ILCA Special Interest Groups (SIGs) Luncheon Workshops

12:45–14:00, Saturday, 10 September 2016

SIG 1: Molecular Classification and Signalling Pathways

Single Cell Genome in Liver Cancer

Chairs: Xin Wei Wang, PhD (USA) and Keji Zhao, PhD (USA)


Liver cancer is clinically, molecularly and biologically heterogeneous, and highly resistant to treatment. A major barrier to improving patient outcome is the incomplete understanding of cancer heterogeneity and our inability to define key cancer vulnerabilities for effective therapeutic intervention. Genomic analyses of HCC and ICC by whole genome or exome sequencing reveal a complex mutational landscape with a vast inter-tumour heterogeneity. These studies also reveal that each primary tumour lesion may consist of cells that differ genetically and epigenetically, referred as intra-tumour heterogeneity, which may result in a phenotypic heterogeneity. Currently, it is unclear how these heterogeneous tumour cells cooperate each other and whether collective behavior and collective regulation of these tumour cells exist as an efficient community unique to each tumour subtype. Thus, understanding molecular features of tumour cells at a single cell level would provide a better understanding of tumour cell communities and help define key drivers responsible for tumour metastasis. The recent development of single-cell genome sequencing technologies has generated many new insights into complex biological systems including human cancer. Single tumour cell analysis may provide the level of sensitivity and specificity to understand tumour biology with regard to collective behavior and collective regulation of a given tumour cell community. It is anticipated

that molecular characterisations of tumour cells and immune cells at the single cell levels will provide a detailed molecular portrait of tumour cell communities specific to a particular tumour type with a unique clinical feature and a therapeutic response.

SIG 2: Surveillance, Biomarkers and Molecular Pathology

Biomarkers: A Review of the Present and a Glimpse of the Future

Chair: Neehar Parikh, MD (USA)

Early detection of hepatocellular carcinoma (HCC) is associated with improved patient outcomes, however we lack adequate biomarkers to reliably identify patients with early stage disease. In addition, once HCC is diagnosed, we lack adequate prognostic biomarkers that aid in predicting disease course or response to HCC treatment. Thus, there have been concerted efforts on multiple fronts in order to discover potential biomarkers for HCC. In this session we will discuss the currently available biomarkers for HCC, such as alpha fetoprotein (AFP), alpha fetoprotein-L3 (AFP-L3), and Des-gamma carboxyprothrombin (DCP). We will review the 5 phases of biomarker discovery: 1)

Preclinical exploratory studies; 2) Clinical assay development for clinical disease; 3) Retrospective Longitudinal repository studies; 4) Prospective screening studies; and 5) Cancer control studies. We will discuss investigational biomarkers that are currently under development and the phase of discovery each potential biomarker is in. We will also discuss recent technological advances in genomic profiling in order to identify patients with HCC, including recent data regarding the use of miRNAs. Finally we will discuss the several multicenter ongoing efforts in HCC biomarker discovery, including the National Cancer Institute Early Detection Research Network and the Cancer Prevention and Research Institute of Texas. Attendees of this session will have a greater understanding of the

current landscape of diagnostic and prognostic biomarkers for HCC.

SIG 3: Imaging and Loco-Regional Therapies

Methods of Response Assessment: Comparing Systemic and Locoregional Therapies

Riad Salem, MD (USA) and Bruno Sangro, MD, PhD (Spain)

The second issue relates to “confirmatory progression”. Evaluating cirrhotic livers for new lesions can be quite challenging. Hypervascularity/washout is not a perfect criterion. It is not uncommon for equivocal lesions to become suspicious of HCC, yet at follow-up, become less conspicuous. Hence, confirmatory progression (particularly of new nodules) in HCC should be considered. This approach will minimize premature discontinuation of treatment. We have observed this artifact where a “new nodule” in a patient on sorafenib is declared as progressive disease (PD) with treatment discontinuation. At follow-up, despite no treatment, the lesion has disappeared, suggesting sorafenib was prematurely discontinued (PD overcall). The third issue relates to retrospective adjudication. Guidelines suggest that an equivocal lesion, ultimately determined to represent an HCC, should be retrospectively adjudicated to the time it was first observed. It is therefore possible to exhibit a TTP of 0 if a baseline equivocal lesion was only later confirmed to be HCC. Although unlikely, observing this phenomenon weakens any TTP/survival correlation. The fourth issue relates to the need to capture HCC-related portal vein thrombosis in response guidelines. Despite no change in index lesion size, HCC treatment may result in the retraction/disappearance of portal vein thrombosis (PVT). We acknowledge that mRECIST appropriately labels PVT as non-target with subjective response/progression assessment. Imaging tools that objectively/consistently quantify this relevant finding are needed. The fifth point involves the interobserver reproducibility of measuring the longest uni/bidimensional diameter of enhancing tissue. While RFA may result in clear zones of necrosis and viable tissue, this is not the case with embolotherapies. There are challenges when multiple readers attempt to reliably define the same (or comparable) areas of enhancing tissue following embolotherapy. This is a critical issue needing further investigation, with solutions that may potentially require automated imaging tools. Finally, and potentially most importantly, the mechanism of action and the time-dependence of response are often ignored. Embolic therapies lead to reduced tumour enhancement because of vascular occlusion. Since this finding may be observed on a contrast scan immediately after embolization, this cannot simply be labeled as necrosis. Alternatively, non-embolic therapies (Yttrium-90/radiotherapy/systemic) require time for response to manifest and in fact, may not lead to pronounced “necrotic” features. The lack of reduction in enhancement does not necessarily suggest treatment failure. Rather, it may represent tissue in the process of undergoing cell death, with lack of enhancement observed at a later date. Furthermore, although systemic agents may lead to reduced enhancement, this finding of “necrosis” may not necessarily represent cell death. In fact, Tumoural enhancement may quickly return once the systemic agent is discontinued, suggesting hypoenhancement may not necessarily represent

