Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer

Background Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. Methods A panel of ER+ BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1wt or ESR1Y537S, modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER

Implantable cardioverter-defibrillator programming and electrical storm: Results of the OBSERVational registry On long-term outcome of ICD patients (OBSERVO-ICD)

BACKGROUND Electrical storm (ES) is defined as 3 or more episodes of ventricular fibrillation (VF) or ventricular tachycardia (VT) within 24 hours and is associated with increased cardiac and all-cause mortality.OBJECTIVE The purpose of this study was to test whether aggressive implantable cardioverter-defibrillator (ICD) programming can be associated with ES.METHODS The OBSERVational registry On long-term outcome of ICD patients (OBSERVO-ICD) is a multicenter, retrospective registry enrolling all consecutive patients undergoing ICD implantation from 2010 to 2012 in 5 Italian high-volume arrhythmia centers. Clinical history and risk factors were collected for all patients, as were ICD therapy-related variables such as detection zones and delays. The total number of arrhythmic episodes and therapies delivered by the ICD were collected through out-of-hospital visits and remote monitoring.RESULTS The registry enrolled 1319 consecutive patients, of whom 62 (4.7%) experienced at least 1 ES during follow-up (median 39 months). Patients who experienced ES had a significantly lower VF detection zone (P =.002), more frequently had antitachycardia pacing therapies programmed off during capacitor charge (P =.001), and less frequently had an ICD set with delayed therapies for VT zones (P =.042) and VF zone (P =.036). Patients who experienced ES had a significantly higher incidence of death and heart failure-related death compared to patients with no ventricular arrhythmias and patients with unclustered VTs/VFs (P =.025 and P <.001, respectively).CONCLUSION Patients with ES had a more aggressive ICD programming setup, including lower VF detection rates, shorter detection times, and no antitachycardia pacing therapies during capacitor charge. This kind of ICD programming potentially could increase the likelihood of ES and the related risk of death

Cardiac resynchronization therapy and electrical storm: results of the OBSERVational registry on long-term outcome of ICD patients (OBSERVO-ICD)

Electrical storm (ES) is a condition defined as three or more episodes of ventricular fibrillation (VF) or ventricular tachycardia (VT) within 24\u2009h, and usually coexist with advanced heart failure in patients with structural heart disease. The aim of the present study is to test whether cardiac resynchronization therapy (CRT) can be associated with a lower incidence of ES

IntErnationaL eLeCTRicAl storm registry (ELECTRA): Background, rationale, study design, and expected results

Electrical storm (ES) is defined as three or more episodes of ventricular fibrillation (VF) or ventricular tachycardia (VT) within 24 h and is associated with an increased cardiac and all-cause mortality. ES is a full arrhythmic emergency, its prevalence steadily increasing along with the number of implantable cardioverter-defibrillator implanted every year in developed countries. Nowadays, little evidence exists regarding clinical predictors of ES and their potential association on mortality and heart failure (HF), nor optimal pharmacological and non-pharmacological treatment has ever been codified. The intErnationaL eLeCTRicAl storm registry (ELECTRA) is a multicentre, observational, prospective clinical study with two major aims. First, to create an international database on ES encompassing clinical features, pharmacological management, and interventional treatment strategies. Second, to describe mortality and rehospitalization rates in patients with ES over a long follow-up. The primary endpoint is all-cause mortality 3 years after the ES index event. The main secondary endpoint is hospitalization for all causes 3 years after the ES index event. Other secondary endpoints includes ES recurrences, unclustered VTs/VFs recurrences, and hospitalizations for HF worsening. A minimum of 500 patients will be included in the registry, and all patients will be followed-up for a minimum of three years. The present paper describes the background and current rationale of the ELECTRA study and details the study design, from enrolment strategy to data collection methods to planned data analysis. A brief overview of the expected results and their potential clinical and research implications will also be presented (NCT02882139). Keywords: Arrhythmia, Catheter ablation, Electrical storm, Implantable cardioverter-defibrillator, Ventricular fibrillation, Ventricular tachycardi