Clinical trial NCT05752890: A Novel Biomarker for Response and Prognosis of HBV-related Hepatocellular Carcinoma
Official title: Developing a Novel Biomarker for Response and Prognosis of HBV-related Hepatocellular Carcinoma Treated With Radiotherapy: Personalized Cell-free Virus-host Chimera DNA
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Hepatocellular Carcinoma
Hepatitis b Virus
Radiotherapy
Biomarker
Keywords: Hepatocellular Carcinoma
Hepatitis b Virus
Radiotherapy
Chimera DNA
Biomarker
Lead sponsor: National Taiwan University Hospital
Sponsor class: OTHER
First posted: 2023-03-03
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: we have been prospectively collecting plasma samples from HBV-related HCC patients before/after RT, at 1, 4, 7 months, and at recurrence/metastasis.

Brief summary: The investigators will first use our previously collected serum samples and surgical/biopsied tissues from HBV-related HCC patients undergoing radiotherapy. The consistency of junctional clones by Capture NGS needs to be tested between both pre- and post-RT serums, and serial changes in copy numbers of vh-DNA by ddPCR are quantified in the representative cases. The same junction clones from pre-post-RT serums and surgical tissues will be confirmed and the copy number changes of vh-DNA be correlated with RT response and disease-control status.

The investigators plan to identify HBV integrations by Capture NGS and quantify the specific vh-DNA by ddPCR as personalized biomarkers from the same-patient serum samples. The investigators will further correlate clinical response and recurrence/metastasis with serial changes of vh-DNA copy numbers. The investigators have been prospectively collecting plasma samples from HBV-related HCC patients before/after RT, at 1, 4, 7 months, and at recurrence/metastasis. The investigators plan to confirm the viable role of pre-/post-RT changes of plasma vh-DNA copies of the same junction clone in post-RT response and prognosis. Moreover, The investigators will explore the recurrent/metastatic tumors arising from the original or a de novo one by identifying their clonality with HBV integration patterns. The true value of this novel HBV chimera vh-DNA will be revealed. The results will also support the consolidative use of personalized vh-DNA for earlier evaluating treatment response after RT, for post-RT disease monitoring, and for differentiating clonality at recurrence to design future clinical trial on combinational treatment.

Detailed description: Residual tumors and early recurrence/metastasis after radiotherapy (RT) compromise the patient survival with hepatocellular carcinoma (HCC). Timely detecting residual/recurrence/metastasis and the clonality is required to implement salvage therapies properly. The major unmet needs of radiotherapy to HCC are the difficulties in early evaluating response by images and timely detection of intrahepatic recurrence and extrahepatic metastasis. Thus, an accurate and personalized biomarker for response prediction and disease monitoring is demanded. Cell-free tumor-specific DNA (ctDNA) has garnered attention as a promising biomarker in cancer patients. However, in HCC, the detection rate is low (9-21.2%), mainly due to the limited prevalence of traditional somatic mutations and the difficult separation of ctDNA fragments from normal cells. The investigators aim to develop a novel ctDNA, the virus-host chimera DNA (vh-DNA), as a biomarker for hepatitis B virus (HBV)-related HCC patients undergoing RT. HBV vh-DNA presents in \~90% of HBV-related HCC patients and can be differentiated from DNA released from the normal cells through enrichment by capturing with HBV probes. vh-DNA might be advantageous to the traditional somatic mutation type of ctDNA. The investigators hypothesize that HBV vh-DNA could accurately diagnose residual tumor by 6-12 months earlier than contemporary images and predict early recurrence/metastatsis, thus allows early intervention of salvage therapies.

The investigators will first use our previously collected serum samples and surgical/biopsied tissues from HBV-related HCC patients undergoing radiotherapy. The consistency of junctional clones by Capture NGS needs to be tested between both pre- and post-RT serums, and serial changes in copy numbers of vh-DNA by ddPCR are quantified in the representative cases. The same junction clones from pre-post-RT serums and surgical tissues will be confirmed and the copy number changes of vh-DNA be correlated with RT response and disease-control status.

The investigators plan to identify HBV integrations by Capture NGS and quantify the specific vh-DNA by ddPCR as personalized biomarkers from the same-patient serum samples. The investigators will further correlate clinical response and recurrence/metastasis with serial changes of vh-DNA copy numbers. The investigators have been prospectively collecting plasma samples from HBV-related HCC patients before/after RT, at 1, 4, 7 months, and at recurrence/metastasis. The investigators plan to confirm the viable role of pre-/post-RT changes of plasma vh-DNA copies of the same junction clone in post-RT response and prognosis. Moreover, The investigators will explore the recurrent/metastatic tumors arising from the original or a de novo one by identifying their clonality with HBV integration patterns. The true value of this novel HBV chimera vh-DNA will be revealed. The results will also support the consolidative use of personalized vh-DNA for earlier evaluating treatment response after RT, for post-RT disease monitoring, and for differentiating clonality at recurrence to design future clinical trial on combinational treatment.

Eligibility criteria: Inclusion Criteria:

1. Patients diagnosed with HCC by dynamic image criteria and/or biopsy
2. HBsAg (+)
3. Child-Turcotte-Pugh (CTP) class A-B liver function
4. Radiotherapy to liver tumor as the main treatment

Exclusion Criteria:

1. Child-Turcotte-Pugh (CTP) class C liver functiECOG performance status score \>2
2. Has had prior radiotherapy to the proposed treatment field.
3. \< 18 years old

Primary outcomes:
measure: To retrospectively analyze the Capture-NGS analysis from HBV-related HCC patients
timeFrame: 2031/01/01
measure: To retrospectively analyze the Vh-DNA specific PCR from HBV-related HCC patients
timeFrame: 2031/01/01
measure: To retrospectively analyze the serial changes of serum vh-DNA copies of same junction clone from HBV-related HCC patients
timeFrame: 2031/01/01
measure: To retrospectively analyze the serial changes of survival of same junction clone from HBV-related HCC patients
timeFrame: 2031/01/01
measure: To prospectively test the concordance of vh-DNA copies between serum and plasma samples
timeFrame: 2031/01/01
measure: To prospectively analyze the serial changes of plasma vh-DNA copies of same junction clone are associated with treatment response
timeFrame: 2031/01/01
measure: To prospectively analyze the serial changes of plasma vh-DNA copies of same junction clone are associated with overall survival
timeFrame: 2031/01/01
measure: To distinguish the clonality of recurrent HCC as the original or a de novo one for post-radiotherapy patterns of failure
timeFrame: 2031/01/01
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Employee
name: Chia-Hsien Cheng
role: PRINCIPAL_INVESTIGATOR
References: