Iris van 't Erve

All Publications

• An ultrasensitive method for detection of cell-free RNA. Nature Nesselbush, M. C., Luca, B. A., Jeon, Y. J., Jabara, I., Meador, C. B., Garofalo, A., Binkley, M. S., Hui, A. B., van 't Erve, I., Xu, N., Shi, W. Y., Liu, K. J., Sugio, T., Kastelowitz, N., Hamilton, E. G., Liu, C. L., Olsen, M., Bonilla, R. F., Wang, Y. P., Jiang, A., Lau, B., Eichholz, J., Banwait, M., Schroers-Martin, J., Boegeholz, J., King, D. A., Luikart, H., Esfahani, M. S., Mehrmohamadi, M., Stehr, H., Raclin, T., Tibshirani, R., Khush, K., Srinivas, S., Yu, H., Rogers, A. J., Nair, V. S., Isbell, J. M., Li, B. T., Piotrowska, Z., Sequist, L. V., Hata, A. N., Neal, J. W., Wakelee, H. A., Gentles, A. J., Alizadeh, A. A., Diehn, M. 2025

  Abstract

  Sensitive methods for detection of cell-free RNA (cfRNA) could facilitate non-invasive gene expression profiling and monitoring of diseases1-6. Here we describe RARE-seq (random priming and affinity capture of cfRNA fragments for enrichment analysis by sequencing), a method optimized for cfRNA analysis. We demonstrate that platelet contamination can substantially confound cfRNA analyses and develop an approach to overcome it. In analytical validations, we find RARE-seq to be approximately 50-fold more sensitive for detecting tumour-derived cfRNA than whole-transcriptome RNA sequencing (RNA-seq), with a limit of detection of 0.05%. To explore clinical utility, we profiled 437 plasma samples from 369 individuals with cancer or non-malignant conditions and controls. Detection of non-small-cell lung cancer expression signatures in cfRNA increased with stage (6 out of 20 (30%) in stage I; 5 out of 8 (63%) in stage II; 10 out of 15 (67%) in stage III; 80 out of 96 (83% sensitivity) in stage IV at 95% specificity) and RARE-seq was more sensitive than tumour-naive circulating tumour DNA (ctDNA) analysis. In patients with EGFR-mutant non-small-cell lung cancer who developed resistance to tyrosine kinase inhibitors, we detected both histological transformation and mutation-based resistance mechanisms. Finally, we demonstrate the potential utility of RARE-seq for determination of tissue of origin, assessing benign pulmonary conditions and tracking response to mRNA vaccines. These results highlight the potential value of ultrasensitive cfRNA analysis and provide proof of concept for diverse clinical applications.

  View details for DOI 10.1038/s41586-025-08834-1

  View details for PubMedID 40240612

  View details for PubMedCentralID 8060291

• High Prevalence of Chromosomal Rearrangements and LINE Retrotranspositions Detected in Formalin-Fixed, Paraffin-Embedded Colorectal Cancer Tissue. The Journal of molecular diagnostics : JMD Rubio-Alarcón, C., Stelloo, E., Vessies, D. C., van 't Erve, I., Mekkes, N. J., Swennenhuis, J., Lakbir, S., van Bree, E. J., Tijssen, M., Delis-van Diemen, P., Lanfermeijer, M., Linders, T., van den Broek, D., Punt, C. J., Heringa, J., Meijer, G. A., Abeln, S., Feitsma, H., Fijneman, R. J. 2024; 26 (12): 1065-1080

  Abstract

  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. Analysis of 29 FFPE colorectal tumor samples and 8 matched normal samples revealed tumor-specific SVs in 24 patients (83%), with a median of 2 SVs per patient (range, 1 to 21). A total of 104 SVs were found in the common fragile site-associated genes MACROD2, PRKN, FHIT, and WWOX in 18 patients (62%), and 39 SVs caused by three LINE transposable elements were found in 15 patients (52%). Tumor specificity of SVs was independently verified by droplet digital PCR of tumor tissue DNA, and their applicability as plasma circulating tumor DNA biomarkers was demonstrated. FFPE-TLC sequencing enabled the detection of tumor-specific SVs caused by chromosomal rearrangements and LINE retrotranspositions in FFPE tissue. Therefore, FFPE-TLC sequencing facilitates the investigation of the biological and clinical effects of SVs using FFPE material from (retrospective) cohorts of cancer patients and has potential clinical applicability in the detection of SV biomarkers in the routine molecular diagnostics setting.

