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5. Reproducible radiomics through automated machine learning validated on twelve clinical applications

Author

Starmans, Martijn P. A., van der Voort, Sebastian R., Phil, Thomas, Timbergen, Milea J. M., Vos, Melissa, Padmos, Guillaume A., Kessels, Wouter, Hanff, David, Grunhagen, Dirk J., Verhoef, Cornelis, Sleijfer, Stefan, Bent, Martin J. van den, Smits, Marion, Dwarkasing, Roy S., Els, Christopher J., Fiduzi, Federico, van Leenders, Geert J. L. H., Blazevic, Anela, Hofland, Johannes, Brabander, Tessa, van Gils, Renza A. H., Franssen, Gaston J. H., Feelders, Richard A., de Herder, Wouter W., Buisman, Florian E., Willemssen, Francois E. J. A., Koerkamp, Bas Groot, Angus, Lindsay, van der Veldt, Astrid A. M., Rajicic, Ana, Odink, Arlette E., Deen, Mitchell, T., Jose M. Castillo, Veenland, Jifke, Schoots, Ivo, Renckens, Michel, Doukas, Michail, de Man, Rob A., IJzermans, Jan N. M., Miclea, Razvan L., Vermeulen, Peter B., Bron, Esther E., Thomeer, Maarten G., Visser, Jacob J., Niessen, Wiro J., and Klein, Stefan

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition
Abstract

Radiomics uses quantitative medical imaging features to predict clinical outcomes. Currently, in a new clinical application, finding the optimal radiomics method out of the wide range of available options has to be done manually through a heuristic trial-and-error process. In this study we propose a framework for automatically optimizing the construction of radiomics workflows per application. To this end, we formulate radiomics as a modular workflow and include a large collection of common algorithms for each component. To optimize the workflow per application, we employ automated machine learning using a random search and ensembling. We evaluate our method in twelve different clinical applications, resulting in the following area under the curves: 1) liposarcoma (0.83); 2) desmoid-type fibromatosis (0.82); 3) primary liver tumors (0.80); 4) gastrointestinal stromal tumors (0.77); 5) colorectal liver metastases (0.61); 6) melanoma metastases (0.45); 7) hepatocellular carcinoma (0.75); 8) mesenteric fibrosis (0.80); 9) prostate cancer (0.72); 10) glioma (0.71); 11) Alzheimer's disease (0.87); and 12) head and neck cancer (0.84). We show that our framework has a competitive performance compared human experts, outperforms a radiomics baseline, and performs similar or superior to Bayesian optimization and more advanced ensemble approaches. Concluding, our method fully automatically optimizes the construction of radiomics workflows, thereby streamlining the search for radiomics biomarkers in new applications. To facilitate reproducibility and future research, we publicly release six datasets, the software implementation of our framework, and the code to reproduce this study., Comment: 33 pages, 4 figures, 4 tables, 2 supplementary figures, 3 supplementary table, submitted to Medical Image Analysis; revision

Published
2021

6. Differential diagnosis and molecular stratification of gastrointestinal stromal tumors on CT images using a radiomics approach

Author

Starmans, Martijn P. A., Timbergen, Milea J. M., Vos, Melissa, Renckens, Michel, Grünhagen, Dirk J., van Leenders, Geert J. L. H., Dwarkasing, Roy S., Willemssen, François E. J. A., Niessen, Wiro J., Verhoef, Cornelis, Sleijfer, Stefan, Visser, Jacob J., and Klein, Stefan

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition
Abstract

Distinguishing gastrointestinal stromal tumors (GISTs) from other intra-abdominal tumors and GISTs molecular analysis is necessary for treatment planning, but challenging due to its rarity. The aim of this study was to evaluate radiomics for distinguishing GISTs from other intra-abdominal tumors, and in GISTs, predict the c-KIT, PDGFRA,BRAF mutational status and mitotic index (MI). All 247 included patients (125 GISTS, 122 non-GISTs) underwent a contrast-enhanced venous phase CT. The GIST vs. non-GIST radiomics model, including imaging, age, sex and location, had a mean area under the curve (AUC) of 0.82. Three radiologists had an AUC of 0.69, 0.76, and 0.84, respectively. The radiomics model had an AUC of 0.52 for c-KIT, 0.56 for c-KIT exon 11, and 0.52 for the MI. Hence, our radiomics model was able to distinguish GIST from non-GISTS with a performance similar to three radiologists, but was not able to predict the c-KIT mutation or MI., Comment: Martijn P.A. Starmans and Milea J.M. Timbergen contributed equally

