Heterogeneity and Evolution of hepatoceLlular Carcinoma in Post-transplant HCC Recurrence (HELP-2020)

Translational Study of Molecular-subtype Heterogeneity and Evolution Pattern in Patients With hepatoceLlular Carcinoma Post-transplant Relapse - HELP 2020 Cohort Study

Objective of Study: This study will evaluate the heterogeneity and evolution pathway between primary HCC and tumor relapse after liver transplant.

According to the "Seed-Soil" theory, the primary hypothesis of this study is that HCC patients with different molecular-subtype experience altered different pattern of post-transplant recurrence, thus may have altered postoperative Recurrence-Free Survival (RFS). Because the donors' liver construct different microenvironment for CTC(circulating tumor cells) colonization. The investigators design this translational study to ①explore potential high recurrent risk HCC molecular-subtypes which might benefit from neoadjuvant systematic therapy or early adjuvant systematic therapy;②identify the molecular subtype heterogeneity of primary and recurrent HCC to guide the precision medicine.

Study Overview

• Status: Recruiting
• Conditions: Liver Transplant; Complications; Hepatocellular Carcinoma Recurrent
• Intervention / Treatment: Procedure: liver transplant; Diagnostic test: whole exome sequencing; Diagnostic test: ctDNA

Detailed Description

40 specimens will be obtained from the primary tumor during liver transplant surgery and biopsy/specimens from intrahepatic tumor or lung metastasis when the patients experience postoperative relapse. The molecular-subtype of HCC will be determined via whole exom sequence(WES), immunohistochemistry(IHC) and RNA-Seq.

• Study Type: Observational
• Enrollment (Anticipated): 40

Contacts and Locations

• Study Contact: Name: Zijie Zhang; Phone Number: 008615026626518; Email: sjtuzzj@163.com

Study Locations

• China
  • Shanghai, China, 200127
    • Recruiting
    • Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Cohort 1: HCC patients experienced post-transplant HCC Cohort 2: High recurrence-risk HCC patients who underwent liver transplant

Description

Inclusion Criteria:

• Patients must have pathologically or cytologically or by radiological criteria proven hepatocellular carcinoma; known mixed histology (e.g. hepatocellular carcinoma plus cholangiocarcinoma) or fibrolamellar variant is not allowed
• Patients have post-transplant HCC recurrence(cohort 1), Indication for being an candidate in the waiting list for liver transplant according to multidisciplinary board evaluation(cohort 2)
• The time frame between liver transplant and diagnosis of post-transplant HCC recurrence> 6 months
• No prior hepatectomy or systemic therapy or local therapy (TACE etc.)

Exclusion Criteria:

• History of oncological systemic treatment
• early recurrence(<6 months)
• multiple organ transplantation

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Retrospective cohort; 20 HCC patients experienced post-transplant HCC	Procedure: liver transplant; Liver transplantation for hepatocellular carcinoma has the potential to eliminate both the tumor as well as the underlying cirrhosis and is the ideal treatment for HCC in cirrhotic liver as well as massive HCC in noncirrhotic liver.; Diagnostic test: whole exome sequencing; xome sequencing analysis of liver tumors could reveal mutational signatures associated with specific risk factors of recurrence.
Perspective cohort; 20 HCC patients who underwent liver transplant, the patients would be recruited if recurrence would be diagnosed >6 months after liver transplant	Procedure: liver transplant; Liver transplantation for hepatocellular carcinoma has the potential to eliminate both the tumor as well as the underlying cirrhosis and is the ideal treatment for HCC in cirrhotic liver as well as massive HCC in noncirrhotic liver.; Diagnostic test: whole exome sequencing; xome sequencing analysis of liver tumors could reveal mutational signatures associated with specific risk factors of recurrence.; Diagnostic test: ctDNA; Circulating Tumor DNA Correlates With Microvascular Invasion and Predicts Tumor Recurrence of Hepatocellular Carcinoma

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
molecular-subtype heterogeneity between primary HCC and post-transplant HCC recurrence	It is defined as the change of HCC molecular subtype by comparing the primary tumor with intrahepatic or intrapulmonary recurrent tumor.	up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
molecular-subtype	I.Progenitor Type: defined by the transcriptional and protein overexpression of hepatic progenitor markers, inactivating mutations in RPS6KA3 and AXIN1 and hyperphosphorylation of ERK. The main signalling pathways specifically activated in the progenitor subclass are IGF1R and AKT. II.TGFβ-Wnt Type: characterised by activation of both TGFβ and Wnt pathways and an exhausted immune response. Also, an enrichment in TP53 inactivating mutations, amplification of FGF19 and CCND1, as well as frequent activation of pro-survival signalling pathways including cell cycle, mTOR, RAS-MAPK and MET can be detected. III.G4 Type: It frequently harbour a steatohepatitic phenotype, as well as exhibiting activation of the IL6/JAK-STAT pathway. IV.CTNNB1 Type: a subset of HCC harbouring CTNNB1 mutations. TERT promoter mutations are more frequent in this subclass	up to 2 years
Recurrence-Free Survival (RFS)	RFS is defined as the time from inclusion to first documentation of disease recurrence (intrahepatic or intrapulmonary) as assessed by BICR or by pathology consistent with HCC if required per the site's standard of care, or death due to any cause (both cancer and non-cancer causes of death)	up to 3 years

Collaborators and Investigators

• Sponsor: RenJi Hospital
• Investigators: Study Director: Hao Feng, M.D., Ph.D., Dept. of Liver surgery, Renji Hospital, Medical School of Shanghai Jiaotong University

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 10, 2020
• Primary Completion (ANTICIPATED): August 1, 2021
• Study Completion (ANTICIPATED): August 1, 2022

Study Registration Dates

• First Submitted: August 6, 2020
• First Submitted That Met QC Criteria: August 6, 2020
• First Posted (ACTUAL): August 10, 2020

Study Record Updates

• Last Update Posted (ACTUAL): June 24, 2021
• Last Update Submitted That Met QC Criteria: June 21, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: Renji-IIT-2020-0007

Drug and device information, study documents

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