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HBV-host cfDNA as Minimal Residual Tumor Marker for HBV-related HCC

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ClinicalTrials.gov Identifier: NCT03020342
Recruitment Status : Recruiting
First Posted : January 13, 2017
Last Update Posted : January 13, 2017
Sponsor:
Information provided by (Responsible Party):
National Taiwan University Hospital

Brief Summary:

Early stage HCC is treated by curative surgical resection or by local ablation (such as radio-frequency) as the current standard of care. The complete removal of clinical visible HCC is then confirmed by imaging by MRI or CT, or by a decline of tumor marker (AFP or PIVKA). However, despite an apparent complete removal of the HCC, those post-curative patients frequently develop tumor recurrence at a rate ranging 10-50% within the first year. The high rate of early HCC recurrence indicated a minimal residual HCC after the curative therapies in a significant proportion of patients. A better and more specific biomarker for detecting the residual HCC will improve the patients' prognosis prediction and therapeutic plan.

To detect the minimal residual HCC, a biomarker unique to the tumor is needed. Currently, the cell-free circulating DNA carrying tumor-specific somatic mutations has been advocated as a promising one. It has been applied to investigate the tumor responses or resistances to cancer therapy. However, currently it is restricted to detect or follow only large advanced cancer, because of the difficulty in separating or enriching the cfDNA with tumor-specific mutations from the cfDNA from normal cells. In this project, the investigators proposed that one class of somatic mutation in HBV-related HCC, namely the insertion mutagenesis by integrated HBV DNA, could be adopted to circumvent this difficulty. HBV DNA integration has been found in the chromosomes of about 90% of HBV-related HCC and the integration site is unique to individual HCC. The HBV-host junction DNA fragment from one HCC is therefore a tumor-specific biomarker. Such fragments can be released into the circulation as cell-free circulating DNAs, and the detection of the HBV-host chimera DNAs in the circulation is a reliable evidence for the presence of the tumor in the patient. Therefore the cf circulating HBV-host chimera DNA is proposed to assay any minimal residual HCC after curative therapies.


Condition or disease
Carcinoma, Hepatocellular

Detailed Description:

Development stages:

Stage I: Identification of integrated HBV DNA sites in HBV-related HCC tissues. the investigators will develop either HBV-specific inverse PCRs or capture-sequencing protocols to identify HBV integrations sites in the tumor chromosomes. The viral-host junction sequences of individual HCC identified and used as the template for developing assays for detecting the same HBV-host chimera DNA fragment in the circulation.

Stage II: New platforms to accurately detect or even quantitate the circulating vh-chimera DNA fragment.

These tumor-specific vh-chimera DNA will only represent a tiny fraction of total cfDNAs. However, as these sequences of the tumor-specific vh-chimera DNA have been known from stage 1, the investigators may develop better and more specific assays for quantitation.

Stage III: Assays for cell-free tumor specific vh-chimera DNA applied to the blood samples from post-curative HCC patients.

To demonstrate the efficacy of these assays, blood samples obtained at 4 weeks after curative therapies from 50 HBV-related HCC patients, and tested for the presence of cf tumor-specific vh-chimera DNAs. The presence or absence of such vh-chimera DNA will be correlated with the early HCC recurrence within the first year to determine any clinical significance. There will be one blood sampling at the time of HCC recurrence.

Sample collection In stage I and II, the investigators will set up methods for chimera DNA identification and quantification, which need tumor samples to support the development and evaluation of the feasibility for each assay. Therefore, the investigators will apply the approval for use the tissues from the Taiwan Liver Cancer Network (TLCN), including 20 pairs of HBV-related male HCC, 20 pairs of HBV-related female HCC (for positive control), 20 pairs of HCV related male HCC, 20 pairs of HCV related female HCC (for negative control), 20 pairs of HBV- and HCV-related male HCC, and 20 pairs of HBV- and HCV-related female HCC (to see if vh-chimera DNA is also applicable for HBV- and HCV-related HCC). Both the genomic DNA and RNA will be applied for these 120 patients in total. Genomic DNA will be used in assay development, including identification, detection and quantification; whereas RNA will be used in validation of the insertional mutagenic RNA transcripts, which will provide supporting evidence for tumor specific integration from transcription level.

