Gerrit A Meijer

• MD, PhD
• Head of Department at Netherlands Cancer Institute

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. 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 re...

While structural variants (SVs) are a clear sign of genomic instability, they have not been systematically quantified per patient. 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....

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR016) of the Conference Program/Proceedings. Citation Format: Nicholas A. Vulpescu, Zachariah H. Foda, Pieter H.A. Wisse, Christopher Cherry, Jaime E. Medina, Vilmos Adleff, Remond J.A. Fijneman, Robert B. Scha...

The stepwise progression of colorectal cancer (CRC) from healthy epithelium, to premalignant adenoma, to cancer is accompanied by genome-wide epigenetic reprogramming which may be reflected in circulating cell-free DNA (cfDNA). However, current analyses of these processes have been hampered by complex mixtures of cells in normal, adenoma and cancer...

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...

Background Non‐invasive biomarkers may reduce post‐colonoscopy colorectal cancer (CRC) rates and colonoscopy overuse in Lynch syndrome. Unlike faecal immunochemical test (FIT), faecal volatile organic compounds (VOCs) may accurately detect both advanced and non‐advanced colorectal neoplasia. Aim The aim of this study was to evaluate the potential...

Ovarian cancer is a leading cause of death for women worldwide, in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker [cancer antigen 125 (CA-125) and human epididymis protein 4 (HE4)] analyses to evaluate 591 women with ovarian cancer, with benign adnexal masses, o...

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. We developed CIBRA (Computational Identification of Biologically Relevant Alterations), a met...

Plain language summary Effectiveness and cost-effectiveness of circulating tumour DNA-guided selection for adjuvant chemotherapy in patients with stage II colon cancer Most patients with stage II colon cancer (CC) are cured by surgery. Therefore, guidelines recommend to only offer adjuvant chemotherapy to patients who have a tumor with high-risk fe...

Objectives Colonoscopy surveillance for Lynch syndrome is burdensome and post-colonoscopy colorectal cancers (CRCs) still occur. The non-invasive fecal immunochemical test (FIT) might guide optimal colonoscopy intervals. Methods Prospective, multi-center observational study in which individuals with Lynch syndrome performed a quantitative FIT prio...

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 biomark...

Distinguishing postoperative fibrosis from isolated local recurrence (ILR) after resection of pancreatic ductal adenocarcinoma (PDAC) is challenging. A prognostic model that helps to identify patients at risk of ILR can assist clinicians when evaluating patients’ postoperative imaging. This nationwide study aimed to develop a clinically applicable...

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. coli measured in fecal immunochemical test (FIT) samples and the detection of advanced neoplasia (AN) at colonoscopy w...

Introduction: Surgery followed by adjuvant chemotherapy (ACT) is standard of care in stage III colon cancer. However, only 15-20% of patients benefit from ACT, as half of patients are cured by surgery, and 25-30% still experience a recurrence. Detection of circulating tumor DNA (ctDNA) after resection of the primary tumor is a strong prognostic bio...

Introduction: Patients with stage II colon cancer not classified as high risk (pT4 microsatellite stable) do not receive adjuvant chemotherapy (ACT) according to Dutch guidelines. However, 15-20% of patients with stage II colon cancer experience a disease recurrence, indicating that there is an unmet clinical need to identify patients who could ben...

Background: Cancer is caused by somatic DNA alterations, such as single nucleotide variants, somatic copy number alterations and structural variants (SVs). PRKN is among the genes most frequently affected by SVs in colorectal cancer (CRC), with 37% of primary cancers and 56% of metastatic lesions having focal deletions in PRKN. PRKN encodes the E3...

Background The fecal immunochemical test (FIT) is widely used in population based colorectal cancer (CRC) screening programs. Recently, circulating cell-free DNA (cfDNA) analyses have emerged as a new avenue for early cancer detection. The performance of cfDNA methods in comparison with FIT is currently unknown. The present study compared pre-opera...

Background: Accurate monitoring of treatment response in patients with metastatic colorectal cancer (mCRC) is important to decide when to adjust treatment regimen or to proceed to local therapy of metastases. At present, clinical response is determined by computed tomography (CT) imaging-based assessment of changes in tumor size. However, this moni...

Noninvasive approaches for detection of tumor-specific mutations in cell-free DNA (cfDNA) have the potential to track a patient’s response to treatment, enabling effective and timely decisions on therapy. However, mutations in cfDNA arising from clonal hematopoeisis (CH) are common and tumor biopsies for definitive identification of the origin of t...

