Tumor break load quantitates structural variant-associated genomic instability with biological and clinical relevance across cancers.

While structural variants (SVs) are a clear sign of genomic instability, they have not been systematically quantified per patient since declining costs have only recently enabled large-scale profiling. Therefore, the biological and clinical impact of high numbers of SVs in patients is unknown. We introduce tumor break load (TBL), defined as the sum of unbalanced SVs, as a measure for SV-associated genomic instability.

Towards Recommendations for Cost-Effectiveness Analysis of Predictive, Prognostic, and Serial Biomarker Tests in Oncology.

Background: Cost-effectiveness analysis (CEA) of biomarkers is challenging due to the indirect impact on health outcomes and the lack of sufficient fit-for-purpose data. Hands-on guidance is lacking.

Objective: We aimed firstly to explore how CEAs in the context of three different types of biomarker applications have addressed these challenges, and secondly to develop recommendations for future CEAs.

Cancer treatment monitoring using cell-free DNA fragmentomes.

Circulating cell-free DNA (cfDNA) assays for monitoring individuals with cancer typically rely on prior identification of tumor-specific mutations. Here, we develop a tumor-independent and mutation-independent approach (DELFI-tumor fraction, DELFI-TF) using low-coverage whole genome sequencing to determine the cfDNA tumor fraction and validate the method in two independent cohorts of patients with colorectal or lung cancer. DELFI-TF scores strongly correlate with circulating tumor DNA levels (ctDNA) (r = 0.

Early Detection of Ovarian Cancer Using Cell-Free DNA Fragmentomes and Protein Biomarkers.

There is an unmet need for effective ovarian cancer screening and diagnostic approaches that enable earlier-stage cancer detection and increased overall survival. We have developed a high-performing accessible approach that evaluates cfDNA fragmentomes and protein biomarkers to detect ovarian cancer.

High Prevalence of Chromosomal Rearrangements and LINE Retrotranspositions Detected in Formalin-Fixed, Paraffin-Embedded Colorectal Cancer Tissue.

Structural variants (SVs) caused by chromosomal rearrangements in common fragile sites or long interspersed nuclear element (LINE) retrotranspositions are highly prevalent in colorectal cancer. However, methodology for the targeted detection of these SVs is lacking. This article reports the use of formalin-fixed, paraffin-embedded targeted-locus capture (FFPE-TLC) sequencing as a novel technology for the targeted detection of tumor-specific SVs.

CIBRA identifies genomic alterations with a system-wide impact on tumor biology.

Motivation: Genomic instability is a hallmark of cancer, leading to many somatic alterations. Identifying which alterations have a system-wide impact is a challenging task. Nevertheless, this is an essential first step for prioritizing potential biomarkers.

Early evaluation of the effectiveness and cost-effectiveness of ctDNA-guided selection for adjuvant chemotherapy in stage II colon cancer.

Background: Current patient selection for adjuvant chemotherapy (ACT) after curative surgery for stage II colon cancer (CC) is suboptimal, causing overtreatment of high-risk patients and undertreatment of low-risk patients. Postoperative circulating tumor DNA (ctDNA) could improve patient selection for ACT.

Objectives: We conducted an early model-based evaluation of the (cost-)effectiveness of ctDNA-guided selection for ACT in stage II CC in the Netherlands to assess the conditions for cost-effective implementation.

Head-to-head comparison of composite and individual biomarkers to predict clinical benefit to PD-1 blockade in non-small cell lung cancer.

Background: The efficacy of PD-1 blocking agents in advanced NSCLC has shown prolonged effectiveness, but only in a minority of patients. Multiple biomarkers have been explored to predict treatment benefit, yet their combined performance remains inadequately examined. In this study, we assessed the combined predictive performance of multiple biomarkers in NSCLC patients treated with nivolumab.

Polyketide synthase positive Escherichia coli one-time measurement in stool is not informative of colorectal cancer risk in a screening setting.

Environmental factors like the pathogenicity island polyketide synthase positive (pks+) Escherichia coli (E. coli) could have potential for risk stratification in colorectal cancer (CRC) screening. The association between pks+ E.

Aberrant PRDM2 methylation as an early event in serrated lesions destined to evolve into microsatellite-instable colorectal cancers.

Up to 30% of colorectal cancers (CRCs) develop from sessile serrated lesions (SSLs). Within the serrated neoplasia pathway, at least two principally distinct oncogenetic routes exist generating microsatellite-stable and microsatellite-instable CRCs, respectively. Aberrant DNA methylation (DNAm) is found early in the serrated pathway and might play a role in both oncogenetic routes.

