Molecular Tumor Board of the University Medical Center Groningen (UMCG-MTB): outcome of patients with rare or complex mutational profiles receiving MTB-advised targeted therapy.

Purpose: Molecular tumor boards (MTBs) are considered beneficial for treatment decision making for patients with cancer with uncommon, rare, or complex mutational profiles. The lack of international MTB guidelines results in significant variation in practices and recommendations. Therefore, periodic follow-up is necessary to assess and govern MTB functioning.

Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer: a phase I study.

Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response.

Levels of circulating tumor DNA correlate with tumor volume in gastro-intestinal stromal tumors: an exploratory long-term follow-up study.

Patients with gastro-intestinal stromal tumors (GISTs) undergoing tyrosine kinase inhibitor therapy are monitored with regular computed tomography (CT) scans, exposing patients to cumulative radiation. This exploratory study aimed to evaluate circulating tumor DNA (ctDNA) testing to monitor treatment response and compare changes in ctDNA levels with RECIST 1.1 and total tumor volume measurements.

Osimertinib and palbociclib in an EGFR-mutated NSCLC with primary CDK4 amplification after progression under osimertinib.

Precision cancer medicine has changed the treatment paradigm of patients with non-small cell lung cancer (NSCLC) with specific molecular aberrations. A major challenge is management of the resistance that tumor cells eventually develop against targeted therapies, either through primary or acquired resistance mechanisms. We report a 61 year-old male patient with metastatic NSCLC harboring an EGFR exon 19 deletion, a PIK3CA mutation, and CDK4 amplification.

Testing Landscape in Ovarian Cancer: A Nationwide, Real-World Data Study.

Analyzing tumor pathogenic variants (TPVs) in epithelial tubal/ovarian cancers (EOCs) has become an essential part of the diagnostic workflow in many centers to guide treatment options and genetic cascade testing. However, there is no standardization of testing procedures, including techniques, gene assays, or sequencers used, and data on the execution of tumor tests remains scarce. Therefore, we evaluated characteristics of tumor testing in advanced-stage EOC with real-world national data.

Next generation sequencing of high-grade adult-type diffuse glioma in the Netherlands: interlaboratory variation in the primary diagnostic and recurrent setting.

Purpose: Next generation sequencing (NGS) is an important tool used in clinical practice to obtain the required molecular information for accurate diagnostics of high-grade adult-type diffuse glioma (HGG). Since individual centers use either in-house produced or standardized panels, interlaboratory variation could play a role in the practice of HGG diagnosis and treatment. This study aimed to investigate the current practice in NGS application for both primary and recurrent HGG.

Tumour-agnostic plasma assay for circulating tumour DNA predicts outcome in recurrent and/or metastatic squamous cell carcinoma of the head and neck treated with a PD-1 inhibitor.

Background: Only 15-20% of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) patients derive long-term benefit from nivolumab or pembrolizumab. We developed a circulating tumour DNA (ctDNA) tumour-agnostic assay aimed at the early prediction of single agent programmed cell death 1 (PD1) inhibitor efficacy in R/M SCCHN.

Patients And Methods: Our tumour-agnostic assay included 37 genes frequently mutated in R/M SCCHN and two HPV16 genes.

Causality and functional relevance of BRCA1 and BRCA2 pathogenic variants in non-high-grade serous ovarian carcinomas.

The identification of causal BRCA1/2 pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision-making. Current recommendations therefore stress sequencing of all EOCs, regardless of histotype. Although it is recognised that BRCA1/2 PVs cluster in high-grade serous ovarian carcinomas (HGSOC), this view is largely unsubstantiated by detailed analysis.

testing rates in epithelial ovarian cancer: a focus on the untested patients.