Background: Metastasis in colorectal cancer (CRC) is a critical factor in patient outcomes, with 20% of patients affected at the time of diagnosis and up to 50% developing metachronous metastatic disease later on. Despite the growing importance of metastatic sites as independent predictors of overall survival (OS) and the ongoing development of new...

Background: Colorectal cancer (CRC) is the third most frequent cancer worldwide, and approximately a third of patients die from the disease. There is therefore an urgent need to better understand CRC biology. A particular feature in (colorectal) cancer is the activation of LINE-1 (L1) retrotransposons: DNA fragments which propagate to other places...

Introduction: The stepwise progression of colorectal cancer from healthy epithelium, to premalignant adenoma, to cancer is accompanied by genome-wide epigenetic reprogramming. However, current analyses of these processes have been hampered by complex mixtures of cells in normal, adenoma and cancer tissue samples, as well as absence of suitable aden...

Introduction: Patients with stage III colon cancer are routinely treated with resection followed by adjuvant chemotherapy (ACT) with a fluoropyrimidine and oxaliplatin. This one-size-fits-all approach does not account for heterogeneity in tumor biology and fails to cure ~30% of patients, highlighting the urgency for biomarkers to better understand...

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...

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 opi...

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 perfo...

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...

Two decades after the genomics revolution, oncology is rapidly transforming into a genome-driven discipline, yet routine cancer diagnostics is still mainly microscopy based, except for tumor type-specific predictive molecular tests. Pathology laboratories struggle to quickly validate and adopt biomarkers identified by genomics studies of new target...

For patients with colorectal cancer liver metastases (CRLM), the genetic mutation status is important in treatment selection and prognostication for survival outcomes. This study aims to investigate the relationship between radiomics imaging features and the genetic mutation status (KRAS mutation versus no mutation) in a large multicenter dataset o...

Introduction: Fecal Immunochemical Testing (FIT) is a central tool in colorectal cancer (CRC) screening. To improve the selection of individuals for colonoscopy, risk models combining FIT with additional CRC risk factors have been developed. This systematic review aims to provide an overview of the current noninvasive FIT-based risk models for CRC...

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-car...

Background Treatment with PD-(L)1 blocking agents has demonstrated durable efficacy in advanced NSCLC, but only in a minority of patients. Multiple biomarkers for predicting treatment benefit have been investigated, but their combined performance has not been extensively studied. Here, we assess the combined predictive performance of multiple bioma...

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 D...

Objective New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. Design A form...

e15664 Background: Currently available circulating cell-free DNA (cfDNA) assays require deep-targeted sequencing to detect cancer-specific mutations at low mutant allele frequency (MAF) levels in the blood. Recently, we developed a tumor-agnostic, mutation-independent approach that utilizes low-coverage whole genome sequencing called DELFI (DNA eva...

Introduction: Structural variants (SVs) caused by chromosomal rearrangements or LINE retrotranspositions are a highly prevalent type of somatic DNA alterations in colorectal cancer (CRC). Studies about the function of SVs in tumor biology and their putative application as biomarkers are currently hampered by the need for fresh frozen tumor material...

BACKGROUND: Cell-free circulating tumor DNA (ctDNA) assays have been adopted to monitor therapeutic response in both early- and late-stage cancer. However, tests currently available require deep-targeted sequencing to detect cancer-specific mutations at low mutant allele frequency (MAF) levels in the circulation. Recently, we developed a tumor-agno...

Introduction: Targeted next-generation sequencing (NGS) of cell-free DNA in plasma, referred to as liquid biopsy, has become a valuable diagnostic tool in clinical oncology. However, detection of variants related to clonal hematopoiesis (CH) is a major confounder that significantly impairs the clinical utility of liquid biopsies. Here we developed...

Introduction: Surgery followed by adjuvant chemotherapy (ACT) is standard of care in stage III colon cancer. However, 50% of the patients would be cured by surgery alone and are being overtreated, while 30-35% will experience a recurrence despite adjuvant treatment, resulting in only 15-20% of the patients benefitting from ACT. Therefore, there is...

Introduction Circulating tumor DNA (ctDNA) is a promising new biomarker with multiple potential applications in cancer care. As part of the “ctDNA on the way to implementation in the Netherlands (COIN)” project, an early, comprehensive Health Technology Assessment (HTA) is ongoing. Information about the costs of ctDNA testing is essential for imple...

