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Vol 20, No. 04, April 2016   |   Issue PDF view/purchase
Improving Overall Survival in Hepatocellular Carcinoma through a Multi-Disciplinary Approach: Intra-Tumoral Heterogeneity, Immunology and the Promise of Better Outcomes
by Dr. Pierce Chow Kah Hoe
National Cancer Center Singapore

Hepatocellular carcinoma (HCC) is the 6th most common cancer in the world and is diagnosed in more than a million new patients a year. It is however the 2nd most important cause of cancer death [1] and the 3rd most important cancer in Asia [2-4]. Surgery is potentially curative in early HCC which applies approximately to only 20% of patients [5] and confers a modest overall survival (OS) of > 60% at 5 years with early cancers defined as those within the Milan criteria. Another 30% may undergo loco-regional therapies such as trans-arterial chemo-embolization (TACE) and Selective Internal Radiation Therapy (SIRT) with median survivals of 18 – 24 months. Untreated patients with intermediate tumour but good liver function survive 6 – 8 months [6,7] and with poor liver function < 3 months [8,9]. Tumour recurrence after surgical resection is > 50% at 5 years even for those with early disease [10] and is responsible for the poor overall surgical survival. Of the common solid cancers, the distinct absence of efficacious systemic therapies for HCC results in poor outcomes for advanced cancer stages, no meaningful adjuvant therapy for resected cases and poor long-term surgical outcomes [11,12].

HCC is a highly heterogeneous cancer with only one systemic therapy namely sorafenib [13] in which its randomized clinical trials showed the survival improved by only 2.3 and 2.8 months in Asian and Western patients respectively [7,14]. The underlying mechanism of sorafenib remains unclear and there is no validated predictive biomarker [15-17]. Therefore, there is an urgent and unmet clinical need to adopt new approaches to identify and develop novel therapeutic options for treating HCC.

Previous approaches to characterize the genomic heterogeneity of HCC (and most other solid cancers) have been based on single tumor samples from retrospective cohorts to identify the presence/ absence of driver alterations. This has not lead to many efficacious therapies [18-24]. Between 2002 and 2012, the 71 anti-cancer drugs approved by FDA (including 52 molecular targeted drugs) have only managed to increase median overall survival by 2.1 months [25,26]. Tumour heterogeneity and specifically Intra-tumour heterogeneity (ITH), is increasingly recognised as being important in drug development strategies in precision medicine for cancer [27]. Previous studies in renal [28], breast [29-31], lung [32], colorectal [33-35], pancreatic [36,37], and glioblastoma cancers [38] have established the presence of significant intra-tumour diversity. However, ITH in HCC has been largely understudied and previously published studies on genetic diversity in HCC did not investigate intra-tumour heterogeneity [21,39].

Recent advances in genomic technology have provided an unprecedented opportunity for longitudinal, spatial and in-depth mapping of tumor samples from surgical resections to reveal genetic variations at the whole genome level. A process of branched tumor evolution [40-42] can be clearly represented by a phylogenetic tree where the trunk represents mutations present in all parts of the tumor and the branches are mutations specific to a particular region [27]. This also reflects relative molecular time acquisition i.e. trunk mutations are acquired prior to branch mutations [43]. With regards to HCC, whole genome sequencing of HCC samples would also have the advantage of analysing hepatitis B virus integration in the genome [44], the hepatitis B virus being one of the most important etiologies in development of HCC.

The inability to identify clonally dominant driver mutations from HCC prevents clinicians from being able to efficaciously select systemic therapy and to personalise therapy to patient. The paucity of efficacious systemic therapy is a main reason for the high case fatality in HCC. Hence there is a compelling need for a more thorough understanding of the genetic heterogeneity of HCC to develop more efficacious therapy. From a therapeutic perspective, targeting clonally dominant driver mutations that are early and constant events on the phylogenetic tree (e.g. KRAS, NRAs, BRAF in colorectal cancer) provides a more effective drug development strategy than considering actionable alterations as being present or absent.

