Clinical Utility of Circulating Tumor DNA in Patients With Advanced KRAS-Mutated NSCLC Treated With Sotorasib.

Introduction: For patients with KRAS-mutated NSCLC who are treated with sotorasib, there is a lack of biomarkers to guide treatment decisions. We therefore investigated the clinical utility of pretreatment and on-treatment circulating tumor DNA (ctDNA) and treatment-emergent alterations on disease progression.

Methods: Patients with KRAS-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372).

Liquid Biopsies for Colorectal Cancer and Advanced Adenoma Screening and Surveillance: What to Measure?

Colorectal cancer (CRC) colonoscopic surveillance is effective but burdensome. Circulating tumor DNA (ctDNA) analysis has emerged as a promising, minimally invasive tool for disease detection and management. Here, we assessed which ctDNA assay might be most suitable for a ctDNA-based CRC screening/surveillance blood test.

Prevalence, clinical and molecular characteristics of early stage EGFR-mutated lung cancer in a real-life West-European cohort: Implications for adjuvant therapy.

Objectives: The landmark ADAURA study recently demonstrated a significant disease-free survival benefit of adjuvant osimertinib in patients with resected EGFR-mutated lung adenocarcinoma. However, data on prevalence rates and stage distribution of EGFR mutations in non-small cell lung cancer in Western populations are limited since upfront EGFR testing in early stage lung adenocarcinoma is not common practice. Here, we present a unique, real-world, unselected cohort of lung adenocarcinoma to aid in providing a rationale for routine testing of early stage lung cancers for EGFR mutations in the West-European population.

Detection of circulating tumour DNA after neoadjuvant chemoradiotherapy in patients with locally advanced oesophageal cancer.

Active surveillance instead of standard surgery after neoadjuvant chemoradiotherapy (nCRT) has been proposed for patients with oesophageal cancer. Circulating tumour DNA (ctDNA) may be used to facilitate selection of patients for surgery. We show that detection of ctDNA after nCRT seems highly suggestive of major residual disease.

Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, IDH-wildtype: Post Hoc Analysis of the EORTC Randomized Phase III CATNON Trial.

Purpose: In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase-wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors].

Patients And Methods: From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis.

In-depth molecular analysis of combined and co-primary pulmonary large cell neuroendocrine carcinoma and adenocarcinoma.

Up to 14% of large cell neuroendocrine carcinomas (LCNECs) are diagnosed in continuity with nonsmall cell lung carcinoma. In addition to these combined lesions, 1% to 7% of lung tumors present as co-primary tumors with multiple synchronous lesions. We evaluated molecular and clinicopathological characteristics of combined and co-primary LCNEC-adenocarcinoma (ADC) tumors.

Liquid biopsy in esophageal cancer: a case report of false-positive circulating tumor DNA detection due to clonal hematopoiesis.

Circulating tumor DNA (ctDNA) analysis is a promising non-invasive technique for active surveillance after chemoradiotherapy for locally advanced resectable esophageal carcinoma. In other malignancies false-positive results in ctDNA analysis have been reported due to clonal hematopoiesis. In this case, we present a 66-year-old male who had adenocarcinoma of the gastroesophageal junction for which he received neoadjuvant chemoradiotherapy and underwent a transhiatal esophagectomy.

Exploring Differentially Methylated Genes in Vulvar Squamous Cell Carcinoma.

DNA methylation is the most widely studied mechanism of epigenetic modification, which can influence gene expression without alterations in DNA sequences. Aberrations in DNA methylation are known to play a role in carcinogenesis, and methylation profiling has enabled the identification of biomarkers of potential clinical interest for several cancers. For vulvar squamous cell carcinoma (VSCC), however, methylation profiling remains an under-studied area.

Plasma Predictive Features in Treating EGFR-Mutated Non-Small Cell Lung Cancer.

Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the preferred treatment for patients with -mutated non-small cell lung cancer (NSCLC), not all patients benefit. We therefore explored the impact of the presence of mutations found in cell-free DNA (cfDNA) and TKI plasma concentrations during treatment on progression-free survival (PFS). In the prospective START-TKI study blood samples from 41 patients with -mutated NSCLC treated with EGFR-TKIs were available.

Comparison of variant allele frequency and number of mutant molecules as units of measurement for circulating tumor DNA.

Quantification of tumor-specific variants (TSVs) in cell-free DNA is rapidly evolving as a prognostic and predictive tool in patients with cancer. Currently, both variant allele frequency (VAF) and number of mutant molecules per mL plasma are used as units of measurement to report those TSVs. However, it is unknown to what extent both units of measurement agree and what are the factors underlying an existing disagreement.

The Association Between the Extent of Glioblastoma Resection and Survival in Light of MGMT Promoter Methylation in 326 Patients With Newly Diagnosed IDH-Wildtype Glioblastoma.

The association between contrast enhanced (CE) and non-contrast enhanced (NCE) tumor resection and survival in patients with glioblastoma in relation to molecular subtypes is poorly understood. The aim of this study was to assess the association between CE and NCE tumor resection and survival in light of MGMT promoter methylation in newly diagnosed IDH-wildtype glioblastoma. Patients with newly diagnosed IDH-wildtype glioblastoma who underwent surgery were eligible.

Topographical Mapping of 436 Newly Diagnosed IDH Wildtype Glioblastoma With vs. Without MGMT Promoter Methylation.

O methylguanine-methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase (IDH) mutation status are important prognostic factors for patients with glioblastoma. There are conflicting reports about a differential topographical distribution of glioblastoma with vs. without MGMT promoter methylation, possibly caused by molecular heterogeneity in glioblastoma populations.