  View details for DOI 10.1016/j.jmoldx.2024.08.004

  View details for PubMedID 39332629

• A scenario-drafting study to explore potential future implementation pathways of circulating tumor DNA testing in oncology. Molecular oncology Kramer, A., Rubio-Alarcón, C., van den Broek, D., Vessies, D. C., Van't Erve, I., Meijer, G. A., Vink, G. R., Schuuring, E., Fijneman, R. J., Coupé, V. M., Retèl, V. P. 2024; 18 (11): 2730-2742

  Abstract

  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. Our results showed that the current available evidence differed per application and cancer type. Tumor profiling and monitoring treatment response were found most likely to be implemented in non-small cell lung cancer (NSCLC) within 5 years. For colorectal cancer, applications of ctDNA testing were found to be at an early stage in the implementation process. Demonstrating clinical utility was found a key aspect for successful implementation, but there was no consensus regarding the evidence requirements. The next step toward implementation is to define how clinical utility of biomarkers should be evaluated. Finally, these data indicate that specific challenges for each clinical application and tumor type should be appropriately addressed in a deliberative process involving all stakeholders to ensure implementation of ctDNA testing and timely access for patients.

  View details for DOI 10.1002/1878-0261.13562

  View details for PubMedID 38060377

  View details for PubMedCentralID PMC11547223

• Cancer treatment monitoring using cell-free DNA fragmentomes. Nature communications van 't Erve, I., Alipanahi, B., Lumbard, K., Skidmore, Z. L., Rinaldi, L., Millberg, L. K., Carey, J., Chesnick, B., Cristiano, S., Portwood, C., Wu, T., Peters, E., Bolhuis, K., Punt, C. J., Tom, J., Bach, P. B., Dracopoli, N. C., Meijer, G. A., Scharpf, R. B., Velculescu, V. E., Fijneman, R. J., Leal, A. 2024; 15 (1): 8801

  Abstract

  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 = 0.90, p < 0.0001, Pearson correlation) even in cases where mutations are undetectable. DELFI-TF scores prior to therapy initiation are associated with clinical response and are independent predictors of overall survival (HR = 9.84, 95% CI = 1.72-56.10, p < 0.0001). Patients with lower DELFI-TF scores during treatment have longer overall survival (62.8 vs 29.1 months, HR = 3.12, 95% CI 1.62-6.00, p < 0.001) and the approach predicts clinical outcomes more accurately than imaging. These results demonstrate the potential of using cfDNA fragmentomes to estimate tumor burden in cfDNA for treatment response monitoring and clinical outcome prediction.

  View details for DOI 10.1038/s41467-024-53017-7

  View details for PubMedID 39433569

  View details for PubMedCentralID PMC11493959

• A phase 2 single-arm trial of high-dose precision targeted radiotherapy added to immunotherapy for patients with metastatic non-small cell lung cancer. International journal of radiation oncology, biology, physics Gensheimer, M. F., Kotha, N. V., Vitzthum, L. K., Chin, A. L., Jackson, S., 't Erve, I. v., Pratapneni, A., Le-Budka, M. L., Wong, S., Brown, E., Barnick, K., Wakelee, H. A., Das, M., Ramchandran, K. J., Myall, N. J., Padda, S., Marquez, C. M., Million, L., Chen, T. T., Man, M. C., Cabebe, E. C., Chen, M. C., Hiniker, S., Hancock, S. L., Swift, P. S., Diehn, M., Loo, B. W., Neal, J. W. 2024

  Abstract

  For metastatic non-small cell lung cancer (NSCLC), the addition of radiotherapy (RT) to immune checkpoint inhibitor (ICI) therapy could have synergistic anti-cancer effects and address the most threatening tumors. We posited that the addition of high-dose RT to ICI could prolong progression-free survival (PFS).In this single arm phase 2 trial, 45 patients with metastatic NSCLC who had received an anti-PD-1/anti-PD-L-1 ICI for 4+ weeks were enrolled from July 2017-May 2021. Patients received high-dose RT to 1-4 extracranial tumors and continued ICI until progression or unacceptable toxicity. The primary endpoint was PFS at 24 weeks, comparing to a historical control rate of 35%.Of 44 evaluable patients, median age was 71, 75% had adenocarcinoma, 64% had polymetastatic disease, and 85% of cancers with known PD-L1 percentage were PD-L1 positive. Median number of treated tumors was two and most common dose was 40 Gy in 10 fractions (41/81 tumors). Median follow-up was 23.3 months. The trial met the primary outcome: 24-week PFS was 60% (95% CI 44-75%), higher than the historical control rate (p<0.001). Median PFS was 6.9 months (95% CI 4.0-13.5 mo) and median OS was 27.4 months (95% CI 20.4-not reached). Several patients with pre-study disease progression on ICI treatment achieved durable responses to study treatment, up to 53 months. Local recurrence rate was low: cumulative incidence of 5% at one, two, and three years. Two dose-limiting toxicities were observed (5%), including one grade 5 pneumonitis.The strategy improved 24-week PFS compared to historical controls receiving ICI alone. The excellent local control supports the efficacy of high-dose RT in addressing macroscopic disease.