In stage III, the investigators will investigate whether there is any correlation between tumor-specific vh-chimera DNA level and recurrence-free survival using the assays the investigators developed in stage I and II. Therefore, the investigators will collect the Tumor (T) and non-Tumor (NT) tissue pairs from 50 HBV-related HCC patients that receive surgical removal of tumor, and also the peripheral blood at 4w after surgery. T and NT tissues are for vh-chimera DNA identification, peripheral blood will be used for vh-chimera DNA detection and quantification. On the other hand, clinical information including tumor size, tumor grade, serum markers from routine liver function test (ALT, AST), current HCC marker (AFP), and recurrence-free survival time will be collected for correlation study. All data will be stored in computer with password protection.


Study Type : Observational
Estimated Enrollment : 50 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: A New Biomarker for Detection of Minimal Residual Tumor in Hepatitis-B Virus Related Hepatocellular Carcinoma After Curative Therapies: The Cell-free Circulating HBV-host Chimera DNA Fragment
Study Start Date : May 2016
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : January 2019



Primary Outcome Measures :
  1. vh-chimera DNA [ Time Frame: week 4 after surgery. ]
    Detection of the HBV-host chimera DNA in blood sample.----- one blood sampling at the time of HCC recurrence.


Secondary Outcome Measures :
  1. Tumor size (measured in the longest dimension in cm) [ Time Frame: after medical imaging or pathology report completion, up to 2 weeks. ]
    clinical information about HCC recurrence. detection by CT or MRI.

  2. tumor grade (Grades I-IV) [ Time Frame: after medical imaging or pathology report completion, up to 2 weeks. ]
    clinical information about HCC recurrence. detection by CT or MRI.

  3. recurrence-free survival time ----measurement in weeks [ Time Frame: from the date of surgery until the date of first documented HCC recurrence or date of death from any cause, whichever came first, assessed up to 24 months ]
    clinical information about HCC recurrence.


Other Outcome Measures:
  1. Routine liver function test (ALT in IU/L) [ Time Frame: week 4 after surgery, ---- one blood sampling at the time of HCC recurrence. ]
    serum markers.

  2. Routine liver function test (AST in IU/L) [ Time Frame: week 4 after surgery, ---- one blood sampling at the time of HCC recurrence. ]
    serum markers.

  3. current HCC marker (AFP ng/ml) [ Time Frame: week 4 after surgery, ---- one blood sampling at the time of HCC recurrence. ]
    serum markers.(ALT and AFP)


Biospecimen Retention:   Samples With DNA
Tumor (T) and non-Tumor (NT) tissue, and peripheral blood.


Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
HBV-related HCC patients that receive surgical removal of tumor.
Criteria

Inclusion Criteria:

  • HBV-related HCC patients that receive surgical removal of tumor.

Exclusion Criteria:

  • unsuitable for surgery.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03020342


Contacts
Contact: Pei-Jer Chen, MD-PhD +886-2-23123456 ext 67072 peijerchen@ntu.edu.tw
Contact: Shiou-Hwei Yeh, Ph.D. +886-2-23123456 ext 66644 shyeh@ntu.edu.tw

Locations
Taiwan
National Taiwan University Hospital Recruiting
Taipei, Taiwan, 100
Contact: Pei-Jer Chen, MD/PhD    +886-2-23123456 ext 67072    peijerchen@ntu.edu.tw   
Contact: Shiou-Hwei Yeh, PhD    +886-2-23123456 ext 66644    shyeh@ntu.edu.tw   
Sponsors and Collaborators
National Taiwan University Hospital
Investigators
Principal Investigator: Pei-Jer Chen, MD-PhD National Taiwan University Hospital

Responsible Party: National Taiwan University Hospital
ClinicalTrials.gov Identifier: NCT03020342     History of Changes
Other Study ID Numbers: 201510056RINA
First Posted: January 13, 2017    Key Record Dates
Last Update Posted: January 13, 2017
Last Verified: January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by National Taiwan University Hospital:
HCC
chimera DNA
circulating DNA
biomarker

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Hepatocellular
Neoplasm, Residual
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Neoplastic Processes
Pathologic Processes