NanoCMSer: a consensus molecular subtype stratification tool for fresh-frozen and paraffin-embedded colorectal cancer samples.

Colorectal cancer (CRC) is a significant contributor to cancer-related mortality, emphasizing the need for advanced biomarkers to guide treatment. As part of an international consortium, we previously categorized CRCs into four consensus molecular subtypes (CMS1-CMS4), showing promise for outcome prediction. To facilitate clinical integration of CMS classification in settings where formalin-fixed paraffin-embedded (FFPE) samples are routinely used, we developed NanoCMSer, a NanoString-based CMS classifier using 55 genes.

Efficacy and safety in early-phase clinical trials for refractory colorectal cancer: A meta-analysis.

Background: Despite recent metastatic colorectal cancer (mCRC) therapeutic innovations a comprehensive synthesis of patient outcome and risk-benefit assessment of phase 1/2 trials is missing. The aim of this meta-analysis is to assess efficacy, safety, and trends over time for phase 1 and 2 mCRC trials by examining clinical benefit rate (CBR), overall response rate (ORR), grade 3 or higher adverse events (AE), and discontinuation due to AE.

Methods: The PRISMA guidelines were followed.

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.

Benefit of adjuvant chemotherapy on recurrence free survival per consensus molecular subtype in stage III colon cancer.

The consensus molecular subtype (CMS) classification divides colon tumors into four subtypes holding promise as a predictive biomarker. However, the effect of adjuvant chemotherapy on recurrence free survival (RFS) per CMS in stage III patients remains inadequately explored. With this intention, we selected stage III colon cancer (CC) patients from the MATCH cohort (n = 575) and RadboudUMC (n = 276) diagnosed between 2005 and 2018.

Survival and patient-reported outcomes of real-world high-risk stage II and stage III colon cancer patients after reduction of adjuvant CAPOX duration from 6 to 3 months.

Aim: Adjuvant chemotherapy has been advised for high-risk stage II and III colon cancer since 2004. After the IDEA study showed no clinically relevant difference in outcome, reduction of adjuvant CAPOX duration from 6 to 3 months was rapidly adopted in the Dutch treatment guideline in 2017. This study investigates the real-world impact of the guideline change on overall survival (OS) and patient-reported outcomes (PROs).

Efficacy-effectiveness analysis on survival in a population-based real-world study of BRAF-mutated metastatic colorectal cancer patients treated with encorafenib-cetuximab.

Background: Encorafenib-cetuximab has been approved for pretreated BRAF-mutated metastatic colorectal cancer (mCRC) patients based on efficacy demonstrated in the randomized phase III BEACON trial. The aim of this real-world effectiveness study is to improve knowledge on the generalizability of trial results.

Methods: This population-based real-world study includes all mCRC patients in the Netherlands treated with encorafenib-cetuximab since approval.

Extrahepatic perfusion and incomplete hepatic perfusion after hepatic arterial infusion pump implantation: incidence and clinical implications.

Introduction: This study investigates the incidence of extrahepatic perfusion and incomplete hepatic perfusion at intraoperative methylene blue testing and on postoperative nuclear imaging in patients undergoing hepatic arterial infusion pump (HAIP) chemotherapy.

Methods: The first 150 consecutive patients who underwent pump implantation in the Netherlands were included. All patients underwent surgical pump implantation with the catheter in the gastroduodenal artery.

Harnessing the Potential of Real-World Evidence in the Treatment of Colorectal Cancer: Where Do We Stand?

Treatment guidelines for colorectal cancer (CRC) are primarily based on the results of randomized clinical trials (RCTs), the gold standard methodology to evaluate safety and efficacy of oncological treatments. However, generalizability of trial results is often limited due to stringent eligibility criteria, underrepresentation of specific populations, and more heterogeneity in clinical practice. This may result in an efficacy-effectiveness gap and uncertainty regarding meaningful benefit versus treatment harm.

Stromal localization of inactive CD8 T cells in metastatic mismatch repair deficient colorectal cancer.

Background: The determinants of metastasis in mismatch repair deficiency with high levels of microsatellite instability (MSI-H) in colorectal cancer (CRC) are poorly understood. Here, we hypothesized that distinct immune and stromal microenvironments in primary tumors may discriminate between non-metastatic MSI-H CRC and metastatic MSI-H CRC.

Methods: We profiled 46,727 single cells using high-plex imaging mass cytometry and analyzed both differential cell type abundance, and spatial distribution of fibroblasts and immune cells in primary CRC tumors with or without metastatic capacity.

Prognostic value of Lynch syndrome, BRAF , and RAS mutational status in dMMR/MSI-H metastatic colorectal cancer in a pooled analysis of Dutch and French cohorts.

Background: Current knowledge on prognostic biomarkers (especially BRAF /RAS mutations) in metastatic colorectal cancer (mCRC) is mainly based on mCRC patients with proficient mismatch repair (pMMR) tumors. It is uncertain whether these biomarkers have the same prognostic value in mCRC patients with deficient mismatch repair (dMMR) tumors.

Methods: This observational cohort study combined a population-based Dutch cohort (2014-2019) and a large French multicenter cohort (2007-2017).

Lymphatic Invasion of Plakoglobin-Dependent Tumor Cell Clusters Drives Formation of Polyclonal Lung Metastases in Colon Cancer.