Somatic mutations and copy number variations in breast cancers with heterogeneous HER2 amplification.

Intratumour heterogeneity fuels carcinogenesis and allows circumventing specific targeted therapies. HER2 gene amplification is associated with poor outcome in invasive breast cancer. Heterogeneous HER2 amplification has been described in 5-41% of breast cancers.

Plasma Cell-Free DNA Testing of Patients With EGFR Mutant Non-Small-Cell Lung Cancer: Droplet Digital PCR Versus Next-Generation Sequencing Compared With Tissue-Based Results.

Purpose: To compare the results of plasma cell-free DNA (cfDNA) droplet digital PCR (ddPCR) and next-generation sequencing (NGS) on detection of epidermal growth factor receptor () primary activating mutations and p.T790M with results of tissue analysis in patients with mutated non-small-cell lung cancer.

Methods: All patients with EGFR mutated non-small cell lung cancer for which a pathology and a plasma specimen were available upon progression between November 2016 and July 2018 were selected.

Survival of diffuse astrocytic glioma, IDH1/2 wildtype, with molecular features of glioblastoma, WHO grade IV: a confirmation of the cIMPACT-NOW criteria.

Background: The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) has recommended that isocitrate dehydrogenase 1 and 2 wildtype (IDH1/2wt) diffuse lower-grade gliomas (LGGs) World Health Organization (WHO) grade II or III that present with (i) a telomerase reverse transcriptase promoter mutation (pTERTmt), and/or (ii) gain of chromosome 7 combined with loss of chromosome 10, and/or (iii) epidermal growth factor receptor (EGFR) amplification should be reclassified as diffuse astrocytic glioma, IDH1/2 wildtype, with molecular features of glioblastoma, WHO grade IV (IDH1/2wt astrocytomas WHO IV). This paper describes the overall survival (OS) of IDH1/2wt astrocytoma WHO IV patients, and more in detail patients with tumors with pTERTmt only.

Methods: In this retrospective multicenter study, we compared the OS of 71 IDH1/2wt astrocytomas WHO IV patients, with radiological characteristics of LGGs, with the OS of 197 IDH1/2wt glioblastoma patients.

Differences in spatial distribution between WHO 2016 low-grade glioma molecular subgroups.

Background: Several studies reported a correlation between anatomic location and genetic background of low-grade gliomas (LGGs). As such, tumor location may contribute to presurgical clinical decision-making. Our purpose was to visualize and compare the spatial distribution of different WHO 2016 gliomas, frequently aberrated single genes and DNA copy number alterations within subgroups, and groups of postoperative tumor volume.

Clinical evaluation of a dedicated next generation sequencing panel for routine glioma diagnostics.

Since 2013 next-generation sequencing (NGS) targeting genes mutated in diffuse gliomas is part of routine diagnostics in our institute. In the present report, we evaluate the use of this custom tailored NGS platform on 434 samples. The NGS panel assesses mutations in ATRX, CIC, EGFR, FUBP1, NOTCH1, PTEN; H3F3A, IDH1/2, PIK3CA, and BRAF, amplifications in EGFR or MDM2 and copy number alterations (CNA) of chromosome 1p, 7, 10 and 19q.

Prognostic relevance of mutations and copy number alterations assessed with targeted next generation sequencing in IDH mutant grade II glioma.

Background: At current prognostication of low grade glioma remains suboptimal and might be improved with additional markers. These may guide treatment decisions, in particular on early adjuvant therapy versus wait and see after surgery.

Methods: We used a targeted Next-Generation Sequencing panel to assess mutational and copy number status of selected genes and chromosomes in a consecutive series of adult grade II supratentorial glioma, and assessed the impact of molecular markers of interest on overall survival.

Double somatic mutations in mismatch repair genes are frequent in colorectal cancer after Hodgkin's lymphoma treatment.

Objective: Hodgkin's lymphoma survivors who were treated with infradiaphragmatic radiotherapy or procarbazine-containing chemotherapy have a fivefold increased risk of developing colorectal cancer (CRC). This study aims to provide insight into the development of therapy-related CRC (t-CRC) by evaluating histopathological and molecular characteristics.

Design: 54 t-CRCs diagnosed in a Hodgkin's lymphoma survivor cohort were analysed for mismatch repair (MMR) proteins by immunohistochemistry, microsatellite instability (MSI) and / mutations.

SNPitty: An Intuitive Web Application for Interactive B-Allele Frequency and Copy Number Visualization of Next-Generation Sequencing Data.

Exploration and visualization of next-generation sequencing data are crucial for clinical diagnostics. Software allowing simultaneous visualization of multiple regions of interest coupled with dynamic heuristic filtering of genetic aberrations is, however, lacking. Therefore, the authors developed the web application SNPitty that allows interactive visualization and interrogation of variant call format files by using B-allele frequencies of single-nucleotide polymorphisms and single-nucleotide variants, coverage metrics, and copy numbers analysis results.

The impact of surgery in molecularly defined low-grade glioma: an integrated clinical, radiological, and molecular analysis.

Background: Extensive resections in low-grade glioma (LGG) are associated with improved overall survival (OS). However, World Health Organization (WHO) classification of gliomas has been completely revised and is now predominantly based on molecular criteria. This requires reevaluation of the impact of surgery in molecularly defined LGG subtypes.

Identification of Mutations in Cell-Free Circulating Tumor DNA in Adrenocortical Carcinoma: A Case Series.

Context: The disease course of adrenocortical carcinoma (ACC) patients is heterogeneous. A marker for prognosis and treatment response would facilitate choices for diagnosis and therapy. In other cancer types, circulating cell-free tumor DNA predicted tumor dynamics.