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  • Evaluating the effectiveness of pre-operative diagnosis of ovarian cancer using minimally invasive liquid biopsies by combining serum human epididymis protein 4 and cell-free DNA in patients with an ovarian mass

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Original research
Evaluating the effectiveness of pre-operative diagnosis of ovarian cancer using minimally invasive liquid biopsies by combining serum human epididymis protein 4 and cell-free DNA in patients with an ovarian mass
  1. Duco H K Gaillard1,2,
  2. Pien Lof3,
  3. Erik A Sistermans4,5,
  4. Tom Mokveld2,
  5. Hugo Mark Horlings6,
  6. Constantijne H Mom3,
  7. Marcel J T Reinders2,
  8. Frédéric Amant3,7,
  9. Daan van den Broek8,
  10. Lodewyk F A Wessels1 and
  11. Christianne A R Lok3
  12. HE4 Study Group
      1. 1 Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands
      2. 2 Delft Bioinformatics Lab, Delft University of Technology, Delft, Netherlands
      3. 3 Department of Gynecological Oncology, Center for Gynecologic Oncology Amsterdam, Amsterdam, Netherlands
      4. 4 Department of Human Genetics, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
      5. 5 Amsterdam Reproduction & Development, Amsterdam UMC Location VUmc, Amsterdam, Netherlands
      6. 6 Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
      7. 7 Division of Gynecologic Oncology, UZ Leuven, Leuven, Belgium
      8. 8 Department of Laboratory Medicine, Netherlands Cancer Institute, Amsterdam, Netherlands
      9. 9 Netherlands Cancer Institute, Amsterdam, Netherlands
      1. Correspondence to Christianne A R Lok, Department of Gynecological Oncology, Netherlands Cancer Institute, Amsterdam, Noord-Holland, The Netherlands; c.lok{at}nki.nl

      Abstract

      Objective To assess the feasibility of scalable, objective, and minimally invasive liquid biopsy-derived biomarkers such as cell-free DNA copy number profiles, human epididymis protein 4 (HE4), and cancer antigen 125 (CA125) for pre-operative risk assessment of early-stage ovarian cancer in a clinically representative and diagnostically challenging population and to compare the performance of these biomarkers with the Risk of Malignancy Index (RMI).

      Methods In this case–control study, we included 100 patients with an ovarian mass clinically suspected to be early-stage ovarian cancer. Of these 100 patients, 50 were confirmed to have a malignant mass (cases) and 50 had a benign mass (controls). Using WisecondorX, an algorithm used extensively in non-invasive prenatal testing, we calculated the benign-calibrated copy number profile abnormality score. This score represents how different a sample is from benign controls based on copy number profiles. We combined this score with HE4 serum concentration to separate cases and controls.

      Results Combining the benign-calibrated copy number profile abnormality score with HE4, we obtained a model with a significantly higher sensitivity (42% vs 0%; p<0.002) at 99% specificity as compared with the RMI that is currently employed in clinical practice. Investigating performance in subgroups, we observed especially large differences in the advanced stage and non-high-grade serous ovarian cancer groups.

      Conclusion This study demonstrates that cell-free DNA can be successfully employed to perform pre-operative risk of malignancy assessment for ovarian masses; however, results warrant validation in a more extensive clinical study.

      • Area Under Curve
      • Carcinoma, Ovarian Epithelial
      • Ovarian Cancer
      • Ovarian Neoplasms

      Data availability statement

      Data are available upon reasonable request. WisecondorX-based copy number profiles dataset used for predictor training.

      https://doi.org/10.1136/ijgc-2023-005073

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        Data availability statement

        Data are available upon reasonable request. WisecondorX-based copy number profiles dataset used for predictor training.

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        Footnotes

        • Collaborators HE4 Prediction Study Group: M van Gent, M Hemelaar, WM van Baal, M Verbruggen, FMF Rosier-van Dunné, BBJ Hermsen.

        • Contributors DHKG: Conceptualization, methodology, software, formal analysis, data curation, writing - original draft, writing - review and editing, visualization, investigation. PL: Conceptualization, methodology, formal analysis, resources, data curation, writing - original draft, writing - review and editing, visualization, project administration, investigation. EAS: Formal analysis, writing - review and editing. TM: formal analysis, writing - review and editing, software, formal analysis. HMH: writing - review and editing. CHM: Investigation, resources. MJTR: Writing - review and editing, supervision. FA: Writing - review and editing. DvdB: Writing - review and editing, supervision. LFAW: Methodology, writing - review and editing, supervision. CARL: Conceptualization, methodology, writing - review and editing, supervision, funding acquisition, Guarantor. HE4 Study Group members: M van Gent: Investigation, resources. MH: Investigation, resources. WMvB: Investigation, resources. MV: Investigation, resources. FMFR-vD: Investigation, resources. BBJH: Investigation, resources.

        • Competing interests DHKG: No conflicting interests. PL: No conflicting interests. EAS: Received funding for a PhD student (not involved in this project) from MRC-Holland; participation on a Data Safety Monitoring Board or Advisory Board of GenQA (unpaid); leadership role at VKGL. TM: Employee and shareholder at Pacific Biosciences. HMH: No conflicting interests. CHM: No conflicting interests. MJTR: Institute received funding from the Dutch Cancer Society for this work; institute receives royalties for commercial use of Wisecondor but with application in non-invasive prenatal testing setting, not in cancer diagnostics, as is the subject of this work. FA: No conflicting interests. DvdB: Institute received ZonMW grant for personalised medicine research; unpaid KWF research board member on biomarkers; ZonMW research board member for early detection. LFAW: Institute received funding from the Dutch Cancer Society for this work; received grant from Bristol Myers Squibb. CARL: No conflicting interests. HE4 Study Group members: MDJMvG: No conflicting interests. MH: No conflicting interests. WMvB: No conflicting interests. MV: No conflicting interests. FMFR-vD: No conflicting interests; BBJH: No conflicting interests.

        • Provenance and peer review Not commissioned; externally peer reviewed.

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