  View details for DOI 10.1016/j.ijrobp.2024.09.038

  View details for PubMedID 39357790

• Metastatic Colorectal Cancer Treatment Response Evaluation by Ultra-Deep Sequencing of Cell-Free DNA and Matched White Blood Cells CLINICAL CANCER RESEARCH van 't Erve, I., Medina, J. E., Leal, A., Papp, E., Phallen, J., Adleff, V., Chiao, E., Arun, A. S., Bolhuis, K., Simmons, J. K., Karandikar, A., Valkenburg, K. C., Sausen, M., Angiuoli, S., Scharpf, R. B., Punt, C. A., Meijer, G. A., Velculescu, V. E., Fijneman, R. A. 2023; 29 (5): 899-909

  Abstract

  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.In total, 183 cfDNA and 49 WBC samples, along with 28 tissue samples, from 52 patients with metastatic colorectal cancer participating in the prospective phase III CAIRO5 clinical trial were analyzed using an ultra-deep targeted sequencing liquid biopsy assay.The combined cfDNA and WBC analysis prevented false-positives due to germline or hematopoietic variants in 40% of patients. Patient-matched tumor tissue sequencing did not provide additional information. Longitudinal analyses of ctDNA were more predictive of overall survival than standard-of-care radiological response evaluation. ctDNA mutations related to primary or acquired resistance to panitumumab were identified in 42% of patients.Accurate calling of ctDNA mutations for treatment response monitoring is feasible in a tumor tissue-independent manner by combined cfDNA and patient-matched WBC genomic DNA analysis. This tissue biopsy-independent approach simplifies sample logistics and facilitates the application of liquid biopsy ctDNA testing for evaluation of emerging therapy resistance, opening new avenues for early adaptation of treatment regimens.

  View details for DOI 10.1158/1078-0432.CCR-22-2538

  View details for Web of Science ID 000991526500001

  View details for PubMedID 36534496

  View details for PubMedCentralID PMC9975664

• KRAS A146 Mutations Are Associated With Distinct Clinical Behavior in Patients With Colorectal Liver Metastases. JCO precision oncology van 't Erve, I., Wesdorp, N. J., Medina, J. E., Ferreira, L., Leal, A., Huiskens, J., Bolhuis, K., van Waesberghe, J. T., Swijnenburg, R. J., van den Broek, D., Velculescu, V. E., Kazemier, G., Punt, C. J., Meijer, G. A., Fijneman, R. J. 2021; 5

  Abstract

  Somatic KRAS mutations occur in approximately half of the patients with metastatic colorectal cancer (mCRC). Biologic tumor characteristics differ on the basis of the KRAS mutation variant. KRAS mutations are known to influence patient prognosis and are used as predictive biomarker for treatment decisions. This study examined clinical features of patients with mCRC with a somatic mutation in KRAS G12, G13, Q61, K117, or A146.A total of 419 patients with colorectal cancer with initially unresectable liver-limited metastases, who participated in a multicenter prospective trial, were evaluated for tumor tissue KRAS mutation status. For the subgroup of patients who carried a KRAS mutation and were treated with bevacizumab and doublet or triplet chemotherapy (N = 156), pretreatment circulating tumor DNA levels were analyzed, and total tumor volume (TTV) was quantified on the pretreatment computed tomography images.Most patients carried a KRAS G12 mutation (N = 112), followed by mutations in G13 (N = 15), A146 (N = 12), Q61 (N = 9), and K117 (N = 5). High plasma circulating tumor DNA levels were observed for patients carrying a KRAS A146 mutation versus those with a KRAS G12 mutation, with median mutant allele frequencies of 48% versus 19%, respectively. Radiologic TTV revealed this difference to be associated with a higher tumor load in patients harboring a KRAS A146 mutation (median TTV 672 cm3 [A146] v 74 cm3 [G12], P = .036). Moreover, KRAS A146 mutation carriers showed inferior overall survival compared with patients with mutations in KRAS G12 (median 10.7 v 26.4 months; hazard ratio = 2.5; P = .003).Patients with mCRC with a KRAS A146 mutation represent a distinct molecular subgroup of patients with higher tumor burden and worse clinical outcomes, who might benefit from more intensive treatments. These results highlight the importance of testing colorectal cancer for all KRAS mutations in routine clinical care.