Background: Since 2015, Dutch guidelines have recommended pathogenic variant testing for all patients with epithelial ovarian cancer. Recently, recommendations shifted from germline testing to the tumor-first approach, in which tumor tissue is tested first, and subsequent germline testing is performed only in those with tumor pathogenic variants or a positive family history. Data on testing rates and on characteristics of patients missing out on testing remain scarce.

High dose osimertinib in patients with advanced stage EGFR exon 20 mutation-positive NSCLC: Results from the phase 2 multicenter POSITION20 trial.

Introduction: Patients with life-threatening advanced non-small cell lung cancer (NSCLC) who harbor an exon 20 deletion and/or insertion mutation (EGFRex20 + ) have limited effective treatment options. The high dose 3rd generation tyrosine kinase inhibitor (TKI) osimertinib shows promising in vitro activity in EGFRex20 + NSCLC tumors.

Methods: The POSITION20 is a single arm phase II, multicenter study investigating 160 mg osimertinib in patients with EGFRex20+, T790M negative NSCLC.

Circulating tumor DNA as a biomarker for monitoring early treatment responses of patients with advanced lung adenocarcinoma receiving immune checkpoint inhibitors.

Immunotherapy for metastasized non-small-cell lung cancer (NSCLC) can show long-lasting clinical responses. Selection of patients based on programmed death-ligand 1 (PD-L1) expression shows limited predictive value for durable clinical benefit (DCB). We investigated whether early treatment effects as measured by a change in circulating tumor DNA (ctDNA) level is a proxy of early tumor response to immunotherapy according to response evaluation criteria in solid tumors v1.

Actionability of on-target ALK Resistance Mutations in Patients With Non-Small Cell Lung Cancer: Local Experience and Review of the Literature.

Introduction: Non-small cell lung cancer (NSCLC) patients with Anaplastic Lymphoma Kinase (ALK) gene fusions respond well to ALK inhibitors but commonly develop on-target resistance mutations. The objective of this study is to collect clinical evidence for subsequent treatment with ALK inhibitors.

Patients And Methods: Local experience with on-target ALK resistance mutations and review of the literature identified 387 patients with ALK inhibitor resistance mutations.

Safety of systemic anti-cancer treatment in oncology patients with non-severe COVID-19: a cohort study.

Background: The viral pandemic coronavirus disease 2019 (COVID-19) has disrupted cancer patient management around the world. Most reported data relate to incidence, risk factors, and outcome of severe COVID-19. The safety of systemic anti-cancer therapy in oncology patients with non-severe COVID-19 is an important matter in daily practice.

Clinical Value of EGFR Copy Number Gain Determined by Amplicon-Based Targeted Next Generation Sequencing in Patients with EGFR-Mutated NSCLC.

Background: The clinical relevance of epidermal growth factor receptor (EGFR) copy number gain in patients with EGFR mutated advanced non-small cell lung cancer on first-line tyrosine kinase inhibitor treatment has not been fully elucidated.

Objective: We aimed to estimate EGFR copy number gain using amplicon-based next generation sequencing data and explored its prognostic value.

Patients And Methods: Next generation sequencing data were obtained for 1566 patients with non-small cell lung cancer.

Relevance and Effectiveness of Molecular Tumor Board Recommendations for Patients With Non-Small-Cell Lung Cancer With Rare or Complex Mutational Profiles.

Purpose: Molecular tumor boards (MTBs) provide physicians with a treatment recommendation for complex tumor-specific genomic alterations. National and international consensus to reach a recommendation is lacking. In this article, we analyze the effectiveness of an MTB decision-making methodology for patients with non-small-cell lung cancer (NSCLC) with rare or complex mutational profiles as implemented in the University Medical Center Groningen (UMCG).

Multicenter Comparison of Molecular Tumor Boards in The Netherlands: Definition, Composition, Methods, and Targeted Therapy Recommendations.

Background: Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands.

Combined osimertinib, dabrafenib and trametinib treatment for advanced non-small-cell lung cancer patients with an osimertinib-induced BRAF V600E mutation.