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 tis...

Background Many screening programs for colorectal cancer (CRC) use the fecal immunochemical test (FIT) to triage individuals for colonoscopy. Although these programs reduce CRC incidence and CRC-related mortality, the detection of advanced precursor lesions (advanced adenomas and advanced serrated polyps) by FIT could be improved. As an alternative...

Background In ∼3%-5% of patients with metastatic disease, tumor origin remains unknown despite modern imaging techniques and extensive pathology work-up. With long diagnostic delays and limited and ineffective therapy options, the clinical outcome of patients with cancer of unknown primary (CUP) remains poor. Large-scale genome sequencing studies h...

Introduction: In colorectal cancer (CRC) surveillance, adenoma characteristics such as size, number of adenomas, dysplasia, and villous components, are used as indicators for risk of developing metachronous cancer and guide the surveillance interval. The current risk groups (e.g., advanced adenomas) cannot optimally distinguish high risk from low r...

Background: Cancer is caused by somatic DNA alterations, comprising single/small nucleotide variants (SNVs), somatic copy number alterations (SCNAs) and chromosomal rearrangement structural variants (SVs). We previously demonstrated that SVs are recurrently identified in hundreds of genes and are highly prevalent in common fragile site genes, e.g.,...

Background: For optimizing fecal immunochemical test (FIT)-based screening programs, reducing the rate of missed colorectal cancers (CRCs) by FIT (FIT-interval CRCs) is an important aspect. Knowledge of the molecular make-up of these missed lesions could facilitate more accurate detection of all (precursor) lesions. Aim: To compare the molecular...

Circulating tumor DNA (ctDNA) is a promising new biomarker with multiple potential applications in cancer care. Estimating total cost of ctDNA-testing is necessary for reimbursement and implementation, but challenging due to variations in workflow. We aimed to develop a micro-costing framework for consistent cost calculation of ctDNA-testing. First...

Gain of chromosome arm 13q is one of the most prevalent DNA copy number alterations associated with colorectal adenoma-to-carcinoma progression. The oncogenic miR-17-92 cluster, located at 13q, was found to be overexpressed in colorectal cancer and in adenomas harboring 13q gain. However, to what extent overexpression of this group of microRNAs act...

Background Clinically implemented prognostic biomarkers are lacking for the 80% of colorectal cancers (CRC) that exhibit chromosomal instability (CIN). CIN is characterized by chromosome segregation errors and double-strand break repair defects that lead to somatic copy number aberrations (SCNAs) and chromosomal rearrangement-associated structural...

Background: The adenoma detection rate (ADR) is an essential quality indicator for endoscopists performing colonoscopies for colorectal cancer (CRC) screening as it is associated with postcolonoscopy CRCs (PCCRCs). Currently, data on ADRs of endoscopists performing colonoscopies in fecal immunochemical testing (FIT)-based screening, the most commo...

Background: Hodgkin lymphoma (HL) survivors (HLS) treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer (CRC). We investigated the cost-effectiveness of CRC surveillance in Dutch HLS to determine the optimal surveillance strategy for different HL subgroups. Methods: The Micr...

Background and aims: Screening for colorectal cancer (CRC) aims to decrease CRC incidence and mortality. Biennial fecal immunochemical test screening started in the Netherlands in 2014 for individuals aged 55-75. This study investigated the effect of screening on stage specific incidence, with focus on stage III and IV CRC. Methods: Inhabitants...

Background: Non-seminoma testicular cancer survivors (TCS) have an increased risk of developing colorectal cancer (CRC) when they have been treated with platinum-based chemotherapy. Previously we demonstrated that among Hodgkin lymphoma survivors (HLS) there is enrichment of rare mismatch repair (MMR) deficient (MMRd) CRCs with somatic hits in MMR...

Longitudinal adherence to colorectal cancer (CRC) screening is reported using different summarizing measures, which hampers international comparison. We provide evidence to guide recommendations on which longitudinal adherence measure to report. Using adherence data over four stool-based CRC screening rounds in three countries, we calculated six su...

Introduction The risk of developing gastric cancer is increased in patients treated with radiotherapy for Hodgkin lymphoma (HL) or testicular cancer (TC). This study aims to assess if gastric adenocarcinoma after treatment for HL/TC (t-GC) is molecularly different from gastric adenocarcinoma in the general population. Methods Patients were diagnos...

