Liver Cancer. Su Jong Yu, M.D. Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine

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1 Liver Cancer Su Jong Yu, M.D. Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine

2 Primary Liver Cancer Hepatocellular carcinoma (HCC) : > 80% Derived from hepatocytes Cholangiocarcinoma (CC) : about 15% Derived from biliary epithelial cells Combined HCC-CC : 1.0% 14.3%

3 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 No effective systemic Tx

4 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

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

6 HCC occurrence in Chronic Liver Disease Tumor factor (size, number, location, vascularity) Underlying liver function Invasiveness & cost of Tx

7 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:

8 Characteristics of HCC Hypervascularity & Washout

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

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

11 Impact on survival of EHM in HCC Lee HS. Dig Dis 2011;29:

12 Sites of Extrahepatic HCC Site 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 16 (11%) 9 / 16 (56%) Brain 3 (2%) 3 / 3 (100%) Rectum 2 (1%) 0 / 2 (0%) Spleen 2 (1%) 1 / 2 (50%) Diaphragm 2 (1%) 2 / 2 (100%) Duodenum 1 (1%) 1 / 1 (100%) Esophagus 1 (1%) 1 / 1 (100%) Pancreas 1 (1%) 1 / 1 (100%) Seminal vesicle 1 (1%) 1 / 1 (100%) Bladder 1 (1%) 1 / 1 (100%) Katyal S et al. Radiology 2000;216:

13 Schematic review of immunotherapy in HCC Adoptive T, NK cell based therapy mab targeting critical pathway VEGF, EGFR Immunostimulating mab Co-stimulatory mab Anti-CD28, CD137, CD40 Co-inhibitory mab anti-ctla-4, anti-pd-1, B7-H1 Recombinant Cytokines IFN-α, IL-2, GM-CSF, TNF-α Cancer Vaccines targeting tumor antigen AFP Dendritic Cells Loaded with tumor antigens Peptides, tumor lysate, mrna Engineered DCs IL-12, CD40-L, IL-15

14 Cancer Research 2004;64:

15 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: Cheng AL et al., Asia-Pacific trial Lancet Oncol 2009;10:25-34

16 Heterogeneity in HCC 1. Etiologies: HBV, HCV, Alcohol, NAFLD, aflatoxin Tumor type: Nodular vs. Infiltrative VS Nodular Infiltrative

17 Heterogeneity in HCC Multiple synchronous tumor (multicentric occurrence) No common somatic mutations were identified in the multicentric tumor pairs suggesting that these tumors developed from independent mutations Nature Genetics 2012:44;760

18 Intratumor heterogeneity in HCC

19 Intratumor heterogeneity in HCC 5/23 (22%) 6/23 (26%) 9/23 (39%) Clin Cancer Res September 23, 2014

20 Intratumor heterogeneity in HCC Clin Cancer Res September 23, 2014

21 Intratumor heterogeneity in HCC Clin Cancer Res September 23, 2014

22 Seven independent gene signatures predict concordant outcome groups in HCC Front. Cell Dev. Biol., 03 April 2014 doi: /fcell

23 A model depicts the relationship btw the biological space & the prognostic space Front. Cell Dev. Biol., 03 April 2014 doi: /fcell

24 Tumor initiation and metastasis in HCC based on CSC model Semin Oncol 39:

25 Signaling pathways altered in hepatic CSCs Semin Oncol 39:

26 Therapeutic strategies targeting CSCs in HCC Semin Oncol 39:

27 Strategies to eradicate liver CSCs Liver Cancer 2014;3:71 84

28 Overview of cross-talk btw EpCAM signaling & Wnt pathway Liver Cancer 2014;3:71 84

29 Potential translation of molecular knowledge of HCC in clinical practice Semin Liver Dis 2014;34:

30 Resistance to Targeted Therapies Molecular targeted therapies are liable to generate acquired drug resistances the alterations targeted by the drug tumor cells may trigger drug resistance mechanisms after the initial drug response crizotinib designed to inhibit the fusion protein EML4-ALK in nonsmall-cell lung cancer vemurafenib directed to B-Raf in melanoma

31 Resistance to Targeted Therapies Approaches to overcome this merging strategies based on combining drugs specifically targeting drivers and broad spectrum drugs based on the molecular classification of the patients Generating second-generation drugs circumventing acquisition of resistance mechanisms

32 Take Home Messages Cirrhosis is an almost invariable precursor to HCC, except in chronic hepatitis B HCC : hypervascularity & washout on image only arterial blood supply Frequent intrahepatic recurrence after curative Tx Frequent EHM: Lung, LN, Bone, Adrenal, Effective systemic therapies (?) Intratumor heterogeneity Cancer Stem Cells: Wnt/β-catenin pathway