Introduction: Previous studies have reported an acquiredBRAF V600E mutation as a potential resistance mechanism to osimertinib treatment in advanced NSCLC patients with an activating mutation in EGFR. However, the therapeutic effect of combining dabrafenib and trametinib with osimertinib remains unclear. Here we report treatment efficacy in two cases with acquired BRAF V600E mutations.

Comparison of Circulating Cell-Free DNA Extraction Methods for Downstream Analysis in Cancer Patients.

Circulating cell-free DNA (ccfDNA) may contain DNA originating from the tumor in plasma of cancer patients (ctDNA) and enables noninvasive cancer diagnosis, treatment predictive testing, and response monitoring. A recent multicenter evaluation of workflows by the CANCER-ID consortium using artificial spiked-in plasma showed significant differences and consequently the importance of carefully selecting ccfDNA extraction methods. Here, the quantity and integrity of extracted ccfDNA from the plasma of cancer patients were assessed.

Editor's Choice - Nationwide Analysis of Patients Undergoing Iliac Artery Aneurysm Repair in the Netherlands.

Objective: The new 2019 guideline of the European Society for Vascular Surgery (ESVS) recommends consideration for elective iliac artery aneurysm (eIAA) repair when the iliac diameter exceeds 3.5 cm, as opposed to 3.0 cm previously.

Comprehensive routine diagnostic screening to identify predictive mutations, gene amplifications, and microsatellite instability in FFPE tumor material.

Background: Sensitive and reliable molecular diagnostics is needed to guide therapeutic decisions for cancer patients. Although less material becomes available for testing, genetic markers are rapidly expanding. Simultaneous detection of predictive markers, including mutations, gene amplifications and MSI, will save valuable material, time and costs.

A case report of an unusual non-mucinous papillary variant of CPAM type 1 with KRAS mutations.

Background: congenital pulmonary airway malformation (CPAM) is the most frequent congenital lung disorder. CPAM type 1 is the most common subtype, typically having a cystic radiological and histological appearance. Mucinous clusters in CPAM type 1 have been identified as premalignant precursors for mucinous adenocarcinoma.

Peptide microarray of pediatric acute myeloid leukemia is related to relapse and reveals involvement of DNA damage response and repair.

The majority of acute myeloid leukemia (AML) patients suffer from relapse and the exact etiology of AML remains unclear. The aim of this study was to gain comprehensive insights into the activity of signaling pathways in AML. In this study, using a high-throughput PepChip™ Kinomics microarray system, pediatric AML samples were analyzed to gain insights of active signal transduction pathway.

Recommendations for the clinical interpretation and reporting of copy number gains using gene panel NGS analysis in routine diagnostics.

Next-generation sequencing (NGS) panel analysis on DNA from formalin-fixed paraffin-embedded (FFPE) tissue is increasingly used to also identify actionable copy number gains (gene amplifications) in addition to sequence variants. While guidelines for the reporting of sequence variants are available, guidance with respect to reporting copy number gains from gene-panel NGS data is limited. Here, we report on Dutch consensus recommendations obtained in the context of the national Predictive Analysis for THerapy (PATH) project, which aims to optimize and harmonize routine diagnostics in molecular pathology.

Diagnosis and Treatment Monitoring of a Patient with Gastrointestinal Stromal Tumor by Next-Generation Sequencing and Droplet Digital Polymerase Chain Reaction Assay of a PDGFRA Mutation in Plasma-Derived Cell-Free Tumor DNA.

In patients with a suspected malignancy, standard-of care management currently includes histopathologic examination and analysis of tumor-specific molecular abnormalities. Herein, we present a 77-year-old patient with an abdominal mass suspected to be a gastrointestinal stromal tumor (GIST) but without the possibility to collect a tumor biopsy. Cell-free DNA extracted from a blood sample was analyzed for the presence of mutations in GIST-specific genes using next generation sequencing.