Estrogen receptor 1 chromatin profiling in human breast tumors reveals high inter-patient heterogeneity with enrichment of risk SNPs and enhancer activity at most-conserved regions.

Estrogen Receptor 1 (ESR1; also known as ERα, encoded by ESR1 gene) is the main driver and prime drug target in luminal breast cancer. ESR1 chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ESR1 chromatin action, along with its biological implications. Here, we use a large set of ESR1 ChIP-seq data from 70 ESR1+ breast cancers to explore inter-patient heterogeneity in ESR1 DNA binding to reveal a striking inter-tumor heterogeneity of ESR1 action. Of note, commonly shared ESR1 sites show the highest estrogen-driven enhancer activity and are most engaged in long-range chromatin interactions. In addition, the most commonly shared ESR1-occupied enhancers are enriched for breast cancer risk SNP loci. We experimentally confirm SNVs to impact chromatin binding potential for ESR1 and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we can confirm these variations to associate with differences in expression for the target gene. Cumulatively, we reveal a natural hierarchy of ESR1-chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ESR1 landscape, with the most common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.

Breast cancer risk SNPs converge on estrogen receptor binding sites commonly shared between breast tumors to locally alter estrogen signalling output.

Estrogen Receptor alpha (ERα) is the main driver and prime drug target in luminal breast. ERα chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ERα chromatin action, along with its biological implications. Here, we use a large set of ERα ChIP-seq data from 70 ERα+ breast cancers to explore inter-patient heterogeneity in ERα DNA binding, to reveal a striking inter-tumor heterogeneity of ERα action. Interestingly, commonly-shared ERα sites showed the highest estrogen-driven enhancer activity and were most-engaged in long-range chromatin interactions. In addition, the most-commonly shared ERα-occupied enhancers were enriched for breast cancer risk SNP loci. We experimentally confirm SNVs to impact chromatin binding potential for ERα and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we could confirm these variations to associate with differences in expression for the target gene. Cumulatively, we reveal a natural hierarchy of ERα-chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ERα landscape, with the most-common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.

Biological therapy management from the initial selection of biologics to switching between biologics in severe asthma.

The aim of this review is to elaborate the management of biologic therapy from initial selection to switching biologics in severe asthma. A nonsystematic review was performed for biological therapy management in severe asthma. Depending on clinical characteristics and biomarkers, selecting the preferred biologic based on super-responder criteria from previous studies may result in adequate clinical efficacy in most patients. On the other hand, no matter how carefully the choice is made, in some patients, it may be necessary to discontinue the drug due to suboptimal clinical response or even no response. This may result in the need to switch to a different biological therapy. How long the biological treatment of patients whose asthma is controlled with biologics will be continued and according to which criteria they will be terminated remains unclear. It has been shown that in patients with a long history of good response to biologics, asthma control may be impaired when biologics are discontinued, while it may persist in others. Therefore, discontinuation of biologics may be a viable strategy in a particular patient group. Clinicians should make the best use of all predictive factors to identify patients who will most benefit from each biologic. Patients who do not meet a predefined response criterion after sufficient time for response evaluation and who are eligible for one or more alternative biological agents should be offered the opportunity to switch to another biologic. There is no consensus on when the biologics used in severe asthma that produce favorable results should be discontinued. In our opinion, treatment should continue for at least five years, as premature termination may potentially deteriorate asthma control.