Background:
Primary liver cancer (PLC) is the 2nd most common cause of cancer-related death worldwide
and the one cancer with the fastest rising incidence and mortality in the U.S. PLC
consists of two main histological subtypes, i.e., hepatocellular carcinoma (HCC) and
cholangiocarcinoma (CCA), in which diagnoses and treatment decisions are solely based on
their baseline clinical features. However, whether these subtypes are truly distinct or
share some fundamental features which can be pursued to improve clinical management is
currently unclear. In addition, chronic liver diseases, due to complex etiologies such as
viral hepatitis, alcohol consumption, chemicals, parasites or dietary factors, underlie
and contribute to liver damage, increasing the risk of HCC and CCA development and
progression. Consequently, PLC is clinically and biologically heterogeneous which has
impeded biological assessment and clinical treatment.
Despite considerable efforts towards improving diagnosis and development of new treatment
modalities, the improvement of PLC patient survival is minimal. For certain patients at
early or intermediate disease stages, resection and percutaneous local ablation or
Transarterial chemoembolization are available. However, the majority of patients present
at advanced stages of disease, where the current gold standard of treatment is sorafenib,
providing only a minimal improvement in survival time. PLC therefore remains among the
most difficult-to-treat malignancies, with a 5-year survival rate of less than 15% in the
United States. Thus, it is imperative that new treatment modalities are developed to
limit cancer development and treat advanced PLC.
Immunotherapy (IO) is a promising new approach in PLC treatment. Alterations of the
immune system, a component of the revised hallmarks of cancer, is recognized as a central
player in carcinogenesis and cancer progression. Thus, strategies to inhibit or re-direct
the immune response to the presence of tumors are currently being employed or developed.
Immune-checkpoint inhibitors have shown promise in clinical trials of several solid
tumors. Of particular note are monoclonal antibody-based therapy to block
immune-inhibitory molecules, including programmed cell death protein-1 (PD-1), programmed
cell death 1 ligand 1 (PDL-1) and cytotoxic T lymphocyte antigen 4 (CTLA4), which block
anti-tumor T cell activity. However, the capacity of these therapies to reduce incidence
and progression of PLC are still relatively unknown. Currently, several trials are
underway to study the impact of immune checkpoint inhibitors as single agents or in
combination with targeted therapy, on PLC development and outcome. Initial findings from
Phase I/II clinical trials of PLC are promising but suggest that only certain patients
respond to such treatment regimens while others do not or suffer from resistance/relapse.
At the moment, it is difficult to determine which patient may benefit from immune
therapy, due in large part to the lack of large comprehensive studies, biobank resources
of specimens and biospecimen collection in clinical trial protocols, which deter our
ability to understand and define critical genomic or genetic factors that contribute to
patient response. Hence, we plan to collect PLC patient specimens and clinical data from
those undergoing immunotherapies at NIH Clinical Center and a few extramural clinical
sites to develop predictors for (a) response or resistance to immunotherapy and (b)
acquired resistance to immunotherapy.
Objective:
To establish a biospecimen repository for genomic, genetic and epigenetic analysis to
study the biology of PLC development and progression.
Eligibility:
Patients with histologically/ultrasound/imaging confirmed or suspicious lesions of HCC or
CCA.
Patients with planned or a history of at least 1 dose of immunotherapy for HCC or CCA.
Age >= 18 years old at date of study consent
Design:
This will be a long-term multi-center study to comprehensively study patients with
primary liver cancer (PLC).
Participants will provide clinical information (including medical history, clinical
tests, imaging studies and reports, surgical pathology reports, genetic test results).
Tissue samples, blood, urine and fecal samples will be obtained from participants during
this study.
Broad spectrum of scientific experiments, including genomics, metabolome, microbiome and
immune monitoring will be performed.
Local physicians will be provided with test results of genomics panel evaluation
(TruSight Oncology 500 (TSO-500).
Since long-term follow-up of individuals with PLC is a major feature of the study, local
sites intend to maintain active contact with study subjects for as long as possible.
Patients will be followed throughout the course of their illnesses, with particular
attention to patterns of disease recurrence and progression, response to therapies and
duration of responses. National death index data can also be utilized to obtain patient
outcome information.