The study of Totoki et al shows similarly significant differences in mutational signatures between ethnicities. These warrant investigations to determine patterns of inter-ethnic heterogeneity which will inform drug development and help stratify therapy in HCC.

Apart from focusing on the genomics characteristic of HCC tumors, alternative treatment targeting the tumor microenvironment (TME) is also another important theme. Of particular interest is targeting the immune microenvironment of HCC which has shown potential prognostic and therapeutic values in several studies [45-47]. The recent introduction and success in immunotherapy in cancer has revolutionized the field of cancer therapy [48] with approval of anti-CTLA4 and anti-PD-1 for melanoma [49-53]. The effectiveness of various immunotherapies which are currently at various stages of clinical trials in HCC is yet to be determined [54-56]. Cancer immunotherapy has tremendous potential role in treating cancers that are highly heterogeneous at the genomic level and lack of effective systemic therapy like HCC.

Given the paucity of efficacious systemic therapy in HCC, a fresh approach is required for precision medicine in HCC. With that, the impact on healthcare will be significant worldwide especially in countries where HCC is endemic.

Dr. Daniel G. Tenen

Pierce K.H Chow MBBS M.Med (Surgery) FRCSE, FAMS, PhD
Professor, Duke-NUS Graduate Medical School, Singapore
Senior Consultant Surgeon, National Cancer Center Singapore
Senior Consultant Surgeon, Singapore General Hospital
Associate Faculty, Genome Institute of Singapore

[email protected]

Pierce Chow is Senior Consultant Surgical Oncologist and Co-Director (Surgical) of the Comprehensive Liver Cancer Clinic at the National Cancer Centre Singapore. He is concurrently Senior Consultant Surgeon in HPB and Transplant Surgery at the Singapore General Hospital and Professor at the Duke-NUS Graduate Medical School, Singapore.

Professor Chow was the Chapter of Surgeon’s Gold Medalist at the conjoint Royal College of Surgeons of Edinburgh/M.Med (Surgery) examination in 1994 and subsequently completed a clinical fellowship in Liver Transplantation in Australia.

Professor Chow specialises in Hepato-Pancreato-Biliary (HPB) surgery and leads the Program in Translational and Clinical Liver Research at the National Cancer Centre Singapore. This multi-disciplinary and multi-institutional programme of translational and clinical researchers focuses on NAFLD/NASH, the genomics of HCC and applications to precision medicine, and brachytherapy and immunotherapy in HCC.

He co-founded the Asia-Pacific Hepatocellular Carcinoma Trials Group in 1998 and has been the protocol chair of 5 multi-national trials. In 2012 the National Medical Research Council Singapore conferred him the National Outstanding Clinician-Scientist Award for improving clinical outcomes of patients with his research on Liver Cancer.