Published
2020
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7. Local treatment in metastatic GIST patients: A multicentre analysis from the Dutch GIST Registry

Author

Brink, Pien, Kalisvaart, Gijsbert M., Schrage, Yvonne M., Mohammadi, Mahmoud, Ijzerman, Nikki S., Bleckman, Roos F., Wal, Tom, de Geus-Oei, Lioe-Fee, Hartgrink, Henk H., Grunhagen, Dirk J., Verhoef, Cornelis, Sleijfer, Stefan, Oosten, Astrid W., Been, Lukas B., van Ginkel, Robert J., Reyners, An K.L., Bonenkamp, Han J., Desar, Ingrid M.E., Gelderblom, Hans, van Houdt, Winan J., Steeghs, Neeltje, Fiocco, Marta, and van der Hage, Jos A.

Published
2023
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8. Health-related Quality of Life of Patients With Non–Intra-abdominal Desmoid-Type Fibromatosis During Active Surveillance: Results of a Prospective Observational Study

Author

Schut, Anne-Rose W., Timbergen, Milea J.M., Nasserinejad, Kazem, van Dalen, Thijs, van Houdt, Winan J., Bonenkamp, Johannes J., Sleijfer, Stefan, Grünhagen, Dirk J., Verhoef, Cornelis, Husson, Olga, Schut, Anne-Rose W., Timbergen, Milea J.M., van Broekhoven, Danique L.M., Sleijfer, Stefan, Grünhagen, Dirk J., Verhoef, Cornelis, van Houdt, Winan J., van Coevorden, Frits, van Dalen, Thijs, van der Hage, Jos. A., Dijkstra, Sander D.S., Bonenkamp, Johannes J., Been, Lukas B., van Ginkel, Robert J., and Bemelmans, Marc H.A.

Published
2023
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11. CABA-V7: a prospective biomarker selected trial of cabazitaxel treatment in AR-V7 positive prostate cancer patients

Author

Isebia, Khrystany T., Mostert, Bianca, Belderbos, Bodine P.S., Buck, Stefan A.J., Helmijr, Jean C.A., Kraan, Jaco, Beaufort, Corine M., Van, Mai N., Oomen - de Hoop, Esther, Sieuwerts, Anieta M., van IJcken, Wilfred F.J., van den Hout - van Vroonhoven, Mirjam C.G.N., Brouwer, Rutger W.W., Oole, Edwin, Hamberg, Paul, Haberkorn, Brigitte C.M., Helgason, Helgi H., de Wit, Ronald, Sleijfer, Stefan, Mathijssen, Ron H.J., Martens, John W.M., Jansen, Maurice P.H.M., van Riet, Job, and Lolkema, Martijn P.

Published
2022
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13. The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact.

Author

van Dessel, Lisanne F, van Riet, Job, Smits, Minke, Zhu, Yanyun, Hamberg, Paul, van der Heijden, Michiel S, Bergman, Andries M, van Oort, Inge M, de Wit, Ronald, Voest, Emile E, Steeghs, Neeltje, Yamaguchi, Takafumi N, Livingstone, Julie, Boutros, Paul C, Martens, John WM, Sleijfer, Stefan, Cuppen, Edwin, Zwart, Wilbert, van de Werken, Harmen JG, Mehra, Niven, and Lolkema, Martijn P