  View details for DOI 10.1200/PO.21.00223

  View details for PubMedID 34820593

  View details for PubMedCentralID PMC8608264

• Postoperative circulating tumour DNA is associated with pathologic response and recurrence-free survival after resection of colorectal cancer liver metastases EBIOMEDICINE Bolhuis, K., van 't Erve, I., Mijnals, C., Delis-Van Diemen, P. M., Huiskens, J., Komurcu, A., Lopez-Yurda, M., van den Broek, D., Swijnenburg, R., Meijer, G. A., Punt, C. A., Fijneman, R. A. 2021; 70: 103498

  Abstract

  Recurrence rates after resection of colorectal cancer liver metastases (CRLM) are high and correlate with worse survival. Postoperative circulating tumour DNA (ctDNA) is a promising prognostic biomarker. Focusing on patients with resected CRLM, this study aimed to evaluate the association between the detection of postoperative ctDNA, pathologic response and recurrence-free survival (RFS).Twenty-three patients were selected from an ongoing phase-3 trial who underwent resection of RAS-mutant CRLM after induction systemic treatment. CtDNA analysis was performed by droplet digital PCR using blood samples collected at baseline, before and after resection. Pathologic response of CRLM was determined via the Tumour Regression Grading system.With a median follow-up of 19.6 months, the median RFS for patients with detectable (N = 6, [26%]) and undetectable (N = 17, [74%]) postoperative ctDNA was 4.8 versus 12.1 months, respectively. Among 21 patients with available tumour tissue, pathologic response in patients with detectable compared to undetectable postoperative ctDNA was found in one of six (17%) and 15 of 15 (100%) patients, respectively (p < 0.001). In univariable Cox regression analyses both postoperative detectable ctDNA (HR = 3.3, 95%CI = 1.1-9.6, p = 0.03) and pathologic non-response (HR = 4.6, 95%CI = 1.4-15, p = 0.01) were associated with poorer RFS and were strongly correlated (r = 0.88, p < 0.001). After adjusting for clinical characteristics in pairwise multivariable analyses, postoperative ctDNA status remained associated with RFS.The detection of postoperative ctDNA after secondary resection of CRLM is a promising prognostic factor for RFS and appeared to be highly correlated with pathologic response.None.

  View details for DOI 10.1016/j.ebiom.2021.103498

  View details for Web of Science ID 000689246500007

  View details for PubMedID 34333237

  View details for PubMedCentralID PMC8340125

• Perioperative Systemic Therapy vs Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Alone for Resectable Colorectal Peritoneal Metastases A Phase 2 Randomized Clinical Trial JAMA SURGERY Rovers, K. P., Bakkers, C., Nienhuijs, S. W., Burger, J. A., Creemers, G. M., Thijs, A. J., Brandt-Kerkhof, A. M., Madsen, E. E., van Meerten, E., Tuynman, J. B., Kusters, M., Versteeg, K. S., Aalbers, A. J., Kok, N. M., Buffart, T. E., Wiezer, M. J., Boerma, D., Los, M., de Reuver, P. R., Bremers, A. A., Verheul, H. W., Kruijff, S., de Groot, D. A., Witkamp, A. J., van Grevenstein, W. U., Koopman, M., Nederend, J., Lahaye, M. J., Kranenburg, O., Fijneman, R. A., van 't Erve, I., Snaebjornsson, P., Hemmer, P. J., Dijkgraaf, M. W., Punt, C. A., Tanis, P. J., de Hingh, I. T., Dutch Peritoneal Oncology Grp, Dutch Colorectal Canc Grp 2021; 156 (8): 710-720