“necrosis” as we understand it pathologically. The enthusiasm for new imaging methodologies should be tempered until more controlled studies are completed, including radiology–pathology correlation. The above mentioned methodological complexities/nuances, among others, need to be incorporated in future versions of guidelines as we believe this granularity of detail is essential

when reporting response in HCC studies. When it comes to HCC and response assessment, there is still a lot of work to do including standardisation, interobserver reproducibility, volume analysis, radiology–pathology correlation and imaging surrogates of survival. While automated software appears to be an attractive tool for response assessment, further research and validation are needed before being able to implement these in routine clinical care.

SIG 4: Target and Systemic Therapies

Emerging Systemic Therapies on Advanced Hepatocellular Carcinoma

Joong-Won Park, MD, PhD (South Korea) and Tim Meyer, MD, PhD (United Kingdom)

Although a significant survival advantage was achieved with sorafenib, prolongation of survival was modest, even in the cases of Child-Pugh class A. Unfortunately, subsequent RCTs in the first-line or the second-line setting with potent molecular targeted agents (MTAs) (sunitinib, brivanib, linifanib, erlotinib, everolimus, ramucirumab, ADI-PEG) resulted in failure suggesting that tumour heterogeneity and a lack of predictive response biomarkers remain a challenge. A recently reported first line trial of doxorubicin combined with sorafenib was also negative but, in the second line, the oral multi-kinase inhibitor regorafenib has been shown to improve survival compared with placebo, and this represents the first positive randomised trial systemic therapy since the approval of sorafenib. There a number of ongoing or unreported phase III studies including a second line trial of Cabozantinib (XL184), a RTK inhibitor of c-MET/VEGFR2, and a first line trial of Lenvatinib, an oral TKI against VEGFR, FGFR, RET, KIT and PDGFR. Additionally, a number of stratified trials are in progress including Tivantinib, a selective, non-ATPcompetitive inhibitor of c-MET, which is being evaluated in patients with MET-high tumours, Ramucirumab for patients with AFP >400, Refametinib in RAS mutated tumours and BLU9931, a highly specific FGFR4, for which FGF19 expression is a selection criteria. There is also increasing interest in immunotherapy approaches with very promising data reported for Nivolumab in a large phase II trial. Overall, the response rate was 16% and Nivolumab is now being evaluated in first and second line randomised trials.

SIG 5: Liver Surgery and Transplantation

Liver Transplantation vs. Resection for Hepatocellular Carcinoma

Katsuhiko Yanaga, MD, PhD (Japan)

Hepatocellular carcinoma (HCC) complicates patients with concomitant liver diseases. In Western countries, liver cirrhosis is generally regarded as a contraindication to hepatic resection, while in Eastern countries where cadaveric organ donation is scarce, liver transplantation is often reserved for advanced liver cirrhosis with nonadvanced HCC. However, recent studies are showing good results in extended criteria such as resection in patients with portal hypertension, and liver transplantation with extended criteria or after down-staging. During this luncheon, these new data are presented and discussed with the audience.

SIG 6: Non-HCC Hepatic Malignancies

An Update on Risk Factors for Cholangiocarcinoma

Shahid A. Khan, MD, PhD (United Kingdom) and Lewis R. Roberts, PhD (USA)

There are well established risk factors for cholangiocarcinoma but these vary geographically around the world. Over the last few years, although increasing knowledge has accumulated regarding these risk factors, including for different types of cholangiocarcinoma, their individual contributions as risk factors remain unclear. The aim of this session is to analyse established and emerging potential risk factors by a systematic examination of the literature, including case-control series from geographically diverse regions. I will also provide a summary of changing patterns of incidence and mortality rates of cholangiocarcinoma from the international literature.