Subjects
Lymph Nodes, Humans, Bone Neoplasms, Liver Neoplasms, Soft Tissue Neoplasms, Prostatic Neoplasms, Neoplasm Metastasis, Cyclin-Dependent Kinases, Oncogene Proteins, Fusion, BRCA2 Protein, Receptors, Androgen, Genotype, Male, Microsatellite Instability, Enhancer Elements, Genetic, DNA Copy Number Variations, Recombinational DNA Repair, Prostatic Neoplasms, Castration-Resistant, Whole Genome Sequencing, Chromatin Immunoprecipitation Sequencing, Oncogene Proteins, Fusion, Receptors, Androgen, Enhancer Elements, Genetic, Castration-Resistant, Biotechnology, Genetics, Cancer, Prostate Cancer, Urologic Diseases, Human Genome
Abstract

Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12-/- and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12-/- and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups.

Published
2019

17. Comprehensive characterization of circulating tumor cells and cell‐free DNA in patients with metastatic melanoma.

Author

Bos, Manouk K., Kraan, Jaco, Starmans, Martijn P. A., Helmijr, Jean C. A., Verschoor, Noortje, De Jonge, Maja J. A., Joosse, Arjen, van der Veldt, Astrid A. M., te Boekhorst, Peter A. W., Martens, John W. M., Sleijfer, Stefan, and Wilting, Saskia M.

Abstract

Advances in therapeutic approaches for melanoma urge the need for biomarkers that can identify patients at risk for recurrence and to guide treatment. The potential use of liquid biopsies in identifying biomarkers is increasingly being recognized. Here, we present a head‐to‐head comparison of several techniques to analyze circulating tumor cells (CTCs) and cell‐free DNA (cfDNA) in 20 patients with metastatic melanoma. In this study, we investigated whether diagnostic leukapheresis (DLA) combined with multimarker flow cytometry (FCM) increased the detection of CTCs in blood compared to the CellSearch platform. Additionally, we characterized cfDNA at the level of somatic mutations, extent of aneuploidy and genome‐wide DNA methylation. Both CTCs and cfDNA measures were compared to tumor markers and extracranial tumor burden on radiological imaging. Compared to the CellSearch method applied on peripheral blood, DLA combined with FCM increased the proportion of patients with detectable CTCs from 35% to 70% (P = 0.06). However, the median percentage of cells that could be recovered by the DLA procedure was 29%. Alternatively, cfDNA mutation and methylation analysis detected tumor load in the majority of patients (90% and 93% of samples successfully analyzed, respectively). The aneuploidy score was positive in 35% of all patients. From all tumor measurements in blood, lactate dehydrogenase (LDH) levels were significantly correlated to variant allele frequency (P = 0.004). Furthermore, the presence of CTCs in DLA was associated with tumor burden (P < 0.001), whereas the presence of CTCs in peripheral blood was associated with number of lesions on radiological imaging (P < 0.001). In conclusion, DLA tended to increase the proportion of patients with detectable CTCs but was also associated with low recovery. Both cfDNA and CTCs were correlated with clinical parameters such as LDH levels and extracranial tumor burden. [ABSTRACT FROM AUTHOR]

Published
2024
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20. A review of trials investigating ctDNA-guided adjuvant treatment of solid tumors:The importance of trial design

Author

Verschoor, Noortje, Bos, Manouk K., Oomen-de Hoop, Esther, Martens, John W.M., Sleijfer, Stefan, Jager, Agnes, Beije, Nick, Verschoor, Noortje, Bos, Manouk K., Oomen-de Hoop, Esther, Martens, John W.M., Sleijfer, Stefan, Jager, Agnes, and Beije, Nick