  Abstract

  To date, no randomized clinical trials have investigated perioperative systemic therapy relative to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone for resectable colorectal peritoneal metastases (CPM).To assess the feasibility and safety of perioperative systemic therapy in patients with resectable CPM and the response of CPM to neoadjuvant treatment.An open-label, parallel-group phase 2 randomized clinical trial in all 9 Dutch tertiary centers for the surgical treatment of CPM enrolled participants between June 15, 2017, and January 9, 2019. Participants were patients with pathologically proven isolated resectable CPM who did not receive systemic therapy within 6 months before enrollment.Randomization to perioperative systemic therapy or CRS-HIPEC alone. Perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (fluorouracil, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of fluorouracil with leucovorin. Bevacizumab was added to the first 3 (CAPOX) or 4 (FOLFOX/FOLFIRI) neoadjuvant cycles.Proportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade 3 or higher postoperative morbidity. Key secondary outcomes were centrally assessed rates of objective radiologic and major pathologic response of CPM to neoadjuvant treatment. Analyses were done modified intention-to-treat in patients starting neoadjuvant treatment (experimental arm) or undergoing upfront surgery (control arm).In 79 patients included in the analysis (43 [54%] men; mean [SD] age, 62 [10] years), experimental (n = 37) and control (n = 42) arms did not differ significantly regarding the proportions of macroscopic complete CRS-HIPEC (33 of 37 [89%] vs 36 of 42 [86%] patients; risk ratio, 1.04; 95% CI, 0.88-1.23; P = .74) and Clavien-Dindo grade 3 or higher postoperative morbidity (8 of 37 [22%] vs 14 of 42 [33%] patients; risk ratio, 0.65; 95% CI, 0.31-1.37; P = .25). No treatment-related deaths occurred. Objective radiologic and major pathologic response rates of CPM to neoadjuvant treatment were 28% (9 of 32 evaluable patients) and 38% (13 of 34 evaluable patients), respectively.In this randomized phase 2 trial in patients diagnosed with resectable CPM, perioperative systemic therapy seemed feasible, safe, and able to induce response of CPM, justifying a phase 3 trial.ClinicalTrials.gov Identifier: NCT02758951.

  View details for DOI 10.1001/jamasurg.2021.1642

  View details for Web of Science ID 000652632700004

  View details for PubMedID 34009291

  View details for PubMedCentralID PMC8135056

• Detection of tumor-derived cell-free DNA from colorectal cancer peritoneal metastases in plasma and peritoneal fluid JOURNAL OF PATHOLOGY CLINICAL RESEARCH Van't Erve, I., Rovers, K. P., Constantinides, A., Bolhuis, K., Wassenaar, E. E., Lurvink, R. J., Huysentruyt, C. J., Snaebjornsson, P., Boerma, D., van den Broek, D., Buffart, T. E., Lahaye, M. J., Aalbers, A. J., Kok, N. M., Meijer, G. A., Punt, C. A., Kranenburg, O., de Hingh, I. T., Fijneman, R. A. 2021; 7 (3): 203-208

  Abstract

  Tumor-derived cell-free DNA (cfDNA) is an emerging biomarker for guiding the personalized treatment of patients with metastatic colorectal cancer (CRC). While patients with CRC liver metastases (CRC-LM) have relatively high levels of plasma cfDNA, little is known about patients with CRC peritoneal metastases (CRC-PM). This study evaluated the presence of tumor-derived cfDNA in plasma and peritoneal fluid (i.e. ascites or peritoneal washing) in 20 patients with isolated CRC-PM and in the plasma of 100 patients with isolated CRC-LM. Among tumor tissue KRAS/BRAF mutation carriers, tumor-derived cfDNA was detected by droplet digital polymerase chain reaction (ddPCR) in plasma of 93% of CRC-LM and 20% of CRC-PM patients and in peritoneal fluid in all CRC-PM patients. Mutant allele fraction (MAF) and mutant copies per ml (MTc/ml) were lower in CRC-PM plasma than in CRC-LM plasma (median MAF = 0.28 versus 18.9%, p < 0.0001; median MTc/ml = 21 versus 1,758, p < 0.0001). Within patients with CRC-PM, higher cfDNA levels were observed in peritoneal fluid than in plasma (median MAF = 16.4 versus 0.28%, p = 0.0019; median MTc/ml = 305 versus 21, p = 0.0034). These data imply that tumor-derived cfDNA in plasma is a poor biomarker to monitor CRC-PM. Instead, cfDNA detection in peritoneal fluid may offer an alternative to guide CRC-PM treatment decisions.

