataset. TP 53 , PIK 3 CA and GATA 3 were highly recurrent somatic mutation genes. APOBEC ‐associated mutation signature was more frequent in KYBR compared with young TCGA patients. Integrative profiling was used to classify our patients into 3 subgroups based on molecular characteristics. Group A showed luminal A‐like subtype and IGF 1R signal dysregulation. Luminal B patients were classified into groups B and C, which showed chromosomal instability and enrichment for APOBEC 3A/B deletions, respectively. Group B was characterized by 11q13 ( CCND 1) amplification and activation of the ubiquitin‐mediated proteolysis pathway. Group C showed 17q12 ( ERBB 2) amplification and lower ER and progesterone receptor expression. Group C was also distinguished by immune activation and lower epithelial‐mesenchyme transition ( EMT ) degree compared with group B. This study showed that integrative genomic profiling could classify very young patients with breast cancer into molecular subgroups that are potentially linked to different clinical characteristics.

The prognostic and predictive value of ESR1 fusion gene transcripts in primary breast cancer

“…Gene fusions were preferentially detected in high-grade disease and/or endocrine-resistant forms of ESR1 + BC [ 10 , 13 ]. Particularly, an enrichment of ESR1-CCDC170 fusion was previously reported in HER-positive patients (luminal A 9%, luminal B 3–8% and HER2 3.1%) and was correlated with a worse clinical outcome after endocrine therapy [ 9 , 15 , 16 ]. The ESR1-AKAP12 fusion was identified in 6.5% breast cancer that were resistant to letrozole aromatase inhibitor treatment [ 17 ].The novel fusion ESR1-ARMT1 was instead detected in a HER2-negative patient with luminal A-like subtype [ 16 ] and in a breast cancer patient who had not received endocrine therapy [ 18 ].…”

“…Particularly, an enrichment of ESR1-CCDC170 fusion was previously reported in HER-positive patients (luminal A 9%, luminal B 3–8% and HER2 3.1%) and was correlated with a worse clinical outcome after endocrine therapy [ 9 , 15 , 16 ]. The ESR1-AKAP12 fusion was identified in 6.5% breast cancer that were resistant to letrozole aromatase inhibitor treatment [ 17 ].The novel fusion ESR1-ARMT1 was instead detected in a HER2-negative patient with luminal A-like subtype [ 16 ] and in a breast cancer patient who had not received endocrine therapy [ 18 ]. Moreover, a recently study based on molecular characterization of luminal breast cancer in African American women reported the fusions at a frequency of 11% for ESR1-CCDC170, 8% for ESR1-AKAP12 and 6% for ESR1-ARMT1 [ 19 ].…”

Breast Cancer in Young Women: Status Quo and Advanced Disease Management by a Predictive, Preventive, and Personalized Approach

“…Furthermore, group B patients included 11q13 ( CCND1 ) amplification and activation of the ubiquitin-mediated proteolysis pathway. Moreover, 17q12 ( ERBB2 ) amplification and lower ER and PR expressions were observed in group C, which was also determined by immune activation and lower EMT level when compared with group B [52]. The higher incidence of basal-like cancers in very young women may be associated with an increase in the expression of BRCA1 mutations, luminal progenitors, and c-kit in younger patients [53].…”

“…Management of BC depends on the multi-professional cooperation, stratification of patient risk, improvement in the understanding of molecular mechanism and pathology, as well as prognostic and predictive modeling. Nevertheless, due to the heterogeneity, an assignment to mentioned subgroups is not adequate for the establishment of the newest strategies of clinical management [52].…”

Delineation of Pathogenomic Insights of Breast Cancer in Young Women

“…These studies have reported changes in the expression of specific genes, gene sets, or signatures in young patients as compared with those in older patients with BC. For example, patients aged <35 years with ER-positive BC showed an upregulation of signatures pertaining to the insulin-like growth factor receptor and stromal microenvironment in luminal A BC subtype [ 20 ]. Patients aged <45 years with BC showed an increased expression of growth factors and cell cycle progression genes [ 21 ]; patients aged <45 years showed a high prevalence of the GATA3 mutation [ 22 ]; those aged <35 years showed an increased expression and/or mutations of GATA3 and ARID1A [ 23 ]; and patients aged <40 years showed an increased expression of RANKL [ 24 ].…”