Quantitative targeted proteomics for occult cancer screening in patients with unprovoked venous thromboembolism: results from the prospective PLATO-VTE study

Noori A M Guman; Noémie Kraaijpoel; Frits I Mulder; Marc Carrier; Luis Jara-Palomares; Marcello Di Nisio; Walter Ageno; Jan Beyer-Westendorf; Frederikus A Klok; Thomas Vanassche; Johannes M M B Otten; Benilde Cosmi; Mike J L Peters; Marije Ten Wolde; Aurélien Delluc; Pieter W Kamphuisen; Verónica Sánchez-López; Ettore Porreca; Jip Ramaker; Patrick M M Bossuyt; Harry R Büller; Henri H Versteeg; Bart J M van Vlijmen; Nick van Es; Yassene Mohammed

doi:10.1016/j.rpth.2025.103018

Quantitative targeted proteomics for occult cancer screening in patients with unprovoked venous thromboembolism: results from the prospective PLATO-VTE study

Res Pract Thromb Haemost. 2025 Aug 19;9(6):103018. doi: 10.1016/j.rpth.2025.103018. eCollection 2025 Aug.

Authors

Noori A M Guman^{1

2

3}, Noémie Kraaijpoel^{1

2}, Frits I Mulder^{1

2

3}, Marc Carrier⁴, Luis Jara-Palomares^{5

6}, Marcello Di Nisio⁷, Walter Ageno⁸, Jan Beyer-Westendorf⁹, Frederikus A Klok¹⁰, Thomas Vanassche¹¹, Johannes M M B Otten¹², Benilde Cosmi¹³, Mike J L Peters¹⁴, Marije Ten Wolde¹⁵, Aurélien Delluc⁴, Pieter W Kamphuisen^{1

2

3}, Verónica Sánchez-López^{6

16

17}, Ettore Porreca¹⁸, Jip Ramaker¹⁹, Patrick M M Bossuyt²⁰, Harry R Büller^{1

2}, Henri H Versteeg²¹, Bart J M van Vlijmen²¹, Nick van Es^{1

2}, Yassene Mohammed^{22

23

24}

Affiliations

¹ Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
² Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Thrombosis, Amsterdam, the Netherlands.
³ Department of Internal Medicine, Tergooi Medical Center, Hilversum, the Netherlands.
⁴ Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
⁵ Medical-Surgical Unit of Respiratory Diseases, Hospital Universitario Virgen del Rocio, Seville, Spain.
⁶ Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
⁷ Department of Medicine and Ageing Sciences, Gabriele D'Annunzio University, Chieti, Italy.
⁸ Department of Medicine and Surgery, University of Insubria, Varese, Italy.
⁹ Division Thrombosis and Hemostasis, Department of Medicine I, University Hospital "Carl Gustav Carus," Dresden, Germany.
¹⁰ Department of Medicine-Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
¹¹ Department of Cardiovascular Sciences, University Hospitals Leuven, Leuven, Belgium.
¹² Department of Internal Medicine, Meander Medisch Centrum, Amersfoort, the Netherlands.
¹³ Angiology and Blood Coagulation Unit, University of Bologna, Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
¹⁴ Department of Internal Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
¹⁵ Department of Internal Medicine, Flevo Hospital, Almere, the Netherlands.
¹⁶ Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Seville, Spain.
¹⁷ Departamento de Ciencias Sociales y de la Salud, Centro san Isidoro, Seville, Spain.
¹⁸ Department of Innovative Technologies in Medicine and Dentistry, University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy.
¹⁹ Department of Neurosurgery, Brain Tumor Center Amsterdam, Cancer Center Amsterdam, Amsterdam University Medical Center/Vrije Universiteit, Amsterdam, the Netherlands.
²⁰ Department of Epidemiology and Data Science, Amsterdam Public Health, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
²¹ Einthoven Laboratory for Vascular and Regenerative Medicine, Division of Thrombosis and Hemostasis, Department of Internal Medicine, Leiden University Medical Centre, Leiden, the Netherlands.
²² Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
²³ Proteomics Centre, University of Victoria, Victoria, British Columbia, Canada.
²⁴ Gerald Bronfman Department of Oncology, McGill University, Montreal, Québec, Canada.

Abstract

Background: About 5% of patients with unprovoked venous thromboembolism (VTE) have occult cancer. Despite standard cancer screening, 50% of cancers remain undetected.

Objectives: We used quantitative targeted proteomics to identify novel cancer biomarkers among patients with unprovoked VTE.

Methods: Patients aged ≥40 years with a first unprovoked VTE and without a malignancy in the preceding 5 years were invited to an international prospective cohort study. Plasma samples were collected within 10 days after VTE. The primary outcome was an adjudicated cancer diagnosis during 12-month follow-up. Concentrations of 269 plasma proteins covering coagulation, complement, and cancer-associated pathways were measured using quantitative mass spectrometry-based targeted proteomics. In a nested case-control study, protein profiles of patients with cancer were compared with those of randomly sampled unique control patients (ratio 3:1). Proteins with an unadjusted P value < .05 and fold change ≥15% were combined in a multivariable logistic regression model. To address the variability in the obtained model, the protein selection and model-building approach were replicated in 250 bootstrap samples, and an optimism-adjusted c-statistic was calculated.

Results: Of the 476 included participants, 28 (5.9%) were newly diagnosed with cancer. Plasma samples were available for 24 cases, which were compared with those of 75 control patients. Concentrations of P-selectin, β-2 microglobulin, complement component 7, intracellular adhesion molecule 1, and lumican were higher in cases than in controls, whereas coagulation factor (F)VII, FX, and FXII, β-Ala-His dipeptidase, and kalistatin were lower. The optimism-adjusted c-statistic of the multivariable logistic regression model including these proteins was 0.78 (95% CI, 0.70-0.87).

Conclusion: Ten differentially abundant proteins were identified in patients with occult cancer, suggesting potential of plasma proteomic tests as novel biomarker for occult cancer in patients with unprovoked VTE.

Keywords: early detection of cancer; liquid biopsy; neoplasms; proteomics; venous thromboembolism.