Abstract

Circulating tumor DNA (ctDNA) holds promise as a biomarker for guiding adjuvant treatment decisions in solid tumors. This review systematically assembles ongoing and published trials investigating ctDNA-directed adjuvant treatment strategies. A total of 57 phase II/III trials focusing on ctDNA in minimal residual disease (MRD) detection were identified, with a notable increase in initiation over recent years. Most trials target stage II or III colon/colorectal cancer, followed by breast cancer and non-small cell lung cancer. Trial methodologies vary, with some randomizing ctDNA-positive patients between standard-of-care (SoC) treatment and intensified regimens, while others aim to de-escalate therapy in ctDNA-negative patients. Challenges in trial design include the need for randomized controlled trials to establish clinical utility for ctDNA, ensuring adherence to standard treatment in control arms, and addressing the ethical dilemma of withholding treatment in high-risk ctDNA-positive patients. Longitudinal ctDNA surveillance emerges as a strategy to improve sensitivity for recurrence, particularly in less proliferative tumor types. However, ctDNA as longitudinal marker is often not validated yet. Ultimately, designing effective ctDNA interventional trials requires careful consideration of feasibility, meaningful outcomes, and potential impact on patient care.

Published
2024

21. Trastuzumab and first-line taxane chemotherapy in metastatic breast cancer patients with a HER2-negative tumor and HER2-positive circulating tumor cells:a phase II trial

Author

Verschoor, Noortje, Bos, Manouk K., de Kruijff, Ingeborg E., Van, Mai N., Kraan, Jaco, Drooger, Jan C., Zuetenhorst, Johanna M., Wilting, Saskia M., Sleijfer, Stefan, Jager, Agnes, Martens, John W.M., Verschoor, Noortje, Bos, Manouk K., de Kruijff, Ingeborg E., Van, Mai N., Kraan, Jaco, Drooger, Jan C., Zuetenhorst, Johanna M., Wilting, Saskia M., Sleijfer, Stefan, Jager, Agnes, and Martens, John W.M.

Abstract

Purpose: HER2 overexpressing circulating tumor cells (CTCs) are observed in up to 25% of HER2-negative metastatic breast cancer patients. Since targeted anti-HER2 therapy has drastically improved clinical outcomes of patients with HER2-positive breast cancer, we hypothesized that patients with HER2 overexpressing CTCs might benefit from the addition of trastuzumab to chemotherapy. Methods: In this single-arm, phase II trial, patients with HER2-positive CTCs received trastuzumab as addition to first-line treatment with taxane chemotherapy. Patients with detectable CTCs but without HER2 overexpression that received taxane chemotherapy only, were used as control group. The primary outcome measure was progression-free rate at 6 months (PFR6), with a target of 80%. In November 2022, the study was terminated early due to slow patient accrual. Results: 63 patients were screened, of which eight patients had HER2-positive CTCs and were treated with trastuzumab. The median number of CTCs was 15 per 7.5 ml of blood (range 1–131) in patients with HER2-positive CTCs, compared to median 5 (range 1–1047) in the control group. PFR6 was 50% in the trastuzumab group and 54% in the taxane monotherapy group, with no significant difference in median PFS (8 versus 9 months, p = 0.51). Conclusion: No clinical benefit of trastuzumab was observed, although this study was performed in a limited number of patients. Additionally, we observed a strong correlation between the number of evaluable CTCs and the presence of HER2-positive CTCs. We argue that randomized studies investigating agents that are proven to be solely effective in the HER2-positive patient group in patients with HER2-positive CTCs and HER2-negative tissue are currently infeasible. Several factors contribute to this impracticality, including the need for more stringent thresholds, and the rapidly evolving landscape of cancer treatments.

Published
2024

28. High-throughput and affordable genome-wide methylation profiling of circulating cell-free DNA by methylated DNA sequencing (MeD-seq) of LpnPI digested fragments

Author

Deger, Teoman, Boers, Ruben G., de Weerd, Vanja, Angus, Lindsay, van der Put, Marjolijn M. J., Boers, Joachim B., Azmani, Z., van IJcken, Wilfred F. J., Grünhagen, Dirk J., van Dessel, Lisanne F., Lolkema, Martijn P. J. K., Verhoef, Cornelis, Sleijfer, Stefan, Martens, John W. M., Gribnau, Joost, and Wilting, Saskia M.

