Hepatocelluar carcinoma Young Youn Cho, M.D. Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine

Hepatocellular carcinoma (HCC) The 5th most common cancer worldwide The 3rd leading cause of cancer-related deaths Hypervascular tumor “Two diseases” in One organ Intrahepatic recurrence Extrahepatic metastasis

1. RADIOLOGIC DIAGNOSIS WITHOUT BIOPSY

Diagnosis of HCC EASL Clinical Guidelines

Diagram of the mechanism underlying changes in drainage vessels (top) and histologic features (bottom) of HCC during multistep hepatocarcinogenesis Kitao A et al. Radiology 2009;252:605-614

Characteristics of HCC Hypervascularity & Washout

2. INFLAMMATORY TUMOR

The main risk factors for HCC Hepatitis B Hepatitis C Alcoholism Cirrhosis of the liver Non-alcoholic steatohepatitis Type 2 diabetes (probably aided by obesity) Aflatoxin Iron and copper deposition SNUBH

Cirrhosis is a major risk factor of HCC HBV >> HCV, hepatic adenoma, hereditary tyrosinemia Noncirrhotic Pathway Chronic hepatitis LC HCC LC in chronic hepatitis pts 10-20% / 5 yr HCC in LC pts : 1-5% / yr

Pathophysiology of HCC in hepatitis B

Local intra-hepatic inflammation promote hepatocarcinogenesis Cell. 2010 Jan 22;140(2):197-208.

3. HIGH RATE OF RECURRENCE AFTER CURATIVE TREATMENTS

HCC Recurrence rate after resection 5Yr Survival rate: 50-70% 5Yr Recurrence rate: 60-80% H. Imamura et al. Journal of Hepatology 2003;38:200-207

Bimodal recurrence after HCC resection H. Imamura et al. Journal of Hepatology 2003;38:200-207

Early recurrence; intrahepatic metastasis de novo carcinogenesis Late recurrence; de novo carcinogenesis New lesion Intrahepatic microscopic metastatic foci

Sorafenib adjuvant treatment failed - STORM trial Lancet. 2015 Oct, p1344–1354,

HBV treatment reduces RFS J Clin Oncol. 2013 Oct 10;31(29):3647-55.

CIK immunotherapy Gastroenterology. 2015 Jun;148(7):1383-91.e6

4. IMMUNOLOGIC TUMOR?

Sites of Extrahepatic HCC No of Pt. (N=148) No of Pt. with Other metastatic sites at initial Presentation Lungs 81 (55%) 23 / 81 (28%) Lymph Nodes 78 (53%) 56 / 78 (72%) Bone 41 (28%) 27 / 41 (66%) Adrenal 16 (11%) 7 / 16 (44%) Peritoneum +/- omentum 9 / 16 (56%) Brain 3 (2%) 3 / 3 (100%) Rectum 2 (1%) 0 / 2 (0%) Spleen 1 / 2 (50%) Diaphragm 2 / 2 (100%) Duodenum 1 (1%) 1 / 1 (100%) Esophagus Pancreas Seminal vesicle Bladder Katyal S et al. Radiology 2000;216:698-703

Current guidelines : BCLC classification EASL Clinical Guidelines

Mechanism of Sorafenib Cancer Research 2004;64:7099-7109

Sorafenib in Advanced HCC SHARP trial Asia-Pacific trial Median Survival : 10.7 vs 7.9 months Median Survival : 6.5 vs 4.2 months Llovet JM et al., Sorafenib in Advanced HCC NEJM 2008;359:378-90 Cheng AL et al., Asia-Pacific trial Lancet Oncol 2009;10:25-34

Landscape of systemic treatment in hepatocellular carcinoma

Targets of Regorafenib Journal of Cancer Therapy Vol.4 No.2A(2013)

Mutational landscape of HCC Note that some mutations may co-exist in the same patient. Data suggest that background etiology impact mutation rate. Most mutations affect 3 genes, TERT promoter, CTNNB1 and TP53. TERT promoter mutations are the most prevalent genetic event both in HCC and pre-neoplastic lesions (dysplastic nodules) and correlate with aberrant TERT expression. J Hepatol. 2016 Nov;65(5):1031-1042

Locoregional treatments induce immunologic response Clin Cancer Res. 2013 December 15; 19(24):

Recur after cryoablation PLoS One. 2011;6(9):e23621.

HCV infection associated with T-cell exhaustion Adaptive immune responses associated with differential outcome of acute HCV infection. A strong and maintained CD4 T cell response appears to be a critical factor for the outcome of acute HCV infection. In its presence, HCV–specific CD8 T cell populations with an initially “stunned” phenotype acquire multiple effector functions (upper panel). In the absence or loss of a strong CD4 T cell response, CD8 T cells develop exhausted phenotypes, which are attributed to chronic antigen-specific stimulation. Those CD8 T cells that target HCV escape variants remain functional with a memory phenotype in the chronic phase of infection (see text for details). Treg, regulatory T cell. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are associated with manifestations of immune suppression, including upregulation of programmed death-1 (PD-1) receptor,7 T-cell exhaustion, and spontaneous apoptosis of immune cells8 Immunity. 2014 January 16; 40(1): 13–24.

Nivolumab (mAb to PD-1 receptor): interim analysis of phase I/II study Objective responses occurred in 35 of 214 (16%) patients Response occurred regardless of PD-L1 status Nivolumab is a fully human IgG4 monoclonal antibody to the PD-1 receptor, blocking the interaction with PD-L1/PD-L213 and restoring T-cell–mediated antitumor activity Objective responses occurred in 35 of 214 (16%) patients (Table 4) •PD-L1 expression on tumor cells, as assessed by immunohistochemistry, was quantifiable in 128 patients and responses occurred regardless of PD-L1 status (ORR = 5/26 [19%] patients with PD-L1 ≥ 1% and 20/102 [20%] patients with PD-L1 < 1%). For patients without quantifiable PD-L1 expression data, the ORR was 10/86 (12%)  In the study, responses were frequently delayed, with a complete response occurring after 24 months of treatment. When considering those with stable disease, the disease control rate was 65%.  ASCO 2016

Take Home Messages Radiologic diagnosis : hypervascularity & washout on image Inflammatory tumor : Cirrhosis is an almost invariable precursor to HCC, except in chronic hepatitis B Frequent intrahepatic recurrence after curative Tx Immunologic tumor ? Future treatment focus on immunotherapy