Ovarium Cancer Detection by TEP's and ctDNA

Early Detection of Ovarian Cancer and Treatment Response by Tumor Educated Platelets (TEP's) and Circulating Tumor DNA (ctDNA)

Rationale: Cancer is primarily diagnosed by clinical presentation, imaging and pathological analysis of tissue biopsies, increasingly supported by molecular diagnostics tests. However, late diagnosis and misdiagnosis due to limitations of tissue biopsy acquisition remains a major problem. Therefore, a general blood test to pinpoint cancer early and adequately can be considered the 'Holy Grail', because diagnosis in an earlier stage significantly improves the chance of cure from cancer. Several blood-based sources are currently being evaluated as liquid biopsies, including circulating tumor (ct) DNA and circulating tumor cells, but none of these have been implemented for primary (multiclass) cancer diagnostics. Protein tumor markers have been used for decades in diagnosis and monitoring of treatment response in different cancers. Tumor-educated platelets (TEPs) can function as potential blood-based source for (early) cancer diagnostics. Blood platelets are implicated in hemostasis and wound healing. Platelets have recently emerged as central players and immediate responders in the systemic and local responses to tumor growth. Confrontation of platelets by tumor cells via transfer of tumor-associated molecules ('education') results in the sequestration of these molecules (derived from both tumor and its micro-environment), causing a distinct platelet messenger Ribonucleic acid (mRNA) profile. We have previously shown that platelets acquire glioblastoma and prostate cancer mRNA biomarkers and that glioblastoma TEP mRNA profiles harbour diagnostic potential. Furthermore, circulating tumor desoxyrubonucleic acid (ctDNA) has recently been implicated as biomarker for therapy effectiveness and survival. Objective: develop and evaluate the potential of combination of tumor markers, TEPs and ctDNA as liquid biomarkers for (early) ovarium cancer diagnostics and as markers for therapy response and survival. Study design: investigator-initiated, longitudinal, observational study. Study population: patients suspected of having ovarium cancer and are therefore planned for surgery. Main study parameters/endpoints: The difference in biomarker profile from benign ovarium lesions versus cancerous lesions. Nature and extent of the burden and risks associated with participation, benefit and group relatedness. There is no extra burden/risk for the patients in this study. Three extra vials of blood.

Study Overview

• Status: Recruiting
• Conditions: Ovarian Neoplasms
• Intervention / Treatment: Diagnostic test: TEP; Diagnostic test: ctDNA

Detailed Description

Cancer is primarily diagnosed by clinical presentation, radiology, biochemical tests and pathological analysis of tumor tissue, increasingly supported by molecular diagnostic tests. Molecular profiling of tumor tissue samples has emerged as a potential cancer classifying method. In order to overcome limitations of tissue acquisition the use of blood-based liquid biopsies has been suggested. Several blood-based sources are currently being evaluated as liquid biopsies, including plasma DNA and circulating tumor cells. So far, implementation of liquid biopsies for early detection of cancer has been hampered by non-specificity of these sources to pinpoint the nature of the primary tumor. It has been reported that tumor-educated platelets (TEPs) may enable blood-based cancer diagnostics. Platelets are circulating anucleated cell fragments that originate from megakaryocytes in bone marrow, and are traditionally known for their role in hemostasis and initiation of wound healing. More recently, platelets have emerged as central players in the systemic and local responses to tumor growth. Confrontation of platelets with tumor cells via transfer of tumor-associated biomolecules ('education') is an emerging concept and results in the sequestration of such biomolecules. Moreover, external stimuli, such as activation of platelet surface receptors and lipopolysaccharide-mediated platelet activation induce specific splicing of pre-mRNAs in circulating platelets. Platelets may also undergo queue-specific splice events in response to signals released by cancer cells and the tumor microenvironment -such as stromal and immune cells-. The combination of specific splice events in response to external signals and the capacity of platelets to directly ingest (spliced) circulating mRNA can provide TEPs with a highly dynamic mRNA repertoire, with potential applicability to cancer diagnostics. Additionally, the value of other biomarkers that can be derived from a liquid biopsy will be tested in this study. In addition, recently a hallmark paper has shown that combinations of protein tumor markers and ctDNA analysis could discriminate persons with different types of cancer from healthy controls with on average 70% sensitivity (at 99% specificity). In the case of ovarium cancer the sensitivity was 98%. Obvious advantages of liquid biopsy compared to tissue biopsy is the easy accessibility of the material to be obtained and the fact that tumor derived material in blood may cover the cancer heterogeneity where a tissue biopsy is limited to the alterations in the tumor punctured. Therefore, this study investigates the clinical value of longitudinal assessment of liquid biopsy-derived information in diagnosis and monitoring of treatment response in patients suspected of ovarian cancer.