Published
2021
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34. Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling

Author

Angus, Lindsay, primary, Smid, Marcel, additional, Wilting, Saskia M., additional, Bos, Manouk K., additional, Steeghs, Neeltje, additional, Konings, Inge R. H. M., additional, Tjan-Heijnen, Vivianne C. G., additional, van Riel, Johanna M. G. H., additional, van de Wouw, Agnes J., additional, Consortium, CPCT, additional, Cuppen, Edwin, additional, Lolkema, Martijn P., additional, Jager, Agnes, additional, Sleijfer, Stefan, additional, and Martens, John W. M., additional

Published
2023
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36. Pan-cancer whole-genome analyses of metastatic solid tumours

Author

Priestley, Peter, Baber, Jonathan, Lolkema, Martijn P., Steeghs, Neeltje, de Bruijn, Ewart, Shale, Charles, Duyvesteyn, Korneel, Haidari, Susan, van Hoeck, Arne, Onstenk, Wendy, Roepman, Paul, Voda, Mircea, Bloemendal, Haiko J., Tjan-Heijnen, Vivianne C. G., van Herpen, Carla M. L., Labots, Mariette, Witteveen, Petronella O., Smit, Egbert F., Sleijfer, Stefan, Voest, Emile E., and Cuppen, Edwin

Published
2019
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37. The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies

Author

Angus, Lindsay, Smid, Marcel, Wilting, Saskia M., van Riet, Job, Van Hoeck, Arne, Nguyen, Luan, Nik-Zainal, Serena, Steenbruggen, Tessa G., Tjan-Heijnen, Vivianne C. G., Labots, Mariette, van Riel, Johanna M. G. H., Bloemendal, Haiko J., Steeghs, Neeltje, Lolkema, Martijn P., Voest, Emile E., van de Werken, Harmen J. G., Jager, Agnes, Cuppen, Edwin, Sleijfer, Stefan, and Martens, John W. M.

Published
2019
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48. Physical symptom burden in patients with desmoid‐type fibromatosis and its impact on health‐related quality of life and healthcare use

Author

Schut, Anne‐Rose W., primary, de Bruin, Leanne E., additional, de Rooij, Belle H., additional, Lidington, Emma, additional, Timbergen, Milea J. M., additional, van der Graaf, Winette T. A., additional, van Houdt, Winan J., additional, Bonenkamp, Johannes J., additional, Jones, Robin L., additional, Grünhagen, Dirk. J., additional, Sleijfer, Stefan, additional, Gennatas, Spyridon, additional, Verhoef, Cornelis, additional, and Husson, Olga, additional

Published
2023
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49. Abstract 5715: Circulating tumor DNA in colorectal cancer patients with resectable liver metastases: Preliminary results of the MIRACLE study

Author

Wullaert, Lissa, primary, Jansen, Maurice P., additional, Kraan, Jaco, additional, van Rees, Jan M., additional, Beaufort, Corine M., additional, Meyer, Yannick M., additional, Galjart, Boris, additional, Nierop, Pieter M., additional, Buisman, Florian E., additional, Höppener, Diederik J., additional, van der Stok, Erik P., additional, Motta, Gianmarco, additional, Grünhagen, Dirk J., additional, Verheul, Henk M., additional, Sleijfer, Stefan, additional, Wilting, Saskia M., additional, Verhoef, Cornelis, additional, and Martens, John W., additional

Published
2023
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50. Data from Improved Circulating Tumor Cell Detection by a Combined EpCAM and MCAM CellSearch Enrichment Approach in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy

Author

Onstenk, Wendy, primary, Kraan, Jaco, primary, Mostert, Bianca, primary, Timmermans, Mieke M., primary, Charehbili, Ayoub, primary, Smit, Vincent T.H.B.M., primary, Kroep, Judith R., primary, Nortier, Johan W.R., primary, van de Ven, Saskia, primary, Heijns, Joan B., primary, Kessels, Lonneke W., primary, van Laarhoven, Hanneke W.M., primary, Bos, Monique M.E.M., primary, van de Velde, Cornelis J.H., primary, Gratama, Jan W., primary, Sieuwerts, Anieta M., primary, Martens, John W.M., primary, Foekens, John A., primary, and Sleijfer, Stefan, primary

Published
2023
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