  1. Cancer Fact Sheet. World Health Organisation, 2015. (Accessed 19 May 2015, 2015, at https://www.who.int/mediacentre/factsheets/fs297/en/.)
  2. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer 2015;136:E359-E86.
  3. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International journal of cancer Journal international du cancer 2010;127:2893-917.
  4. Bosetti C, Turati F, La Vecchia C. Hepatocellular carcinoma epidemiology. Best practice & research Clinical gastroenterology 2014;28:753-70.
  5. Akoad ME, Pomfret EA. Surgical Resection and Liver Transplantation for Hepatocellular Carcinoma. Clinics in liver disease 2015;19:381-99.
  6. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in Advanced Hepatocellular Carcinoma. New England Journal of Medicine 2008;359:378-90.
  7. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. The Lancet Oncology 2009;10:25-34.
  8. Chow PK, Tai BC, Tan CK, et al. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial. Hepatology 2002;36:1221-6.
  9. Chow PK, Machin D, Chen Y, et al. Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma. British journal of cancer 2011;105:945-52.
  10. Lim KC, Chow PK, Allen JC, et al. Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria. Annals of surgery 2011;254:108-13.
  11. Chan ES, Chow PK, Tai B, Machin D, Soo K. Neoadjuvant and adjuvant therapy for operable hepatocellular carcinoma. The Cochrane database of systematic reviews 2000:CD001199.
  12. Samuel M, Chow PK, Chan Shih-Yen E, Machin D, Soo KC. Neoadjuvant and adjuvant therapy for surgical resection of hepatocellular carcinoma. The Cochrane database of systematic reviews 2009:CD001199.
  13. Kalyan A, Nimeiri H, Kulik L. Systemic Therapy of Hepatocellular Carcinoma: Current and Promising. Clinics in liver disease 2015;19:421-32.
  14. Shao YY, Shau WY, Chan SY, Lu LC, Hsu CH, Cheng AL. Treatment Efficacy Differences of Sorafenib for Advanced Hepatocellular Carcinoma: A Meta-Analysis of Randomized Clinical Trials. Oncology 2015;88:345-52.
  15. Matsuda Y, Fukumoto M. Sorafenib: complexities of Raf-dependent and Raf-independent signaling are now unveiled. Med Mol Morphol 2011;44:183-9.
  16. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis. Cancer Research 2004;64:7099-109.
  17. Arao T, Ueshima K, Matsumoto K, et al. FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma. Hepatology 2013;57:1407-15.
  18. Jhunjhunwala S, Jiang Z, Stawiski EW, et al. Diverse modes of genomic alteration in hepatocellular carcinoma. Genome Biology 2014;15:436.
  19. Ahn S-M, Jang SJ, Shim JH, et al. Genomic portrait of resectable hepatocellular carcinomas: Implications of RB1 and FGF19 aberrations for patient stratification. Hepatology 2014;60:1972-82.
  20. Fujimoto A, Totoki Y, Abe T, et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nature genetics 2012;44:760-4.
  21. Schulze K, Imbeaud S, Letouze E, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nature genetics 2015;47:505-11.
  22. Cleary SP, Jeck WR, Zhao X, et al. Identification of driver genes in hepatocellular carcinoma by exome sequencing. Hepatology 2013;58:1693-702.
  23. Totoki Y, Tatsuno K, Covington KR, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nature genetics 2014;46:1267-73.
  24. Totoki Y, Tatsuno K, Yamamoto S, et al. High-resolution characterization of a hepatocellular carcinoma genome. Nature genetics 2011;43:464-9.
  25. Light DW, Lexchin J. Why do cancer drugs get such an easy ride?; 2015.
  26. Fojo T, Mailankody S, Lo A. Unintended consequences of expensive cancer therapeutics-the pursuit of marginal indications and a me-too mentality that stifles innovation and creativity: the John Conley Lecture. JAMA otolaryngology-- head & neck surgery 2014;140:1225-36.
  27. McGranahan N, Swanton C. Biological and Therapeutic Impact of Intratumor Heterogeneity in Cancer Evolution. Cancer Cell 2015;27:15-26.
  28. Gerlinger M, Horswell S, Larkin J, et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nature genetics 2014;46:225-33.
  29. Martelotto L, Ng C, Piscuoglio S, Weigelt B, Reis-Filho J. Breast cancer intra-tumor heterogeneity. Breast Cancer Research 2014;16:210.