The multitarget faecal immunochemical test for improving stool-based colorectal cancer screening programmes: a Dutch population-based, paired-design, intervention study.

Background: The faecal immunochemical test (FIT) is widely employed for colorectal cancer screening. However, its sensitivity for advanced precursor lesions remains suboptimal. The multitarget FIT (mtFIT), measuring haemoglobin, calprotectin, and serpin family F member 2, has demonstrated enhanced sensitivity for advanced neoplasia, especially advanced adenomas, at equal specificity to FIT.

Post-colonoscopy colorectal cancers in a national fecal immunochemical test-based colorectal cancer screening program.

Background: Post-colonoscopy colorectal cancers (PCCRCs) decrease the effect of colorectal cancer (CRC) screening programs. To enable PCCRC incidence reduction in the long-term, we classified PCCRCs diagnosed after colonoscopies performed in a fecal immunochemical test (FIT)-based screening program.

Methods: PCCRCs diagnosed after colonoscopies performed between 2014-2016 for a positive FIT in the Dutch CRC screening program were included.

A Dysfunctional T-cell Gene Signature for Predicting Nonresponse to PD-1 Blockade in Non-small Cell Lung Cancer That Is Suitable for Routine Clinical Diagnostics.

Purpose: Because PD-1 blockade is only effective in a minority of patients with advanced-stage non-small cell lung cancer (NSCLC), biomarkers are needed to guide treatment decisions. Tumor infiltration by PD-1T tumor-infiltrating lymphocytes (TIL), a dysfunctional TIL pool with tumor-reactive capacity, can be detected by digital quantitative IHC and has been established as a novel predictive biomarker in NSCLC. To facilitate translation of this biomarker to the clinic, we aimed to develop a robust RNA signature reflecting a tumor's PD-1T TIL status.

A scenario-drafting study to explore potential future implementation pathways of circulating tumor DNA testing in oncology.

Circulating tumor DNA (ctDNA) detection has multiple promising applications in oncology, but the road toward implementation in clinical practice is unclear. We aimed to support the implementation process by exploring potential future pathways of ctDNA testing. To do so, we studied four ctDNA-testing applications in two cancer types and elicited opinions from 30 ctDNA experts in the Netherlands.

Impact of genetic counseling strategy on diagnostic yield and workload for genome-sequencing-based tumor diagnostics.

Purpose: Genome sequencing (GS) enables comprehensive molecular analysis of tumors and identification of hereditary cancer predisposition. According to guidelines, directly determining pathogenic germline variants (PGVs) requires pretest genetic counseling, which is cost-ineffective. Referral for genetic counseling based on tumor variants alone could miss relevant PGVs and/or result in unnecessary referrals.

Risk Prediction of Metachronous Colorectal Cancer from Molecular Features of Adenomas: A Nested Case-Control Study.

Unlabelled: Current morphologic features defining advanced adenomas (size ≥10 mm, high-grade dysplasia or ≥25% villous component) cannot optimally distinguish individuals at high risk or low risk of metachronous colorectal cancer (me-CRC), which may result in suboptimal surveillance. Certain DNA copy-number alterations (CNAs) are associated with adenoma-to-carcinoma progression. We aimed to evaluate whether these molecular features can better predict an individual's risk of me-CRC than the morphologic advanced adenoma features.

Cell-free DNA approaches for cancer early detection and interception.

Rapid advancements in the area of early cancer detection have brought us closer to achieving the goals of finding cancer early enough to treat or cure it, while avoiding harms of overdiagnosis. We evaluate progress in the development of early cancer detection tests in the context of the current principles for cancer screening. We review cell-free DNA (cfDNA)-based approaches using mutations, methylation, or fragmentomes for early cancer detection.

Metastatic Colorectal Cancer Treatment Response Evaluation by Ultra-Deep Sequencing of Cell-Free DNA and Matched White Blood Cells.

Purpose: Circulating tumor DNA (ctDNA) has the potential to guide therapy selection and monitor treatment response in patients with metastatic cancer. However, germline and clonal hematopoiesis-associated alterations can confound identification of tumor-specific mutations in cell-free DNA (cfDNA), often requiring additional sequencing of tumor tissue. The current study assessed whether ctDNA-based treatment response monitoring could be performed in a tumor tissue-independent manner by combining ultra-deep targeted sequencing analyses of cfDNA with patient-matched white blood cell (WBC)-derived DNA.