FDG positron emission tomography imaging and ctDNA detection as an early dynamic biomarker of everolimus efficacy in advanced luminal breast cancer.

Biomarkers to identify patients without benefit from adding everolimus to endocrine treatment in metastatic breast cancer (MBC) are needed. We report the results of the Pearl trial conducted in five Belgian centers assessing F-FDG-PET/CT non-response (n = 45) and ctDNA detection (n = 46) after 14 days of exemestane-everolimus (EXE-EVE) to identify MBC patients who will not benefit. The metabolic non-response rate was 66.

ARID1A genomic alterations driving microsatellite instability through somatic MLH1 methylation with response to immunotherapy in metastatic lung adenocarcinoma: a case report.

Background: Tumor molecular screening allows categorization of molecular alterations to select the best therapeutic strategy. AT-rich interactive domain-containing 1A (ARID1A) gene mutations are present in gastric, endometrial, and clear cell ovarian tumors. Inactivation of this gene impairs mismatch repair (MMR) machinery leading to an increased mutation burden that correlates with microsatellite instability (MSI), associated with tumor-infiltrating lymphocytes and programmed death ligand 1 (PD-L1) expression.

Correction to: Use of an Integrated Pan-Cancer Oncology Enrichment Next-Generation Sequencing Assay to Measure Tumour Mutational Burden and Detect Clinically Actionable Variants.

This article was originally published under a [CC BY NC 4.0] license.

Use of an Integrated Pan-Cancer Oncology Enrichment Next-Generation Sequencing Assay to Measure Tumour Mutational Burden and Detect Clinically Actionable Variants.

Introduction: The identification of tumour mutational burden (TMB) as a biomarker of response to programmed cell death protein 1 (PD-1) immunotherapy has necessitated the development of genomic assays to measure this. We carried out comprehensive molecular profiling of cancers using the Illumina TruSight Oncology 500 (TSO500) panel and compared these to whole-genome sequencing (WGS).

Methods: Cancer samples derived from formalin-fixed material were profiled on the TSO500 panel, sequenced on an Illumina NextSeq 500 instrument and processed through the TSO500 Docker pipeline.

c-MET as a Potential Resistance Mechanism to Everolimus in Breast Cancer: From a Case Report to Patient Cohort Analysis.

Background: We describe in a patient with breast cancer the change in c-MET expression during everolimus treatment, opening a better understanding of the resistance to everolimus and a role for cabozantinib.

Objective: The objective of this study was to evaluate c-MET as a potential predictive biomarker for everolimus efficacy in breast cancer.

Methods: We first selected a patient with breast cancer with a long-lasting response to everolimus and retrospectively profiled biopsies that were taken before everolimus initiation (Biopsy 1) and at progression on everolimus (Biopsy 2) using amplicon sequencing and immunohistochemistry.

translocation identification in RNA exosomal cargo () in NSCLC patients: a novel role for liquid biopsy.

The introduction of druggable targets has significantly improved the outcomes of non-small cell lung cancer patients (NSCLC). translocation represents 4-6% of the druggable alterations in NSCLC. With the approval of Crizotinib, first discovered drug for the translocation, on first line treatment for patients with detected mutation meant a complete change on the treatment landscape.

The clinical impact of using complex molecular profiling strategies in routine oncology practice.

Molecular profiling and functional assessment of signalling pathways of advanced solid tumours are becoming increasingly available. However, their clinical utility in guiding patients' treatment remains unknown. Here, we assessed whether molecular profiling helps physicians in therapeutic decision making by analysing the molecular profiles of 1057 advanced cancer patient samples after failing at least one standard of care treatment using a combination of next-generation sequencing (NGS), immunohistochemistry (IHC) and other specific tests.

Circulating tumor DNA in early response assessment and monitoring of advanced colorectal cancer treated with a multi-kinase inhibitor.

Predictive biomarkers are eagerly awaited in advanced colorectal cancer (aCRC). Targeted sequencing performed on tumor and baseline plasma samples in 20 patients with aCRC treated with regorafenib identified 89 tumor-specific mutations of which ≥50% are also present in baseline plasma. Droplet digital PCR (ddPCR) assays were optimized to monitor circulating tumor DNA (ctDNA) levels in plasmatic samples collected throughout the treatment course and showed the importance of using the absolute value for ctDNA rather than the mutant/wild type ratio in monitoring the therapy outcome.

Tumor-biopsy stratification based on mTOR-pathway activity and functional mutations in the upstream genes and .

The mechanistic target of the rapamycin (mTOR) pathway is frequently activated in human cancers. Our objective was to evaluate relationships between mTOR-pathway activity and functional mutations in the upstream genes and in solid-tumor biopsies from a broad selection of cancer types. Formalin-fixed paraffin-embedded (FFPE) tumor samples were analyzed by immunohistochemistry (IHC) and next-generation sequencing (NGS).

A Case Report Demonstrating the Potential Clinical Benefit of Exhaustive Molecular Profiling in an Aggressive Muscle-Invasive High-Grade Metastatic Urothelial Carcinoma.