  View details for DOI 10.1002/cjp2.207

  View details for Web of Science ID 000621904100001

  View details for PubMedID 33635598

  View details for PubMedCentralID PMC8073000

• First-line palliative systemic therapy alternated with electrostatic pressurised intraperitoneal aerosol chemotherapy (oxaliplatin) for isolated unresectable colorectal peritoneal metastases: protocol of a multicentre, single-arm, phase II study (CRC-PIPAC-II) BMJ OPEN Lurvink, R. J., Rauwerdink, P., Rovers, K. P., Wassenaar, E. E., Deenen, M. J., Nederend, J., Huysentruyt, C. R., van 't Erve, I., Fijneman, R. A., van der Hoeven, E. J., Seldenrijk, C. A., Constantinides, A., Kranenburg, O., Los, M., Herbschleb, K. H., Thijs, A. J., Creemers, G. M., Burger, J. A., Wiezer, M. J., Nienhuijs, S. W., Boerma, D., de Hingh, I. T. 2021; 11 (3): e044811

  Abstract

  Despite its increasing use, first-line palliative systemic therapy alternated with electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX), hereinafter referred to as first-line bidirectional therapy, has never been prospectively investigated in patients with colorectal peritoneal metastases (CPM). As a first step to address this evidence gap, the present study aims to assess the safety, feasibility, antitumour activity, patient-reported outcomes, costs and systemic pharmacokinetics of first-line bidirectional therapy in patients with isolated unresectable CPM.In this single-arm, phase II study in two Dutch tertiary referral centres, 20 patients are enrolled. Key eligibility criteria are a good performance status, pathologically proven isolated unresectable CPM, no previous palliative systemic therapy for colorectal cancer, no (neo)adjuvant systemic therapy ≤6 months prior to enrolment and no previous pressurised intraperitoneal aerosol chemotherapy (PIPAC). Patients receive three cycles of bidirectional therapy. Each cycle consists of 6 weeks first-line palliative systemic therapy at the medical oncologists' decision (CAPOX-bevacizumab, FOLFOX-bevacizumab, FOLFIRI-bevacizumab or FOLFOXIRI-bevacizumab) followed by ePIPAC-OX (92 mg/m2) with an intraoperative bolus of intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Study treatment ends after the third ePIPAC-OX. The primary outcome is the number of patients with-and procedures leading to-grade ≥3 adverse events (Common Terminology Criteria for Adverse Events V.5.0) up to 4 weeks after the last procedure. Key secondary outcomes include the number of bidirectional cycles in each patient, treatment-related characteristics, grade ≤2 adverse events, tumour response (histopathological, cytological, radiological, biochemical, macroscopic and ascites), patient-reported outcomes, systemic pharmacokinetics of oxaliplatin, costs, progression-free survival and overall survival.This study is approved by the Dutch competent authority, a medical ethics committee and the institutional review boards of both study centres. Results will be submitted for publication in peer-reviewed medical journals and presented to patients and healthcare professionals.NL8303.

  View details for DOI 10.1136/bmjopen-2020-044811

  View details for Web of Science ID 000636355300008

  View details for PubMedID 33785492

  View details for PubMedCentralID PMC8011718

• Diagnostic Strategies toward Clinical Implementation of Liquid Biopsy RAS/BRAF Circulating Tumor DNA Analyses in Patients with Metastatic Colorectal Cancer JOURNAL OF MOLECULAR DIAGNOSTICS van 't Erve, I., Greuter, E. E., Bolhuis, K., Vessies, D. L., Leal, A., Vink, G. R., van den Broek, D., Velculescu, V. E., Punt, C. A., Meijer, G. A., Coupe, V. H., Fijneman, R. A. 2020; 22 (12): 1430-1437

  Abstract

  Detection of KRAS, NRAS, and BRAF mutations in tumor tissue is currently used to predict resistance to treatment with anti-epidermal growth factor receptor (EGFR) antibodies in patients with metastatic colorectal cancer (mCRC). Liquid biopsies are minimally invasive, and cell-free circulating tumor DNA (ctDNA) mutation analyses may better represent tumor heterogeneity. This study examined the incorporation of liquid biopsy RAS/BRAF ctDNA analyses into diagnostic strategies to determine mCRC patient eligibility for anti-EGFR therapy. Tumor tissue and liquid biopsies were collected from 100 mCRC patients with liver-only metastases in a multicenter prospective clinical trial. Three diagnostic strategies incorporating droplet digital PCR ctDNA analyses were compared with routine tumor tissue RAS/BRAF mutation profiling using decision tree analyses. Tissue DNA mutations in KRAS, NRAS, and BRAF were present in 54%, 0%, and 3% of mCRC patients, respectively. A 93% concordance was observed between tissue DNA and liquid biopsy ctDNA mutations. The proportion of patients with RAS/BRAF alterations increased from 57% to 60% for diagnostic strategies that combined tissue and liquid biopsy mutation analyses. Consecutive RAS/BRAF ctDNA analysis followed by tissue DNA analysis in case of a liquid biopsy-negative result appeared to be the most optimal diagnostic strategy to comprehensively determine eligibility for anti-EGFR therapy in a cost-saving manner. These results highlight the potential clinical utility of liquid biopsies for detecting primary resistance to anti-EGFR-targeted therapies.

