Heterogeneity and Evolution of hepatoceLlular Carcinoma in Post-transplant HCC Recurrence

RenJi Hospital40 enrolled

Overview

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.

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

Conditions

Hepatocellular Carcinoma Recurrent Liver Transplant; Complications

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: up to 2 years

Secondary Outcomes

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

Time frame: 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)

Time frame: up to 3 years