Background & Aims: Patients with colon cancer with liver metastases may be cured with surgery, but the presence of additional lung metastases often precludes curative treatment. Little is known about the processes driving lung metastasis. This study aimed to elucidate the mechanisms governing lung vs liver metastasis formation.

Predicting early extrahepatic recurrence after local treatment of colorectal liver metastases.

Background: Patients who develop early extrahepatic recurrence (EHR) may not benefit from local treatment of colorectal liver metastases (CRLMs). This study aimed to develop a prediction model for early EHR after local treatment of CRLMs using a national data set.

Methods: A Cox regression prediction model for EHR was developed and validated internally using data on patients who had local treatment for CRLMs with curative intent.

Modeling resistance of colorectal peritoneal metastases to immune checkpoint blockade in humanized mice.

Background: The immunogenic nature of metastatic colorectal cancer (CRC) with high microsatellite instability (MSI-H) underlies their responsiveness to immune checkpoint blockade (ICB). However, resistance to ICB is commonly observed, and is associated with the presence of peritoneal-metastases and ascites formation. The mechanisms underlying this site-specific benefit of ICB are unknown.

Correlation of Immunological and Histopathological Features with Gene Expression-Based Classifiers in Colon Cancer Patients.

The purpose of this study was to evaluate the association between four distinct histopathological features: (1) tumor infiltrating lymphocytes, (2) mucinous differentiation, (3) tumor-stroma ratio, plus (4) tumor budding and two gene expression-based classifiers—(1) consensus molecular subtypes (CMS) plus (2) colorectal cancer intrinsic subtypes (CRIS). All four histopathological features were retrospectively scored on hematoxylin and eosin sections of the most invasive part of the primary tumor in 218 stage II and III colon cancer patients from two independent cohorts (AMC-AJCC-90 and AC-ICAM). RNA-based CMS and CRIS assignments were independently obtained for all patients.

External Validation of the Colon Life Nomogram for Predicting 12-Week Mortality in Dutch Metastatic Colorectal Cancer Patients Treated with Trifluridine/Tipiracil in Daily Practice.

Background: Predicting prognosis in refractory metastatic colorectal cancer (mCRC) patients is needed to guide decision making. The Colon Life nomogram was developed to predict 12-week mortality in refractory mCRC patients. The aim of this study is to validate the Colon Life nomogram in last line/refractory patients receiving trifluridine/tipiracil (FTD/TPI) in daily practice.

Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study.

Background: Mesenchymal Consensus Molecular Subtype 4 (CMS4) colon cancer is associated with poor prognosis and therapy resistance. In this proof-of-concept study, we assessed whether a rationally chosen drug could mitigate the distinguishing molecular features of primary CMS4 colon cancer.

Methods: In the ImPACCT trial, informed consent was obtained for molecular subtyping at initial diagnosis of colon cancer using a validated RT-qPCR CMS4-test on three biopsies per tumor (Phase-1, n=69 patients), and for neoadjuvant CMS4-targeting therapy with imatinib (Phase-2, n=5).

External Validation of Two Established Clinical Risk Scores Predicting Outcome after Local Treatment of Colorectal Liver Metastases in a Nationwide Cohort.

Optimized surgical techniques and systemic therapy have increased the number of patients with colorectal liver metastases (CRLM) eligible for local treatment. To increase postoperative survival, we need to stratify patients to customize therapy. Most clinical risk scores (CRSs) which predict prognosis after CRLM resection were based on the outcome of studies in specialized centers, and this may hamper the generalizability of these CRSs in unselected populations and underrepresented subgroups.

External validation of the MSKCC nomogram to estimate five-year overall survival after surgery for stage I-III colon cancer in a Dutch population.

Introduction: The Memorial Sloan Kettering Cancer Centre (MSKCC) nomogram has been developed to estimate five-year overall survival (OS) after curative-intent surgery of colon cancer based on age, sex, T stage, differentiation grade, number of positive and examined regional lymph nodes. This is the first evaluation of the performance of the MSKCC model in a European population regarding prediction of OS.

Material And Methods: Population-based data from patients with stage I-III colon cancer diagnosed between 2010 and 2016 were obtained from the Netherlands Cancer Registry (NCR) for external validation of the MSKCC prediction model.

Mismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy.

DNA mismatch repair deficiency (dMMR) in metastatic colorectal cancer (mCRC) is associated with poor survival and a poor response to systemic treatment. However, it is unclear whether dMMR results in a tumor cell-intrinsic state of treatment resistance, or whether alternative mechanisms play a role. To address this, we generated a cohort of MMR-proficient and -deficient Patient-Derived Organoids (PDOs) and tested their response to commonly used drugs in the treatment of mCRC, including 5-fluorouracil (5-FU), oxaliplatin, SN-38, binimetinib, encorafenib, and cetuximab.

Patient-derived organoids as a predictive biomarker for treatment response in cancer patients.

Effective predictive biomarkers are needed to enable personalized medicine and increase treatment efficacy and survival for cancer patients, thereby reducing toxic side effects and treatment costs. Patient-derived organoids (PDOs) enable individualized tumour response testing. Since 2018, 17 publications have examined PDOs as a potential predictive biomarker in the treatment of cancer patients.