  View details for DOI 10.1016/j.jmoldx.2020.09.002

  View details for Web of Science ID 000591511100008

  View details for PubMedID 32961317

• Repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy (ePIPAC) with oxaliplatin as a palliative monotherapy for isolated unresectable colorectal peritoneal metastases: protocol of a Dutch, multicentre, open-label, single-arm, phase II study (CRC-PIPAC) BMJ OPEN Rovers, K. P., Lurvink, R. J., Wassenaar, E. E., Kootstra, T. M., Scholten, H. J., Tajzai, R., Deenen, M. J., Nederend, J., Lahaye, M. J., Huysentruyt, C. R., van't Erve, I., Fijneman, R. A., Constantinides, A., Kranenburg, O., Los, M., Thijs, A. J., Creemers, G. M., Burger, J. A., Wiezer, M. J., Boerma, D., Nienhuijs, S. W., de Hingh, I. T. 2019; 9 (7): e030408

  Abstract

  Repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX) is offered as a palliative treatment option for patients with isolated unresectable colorectal peritoneal metastases (PM) in several centres worldwide. However, little is known about its feasibility, safety, tolerability, efficacy, costs and pharmacokinetics in this setting. This study aims to explore these parameters in patients with isolated unresectable colorectal PM who receive repetitive ePIPAC-OX as a palliative monotherapy.This multicentre, open-label, single-arm, phase II study is performed in two Dutch tertiary referral hospitals for the surgical treatment of colorectal PM. Eligible patients are adults who have histologically or cytologically proven isolated unresectable PM of a colorectal or appendiceal carcinoma, a good performance status, adequate organ functions and no symptoms of gastrointestinal obstruction. Instead of standard palliative treatment, enrolled patients receive laparoscopy-controlled ePIPAC-OX (92 mg/m2 body surface area (BSA)) with intravenous leucovorin (20 mg/m2 BSA) and bolus 5-fluorouracil (400 mg/m2 BSA) every 6 weeks. Four weeks after each procedure, patients undergo clinical, radiological and biochemical evaluation. ePIPAC-OX is repeated until disease progression, after which standard palliative treatment is (re)considered. The primary outcome is the number of patients with major toxicity (grade ≥3 according to the Common Terminology Criteria for Adverse Events v4.0) up to 4 weeks after the last ePIPAC-OX. Secondary outcomes are the environmental safety of ePIPAC-OX, procedure-related characteristics, minor toxicity, postoperative complications, hospital stay, readmissions, quality of life, costs, pharmacokinetics of oxaliplatin, progression-free survival, overall survival, and the radiological, histopathological, cytological, biochemical and macroscopic tumour response.This study is approved by an ethics committee, the Dutch competent authority and the institutional review boards of both study centres. Results are intended for publication in peer-reviewed medical journals and for presentation to patients, healthcare professionals and other stakeholders.NCT03246321, Pre-results; ISRCTN89947480, Pre-results; NTR6603, Pre-results; EudraCT: 2017-000927-29, Pre-results.

  View details for DOI 10.1136/bmjopen-2019-030408

  View details for Web of Science ID 000485269700088

  View details for PubMedID 31352425

  View details for PubMedCentralID PMC6661551

• Changes in Circulating Levels of 25-hydroxyvitamin D3 in Breast Cancer Patients Receiving Chemotherapy NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL Kok, D. E., van den Berg, M. A., Posthuma, L., van't Erve, I., van Duijnhoven, F. B., de Roos, W. K., Grosfeld, S., Los, M., Sommeijer, D. W., van Laarhoven, H. M., Winkels, R. M., Kampman, E. 2019; 71 (5): 756-766

  Abstract

  Cancer treatments, toxicities and their effects on lifestyle, may impact levels of vitamin D. The aim of this study was to determine serum 25-hydroxyvitamin D3 (25(OH)D3) levels before, directly after and 6 months after chemotherapy in breast cancer patients (n = 95), and a comparison group of women (n = 52) not diagnosed with cancer. Changes in 25(OH)D3 levels over time were compared using linear mixed models adjusted for age and season of blood sampling. Before start of chemotherapy, 25(OH)D3 levels were lower in patients (estimated marginal mean 55.8 nmol/L, 95% confidence interval (95%CI) 51.2-60.4) compared to the comparison group (67.2 nmol/L, 95%CI 61.1-73.3, P = 0.003). Directly after chemotherapy, 25(OH)D3 levels were slightly decreased (-5.1 nmol/L, 95%CI -10.7-0.5, P = 0.082), but ended up higher 6 months after chemotherapy (10.9 nmol/L, 95%CI 5.5-16.4, P < 0.001) compared to pre-chemotherapy values. In women without cancer, 25(OH)D3 levels remained stable throughout the study. Use of dietary supplements did not explain recovery of 25(OH)D3 levels after chemotherapy. We reported lower 25(OH)D3 levels in breast cancer patients, which decreased during chemotherapy, but recovered to levels observed in women without cancer within 6 months after chemotherapy. Suboptimal 25(OH)D3 levels in the majority of the participants highlight the relevance of monitoring in this vulnerable population.