Purpose Durable clinical benefit to PD-1 blockade in non–small cell lung cancer (NSCLC) is currently limited to a small fraction of patients, underlining the need for predictive biomarkers. We recently identified a tumor-reactive tumor-infiltrating T lymphocyte (TIL) pool, termed PD-1T TILs, with predictive potential in NSCLC. Here, we examined PD-...

Secretory leukocyte protease inhibitor (SLPI) is a pleiotropic protein produced by healthy intestinal epithelial cells. SLPI regulates NF-κB activation, inhibits neutrophil proteases and has broad antimicrobial activity. Recently, increased SLPI expression was found in various types of carcinomas and was suggested to increase their metastatic poten...

The current increase in number and diversity of targeted anti‐cancer agents poses challenges to the logistics and timeliness of molecular diagnostics (MolDx), resulting in underdiagnosis and treatment. Whole genome sequencing (WGS) may provide a sustainable solution for addressing current as well as future diagnostic challenges. The present study t...

Introduction: Stage III colon cancer patients are offered surgery followed by adjuvant chemotherapy (ACT) according to Dutch clinical guidelines. However, only 15-20% of the patients benefit from ACT: 50% would be cured by surgery alone and are thus being overtreated, while 30-35% will experience a recurrence despite adjuvant treatment. Therefore,...

Introduction: Measurement of tumor-derived DNA molecules in the plasma (ctDNA) has become a useful tool to determine the overall tumor burden in patients with cancer. The ctDNA burden may change over time, decreasing after treatment response and increasing with development of resistance to therapy. Monitoring the dynamics of ctDNA burden over the c...

Background: Genomic instability is a common feature of colorectal cancer (CRC). More than 80% of CRCs exhibit chromosomal instability (CIN) and 15-20% microsatellite instability (MSI). MSI results in a high ‘tumor mutational burden’ (TMB) and is associated with relatively good prognosis in localized CRC. However, for the large group of CIN CRC pati...

Introduction: The distribution of KRAS mutation variants across tumor types is not uniform. The KRAS A146 mutation is predominantly seen in colorectal cancer (CRC) patients. Here, we evaluated how clinical features like tumor load and overall survival differ between metastatic CRC (mCRC) patients carrying distinct somatic KRAS G12, G13, Q61, K117 o...

Interpreting genomic variants in tumor samples presents a challenge in research and the clinical setting. A major barrier is that information about variants is fragmented across disparate databases, and aggregating information from these requires building extensive infrastructure. To this end, we have developed Genome Nexus, a one stop shop for var...

3541 Background: Measurement of plasma mutant allele fraction (MAF) in patients with cancer provides prognostic information, but this approach typically relies on prior tumor tissue analyses or knowledge of specific mutations. There is a clinical need to develop rapid and accurate noninvasive plasma-only approaches to estimate disease burden dynami...

Background To improve colorectal cancer (CRC) survival and lower incidence rates, colonoscopy and/or fecal immunochemical tests (FIT) screening is widely implemented. Although candidate DNA methylation biomarkers have been published to improve or complement FIT, clinical translation is limited. Here, we describe technical and methodological problem...

Background Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) run a 10-fold increased risk of developing colorectal cancer (CRC) compared to patients with IBD only. The aim of this study was to perform an extensive screen of known carcinogenic genomic alterations in patients with PSC-IBD, and to investigate whet...

Aberrantly methylated genes contribute to the landscape of epigenetic alterations in colorectal adenocarcinoma. The global CpG Island methylator phenotype (CIMP) and individually methylated genes are potential prognostic/predictive biomarkers. Research suggests an association between methylated DCR1 (mDCR1) and lack of benefit with irinotecan (IFL)...

Abstract Background The risk of recurrence after resection of a stage II or III colon cancer, and therefore qualification for adjuvant chemotherapy (ACT), is traditionally based on clinicopathological parameters. However, the parameters used in clinical practice are not able to accurately identify all patients with or without minimal residual disea...

Around 15–30% of colorectal cancers (CRC) develops from sessile serrated lesions (SSLs). After many years of indolent growth, SSLs can develop dysplasia and rapidly progress into CRC through events that are only partially understood. We studied molecular events at very early stages of progression of SSLs via the MLH1 proficient and deficient pathwa...