• Study Type: Observational
• Enrollment (Anticipated): 500

Contacts and Locations

• Study Contact: Name: Jurgen M Piek, MD, PhD; Phone Number: +31(0)40239 9111; Email: jurgen.piek@catharinaziekenhuis.nl
• Study Contact Backup: Name: Volkher Scharnhorst, MD, PhD; Phone Number: +31(0)40239 9111; Email: volkher.scharnhorst@catharinaziekenhuis.nl

Study Locations

• Netherlands
  • Brabant
    • Eindhoven, Brabant, Netherlands, 5623EJ
      • Recruiting
      • Catharina Hospital
      • Contact: Jurgen M Piek, MD. PhD.; Phone Number: +31(0)40 239 9111; Email: jurgen.piek@catharinaziekenhuis.nl
  • Noord Holland
    • Amsterdam, Noord Holland, Netherlands, 1066 CX
      • Recruiting
      • Netherlands Cancer Institute
      • Contact: Christianne Lok, MD; PhD
    • Leiden, Noord Holland, Netherlands, 2333 ZA
      • Recruiting
      • Leiden University Medical Center
      • Contact: Cor D de Kroon, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

all women presenting with an ovarian tumor of unknown nature

Description

Inclusion Criteria:

• Suspicion of ovarian cancer.

Exclusion Criteria:

• Previous intraabdominal malignancies in the history

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
ovarian tumor benign; all pathological proven benign ovarian tumors	Diagnostic test: TEP; Tumor Educated Platelets; Diagnostic test: ctDNA; circulating tumor DNA
ovarian tumor borderline; all pathological proven borderline ovarian tumors	Diagnostic test: TEP; Tumor Educated Platelets; Diagnostic test: ctDNA; circulating tumor DNA
ovarian tumor malignant; all pathological proven malignant ovarian tumors	Diagnostic test: TEP; Tumor Educated Platelets; Diagnostic test: ctDNA; circulating tumor DNA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
accuracy of TEP's to determine the nature of an ovarian tumor	Prior to operation blood will be drawn of patients with an ovarian tumor. TEP's will be analysed as described before.	1 month
accuracy of ctDNA to determine the nature of an ovarian tumor	Prior to operation blood will be drawn of patients with an ovarian tumor. CtDNA will be analysed as described before.	1 month
accuracy of ctDNA to predict treatment response in ovarian cancer	Prior to debulking operation and pre and post chemotherapy ctDNA will be analysed in blood from patients with ovarian cancer as described before.	1 month

Collaborators and Investigators

• Sponsor: Gynaecologisch Oncologisch Centrum Zuid
• Collaborators: Catharina Ziekenhuis Eindhoven; Amsterdam UMC, location VUmc; The Netherlands Cancer Institute; Leiden University Medical Center
• Investigators: Principal Investigator: Thomas Wurdinger, PhD, Amsterdam UMC loc VUmc

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2019
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: July 9, 2019
• First Submitted That Met QC Criteria: July 14, 2019
• First Posted (Actual): July 17, 2019

Study Record Updates

• Last Update Posted (Actual): July 17, 2019
• Last Update Submitted That Met QC Criteria: July 14, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: TEP; ovarian cancer; ctDNA
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Ovarian Neoplasms
• Other Study ID Numbers: NL68037.100.18

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No