  View details for DOI 10.1080/01635581.2018.1559938

  View details for Web of Science ID 000467757800006

  View details for PubMedID 30661404

• Perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone for isolated resectable colorectal peritoneal metastases: protocol of a multicentre, open-label, parralel-group, phase II-III, randomised, superiority study (CAIRO6) BMC CANCER Rovers, K. P., Bakkers, C., Simkens, G. M., Burger, J. A., Nienhuijs, S. W., Creemers, G. M., Thijs, A. J., Brandt-Kerkhof, A. M., Madsen, E. E., Ayez, N., de Boer, N. L., van Meerten, E., Tuynman, J. B., Kusters, M., Sluiter, N. R., Verheul, H. W., van der Vliet, H. J., Wiezer, M. J., Boerma, D., Wassenaar, E. E., Los, M., Hunting, C. B., Aalbers, A. J., Kok, N. M., Kuhlmann, K. D., Boot, H., Chalabi, M., Kruijff, S., Been, L. B., van Ginkel, R. J., de Groot, D. A., Fehrmann, R. N., de Wilt, J. W., Bremers, A. A., de Reuver, P. R., Radema, S. A., Herbschleb, K. H., van Grevenstein, W. U., Witkamp, A. J., Koopman, M., Mohammad, N., van Duyn, E. B., Mastboom, W. B., Mekenkamp, L. M., Nederend, J., Lahaye, M. J., Snaebjornsson, P., Verhoef, C., van Laarhoven, H. M., Zwinderman, A. H., Bouma, J. M., Kranenburg, O., van 't Erve, I., Fijneman, R. A., Dijkgraaf, M. W., Hemmer, P. J., Punt, C. A., Tanis, P. J., de Hingh, I. T., DPOG, DCCG 2019; 19: 390

  Abstract

  Upfront cytoreductive surgery with HIPEC (CRS-HIPEC) is the standard treatment for isolated resectable colorectal peritoneal metastases (PM) in the Netherlands. This study investigates whether addition of perioperative systemic therapy to CRS-HIPEC improves oncological outcomes.This open-label, parallel-group, phase II-III, randomised, superiority study is performed in nine Dutch tertiary referral centres. Eligible patients are adults who have a good performance status, histologically or cytologically proven resectable PM of a colorectal adenocarcinoma, no systemic colorectal metastases, no systemic therapy for colorectal cancer within six months prior to enrolment, and no previous CRS-HIPEC. Eligible patients are randomised (1:1) to perioperative systemic therapy and CRS-HIPEC (experimental arm) or upfront CRS-HIPEC alone (control arm) by using central randomisation software with minimisation stratified by a peritoneal cancer index of 0-10 or 11-20, metachronous or synchronous PM, previous systemic therapy for colorectal cancer, and HIPEC with oxaliplatin or mitomycin C. At the treating physician's discretion, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles. The first 80 patients are enrolled in a phase II study to explore the feasibility of accrual and the feasibility, safety, and tolerance of perioperative systemic therapy. If predefined criteria of feasibility and safety are met, the study continues as a phase III study with 3-year overall survival as primary endpoint. A total of 358 patients is needed to detect the hypothesised 15% increase in 3-year overall survival (control arm 50%; experimental arm 65%). Secondary endpoints are surgical characteristics, major postoperative morbidity, progression-free survival, disease-free survival, health-related quality of life, costs, major systemic therapy related toxicity, and objective radiological and histopathological response rates.This is the first randomised study that prospectively compares oncological outcomes of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone for isolated resectable colorectal PM.Clinicaltrials.gov/ NCT02758951 , NTR/ NTR6301 , ISRCTN/ ISRCTN15977568 , EudraCT/ 2016-001865-99 .

  View details for DOI 10.1186/s12885-019-5545-0

  View details for Web of Science ID 000465873900002

  View details for PubMedID 31023318

  View details for PubMedCentralID PMC6485075