  30. Cottu P, Asselah J, Lae M, et al. Intratumoral heterogeneity of HER2/neu expression and its consequences for the management of advanced breast cancer. Ann Oncol 2008;19:595 - 7.
  31. Heselmeyer-Haddad K, Berroa Garcia L, Bradley A, et al. Single-cell genetic analysis of ductal carcinoma in situ and invasive breast cancer reveals enormous tumor heterogeneity yet conserved genomic imbalances and gain of MYC during progression. Am J Pathol 2012;181:1807 - 22.
  32. Zhang J, Fujimoto J, Wedge DC, et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science (New York, NY) 2014;346:256-9.
  33. Raimondi C, Nicolazzo C, Gradilone A, et al. Circulating tumor cells: exploring intratumor heterogeneity of colorectal cancer. Cancer biology & therapy 2014;15:496-503.
  34. Losi L, Baisse B, Bouzourene H, Benhattar J. Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. Carcinogenesis 2005;26:916-22.
  35. Giaretti W, Rapallo A, Sciutto A, et al. Intratumor heterogeneity of k-ras and p53 mutations among human colorectal adenomas containing early cancer. Analytical cellular pathology : the journal of the European Society for Analytical Cellular Pathology 2000;21:49-57.
  36. Hessman O, Skogseid B, Westin G, Akerstrom G. Multiple allelic deletions and intratumoral genetic heterogeneity in men1 pancreatic tumors. The Journal of clinical endocrinology and metabolism 2001;86:1355-61.
  37. Campbell PJ, Yachida S, Mudie LJ, et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 2010;467:1109-13.
  38. Sottoriva A, Spiteri I, Piccirillo SG, et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proceedings of the National Academy of Sciences of the United States of America 2013;110:4009-14.
  39. Friemel J, Rechsteiner M, Frick L, et al. Intratumor heterogeneity in hepatocellular carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 2015;21:1951-61.
  40. Navin N, Kendall J, Troge J, et al. Tumour evolution inferred by single-cell sequencing. Nature 2011;472:90 - 4.
  41. Yates LR, Campbell PJ. Evolution of the cancer genome. Nature reviews Genetics 2012;13:795-806.
  42. Swanton C. Intratumor heterogeneity: evolution through space and time. Cancer Res 2012;72:4875-82.
  43. Yap TA, Gerlinger M, Futreal PA, Pusztai L, Swanton C. Intratumor heterogeneity: seeing the wood for the trees. Science translational medicine 2012;4:127ps10.
  44. Sung WK, Zheng H, Li S, et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nature genetics 2012;44:765-9.
  45. Chew V, Chen J, Lee D, et al. Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma. Gut 2012;61:427-38.
  46. Chew V, Tow C, Teo M, et al. Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol 2010;52:370-9.
  47. Chew V, Tow C, Huang C, et al. Toll-like receptor 3 expressing tumor parenchyma and infiltrating natural killer cells in hepatocellular carcinoma patients. Journal of the National Cancer Institute 2012;104:1796-807.
  48. Neves H, Kwok HF. Recent advances in the field of anti-cancer immunotherapy. BBA Clinical 2015;3:280-8.
  49. Ascierto PA, Marincola FM. 2015: The Year of Anti-PD-1/PD-L1s Against Melanoma and Beyond. EBioMedicine 2015;2:92-3.
  50. Simeone E, Ascierto PA. Immunomodulating antibodies in the treatment of metastatic melanoma: The experience with anti-CTLA-4, anti-CD137, and anti-PD1. Journal of Immunotoxicology 2012;9:241-7.
  51. Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research 2011;17:6958-62.
  52. Cameron F, Whiteside G, Perry C. Ipilimumab: first global approval. Drugs 2011;71:1093-104.
  53. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science (New York, NY) 2013;342:1432-3.
  54. Cancer Immunotherapy: Liver Cancer. 2014. (Accessed 03/08/2015, 2015, at https://www.cancerresearch.org/cancer-immunotherapy/impacting-all-cancers/liver-cancer.)
  55. Hong YP, Li ZD, Prasoon P, Zhang Q. Immunotherapy for hepatocellular carcinoma: From basic research to clinical use. World J Hepatol 2015;7:980-92.
  56. Pardee AD, Butterfield LH. Immunotherapy of hepatocellular carcinoma: Unique challenges and clinical opportunities. Oncoimmunology 2012;1:48-55.

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