We present a muscle-invasive high-grade metastatic urothelial carcinoma patient, aged 71 years, with rapid progression from the diagnosis and a poor prognosis after 3 lines of treatment. A clinical exhaustive genomic profile was performed with the goal of finding potential actionable molecular alterations. The patient showed significant symptomatic and laboratory improvement with a nonstandard chemotherapy combination treatment identified by the molecular profiling, which would otherwise not have been considered.

The AURORA pilot study for molecular screening of patients with advanced breast cancer-a study of the breast international group.

Several studies have demonstrated the feasibility of molecular screening of tumour samples for matching patients with cancer to targeted therapies. However, most of them have been carried out at institutional or national level. Herein, we report on the pilot phase of AURORA (NCT02102165), a European multinational collaborative molecular screening initiative for advanced breast cancer patients.

Multi-factor data normalization enables the detection of copy number aberrations in amplicon sequencing data.

Motivation: Because of its low cost, amplicon sequencing, also known as ultra-deep targeted sequencing, is now becoming widely used in oncology for detection of actionable mutations, i.e. mutations influencing cell sensitivity to targeted therapies.

IL-12 and type I IFN response of neonatal myeloid DC to human CMV infection.

Following congenital human CMV (HCMV) infection, 15-20% of infected newborns develop severe health problems whereas infection in immunocompetent adults rarely causes illness. The immaturity of neonatal antigen presenting cells could play a pivotal role in this susceptibility. Neonatal myeloid DC were shown to be deficient in IFN-beta and IL-12 synthesis in response to TLR triggering.

Mutation of a potassium channel-related gene in progressive myoclonic epilepsy.

Objective: We investigated a large consanguineous Moroccan family with progressive myoclonic epilepsy (PME) consistent with autosomal recessive inheritance, to describe the phenotype and identify the causal gene.

Methods: We recorded the clinical course of the disease and the response to drug therapy, whereas carefully excluding known causes of progressive myoclonic epilepsy. We then linked the disease by homozygosity mapping using microsatellite markers and single nucleotide polymorphism microarrays (11K GeneChip), and studied candidate genes in the critical linkage region.

Isolation of two regions on rat chromosomes 5 and 18 affecting mammary cancer susceptibility.

We previously mapped several quantitative trait loci (QTLs) controlling DMBA-induced mammary tumor development in female rats derived from a SPRD-Cu3 (susceptible strain) x WKY (resistant strain) cross. Two of these QTLs were assigned to chromosomes 5 and 18. In the present study, we generated and characterized congenic strains in which a segment of WKY chromosomes 5 or 18 was introduced in the SPRD-Cu3 genetic background, thereby physically demonstrating that each of these two chromosomes controls mammary tumor multiplicity.

Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner.

Background: Preclinical and clinical studies have shown that the proteasome inhibitor bortezomib (PS341, Velcade) is highly effective when combined with chemotherapeutic agents. The value of trastuzumab (Herceptin) in HER-2-positive (3+ score by immunohistochemistry or fluorescence in situ hybridization positive) breast cancer is also known; however, the response rate is <40% for metastatic breast cancer. These two pharmacologic agents prevent nuclear factor-kappaB (NF-kappaB) activation and induce nuclear accumulation of the cyclin-dependent kinase inhibitor p27(kip1), suggesting that combining bortezomib with trastuzumab could increase trastuzumab efficacy.

Interferon regulatory factor 3-dependent responses to lipopolysaccharide are selectively blunted in cord blood cells.

The synthesis of interferon-beta (IFNbeta) and IFN-inducible factors elicited by lipopolysaccharide (LPS) depends on the transcriptional activity of interferon regulatory factor 3 (IRF-3) downstream of Toll-like receptor-4 (TLR4). To examine the ability of human newborns to mount TLR4-mediated IRF-3-dependent responses, we analyzed the pattern of genes expressed on the addition of LPS to cord blood or cord blood monocyte-derived dendritic cells (moDCs). Expression of IFNbeta and IFN-inducible genes was selectively impaired in neonatal blood and moDCs as compared with their adult counterparts.

Genetic identification of distinct loci controlling mammary tumor multiplicity, latency, and aggressiveness in the rat.

The rat is considered an excellent model for studying human breast cancer. Therefore, understanding the genetic basis of susceptibility to mammary cancer in this species is of great interest. Previous studies based on crosses involving the susceptible strain WF (crossed with the resistant strains COP or WKY) and focusing on tumor multiplicity as the susceptibility phenotype led to the identification of several loci that control chemically induced mammary cancer.

Alpha-fetoprotein controls female fertility and prenatal development of the gonadotropin-releasing hormone pathway through an antiestrogenic action.

It has been shown previously that female mice homozygous for an alpha-fetoprotein (AFP) null allele are sterile as a result of anovulation, probably due to a defect in the hypothalamic-pituitary axis. Here we show that these female mice exhibit specific anomalies in the expression of numerous genes in the pituitary, including genes involved in the gonadotropin-releasing hormone pathway, which are underexpressed. In the hypothalamus, the gonadotropin-releasing hormone gene, Gnrh1, was also found to be down-regulated.