Prospective Evidence That Hepatocellular Carcinoma Surveillance in Patients with Compensated Viral Cirrhosis Increases the Probability of Curative Treatment and Survival Taking into Account Lead-Time Bias (Anrs Co12 Cirvir Cohort)

ORAL PRESENTATIONS evaluated by the quantitative digital analysis algorithm for immunohistochemistry with regard to their association with time to progression and overall survival (OS). Further, we performed additional validation study using serum samples before sorafenib obtained from different set of HCC patients (n = 40). Results: Endothelin-1 (EDN1) was the only differentially expressed molecule and knock-down of EDN1 in HCC cell line increased sorafenib sensitivity. In test set, low EDN1 expression group showed significantly better response to sorafenib (non-progressive disease) compared to high EDN1 expression group (63.6% vs. 0%, respectively; p < 0.0001). In validation set, END1 expression maintained predictability for sorafenib responsiveness. Survival analysis showed that high EDN1 expression was an independent risk factor for poor OS (hazard ratio [HR], 2.374; 95% confidence interval [CI], 1.051–5.360; p = 0.037) and an independent predictor for rapid tumor progression (HR, 1.907; 95% CI, 1.085–3.350; p = 0.025) after sorafenib treatment. In serum sample set, above mentioned predictability for sorafenib responsiveness was validated. Conclusions: EDN1 expression shows an unprecedented predictability that can distinguish the responders to sorafenib and can be a powerful predictive biomarker for sorafenib in HCC.

Conclusions: This newly proposed simple survival model provides enhanced prognostic accuracy for HCC. The ability of MESH score remains consistently stable among different treatment strategies and viral etiologies. The MESH system is a useful supplement to the BCLC and HKLC classification schemes in refining treatment strategies. PS115 EDN1 EXPRESSION AS A NOVEL BIOMARKER FOR PREDICTING SORAFENIB RESPONSIVENESS IN PATIENTS WITH HEPATOCELLULAR CARCINOMA S.J. Yu1, J.-K. Won2, J.-H. Yoon1, K.-H. Cho3, W.-M. Choi1, H. Cho1, E.-J. Cho1, J.-H. Lee1, Y. J. Kim1, K.-S. Suh4, J.-J. Jang2, C. Y. Kim1. 1Internal Medicine; 2Pathology, Seoul National University Hospital, Seoul; 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon; 4Surgery, Seoul National University Hospital, Seoul, South Korea E-mail: [email protected] Background and Aims: Predictive biomarkers for sorafenib in hepatocellular carcinoma (HCC) are still not available, despite the modest benefit of sorafenib. We present a novel and sensitive biomarker that can predict the responsiveness to sorafenib. Methods: Candidate biomarkers were investigated using public database through differential mRNA expression. A candidate biomarker was tested with in vitro shRNA experiments for its effect to sorafenib-resistance. Consecutive patients with HCC who had undergone sorafenib treatment were included from a prospective cohort and the training set (n = 74) and the validation set (n = 20) were established. Pathological specimens were archived before sorafenib treatment and the expression of a candidate marker was S194

PS116 PROSPECTIVE EVIDENCE THAT HEPATOCELLULAR CARCINOMA SURVEILLANCE IN PATIENTS WITH COMPENSATED VIRAL CIRRHOSIS INCREASES THE PROBABILITY OF CURATIVE TREATMENT AND SURVIVAL TAKING INTO ACCOUNT LEAD-TIME BIAS (ANRS CO12 CIRVIR COHORT) C. Costentin1, R. Layese2, V. Bourcier3, L. Corvi3, V. Petro-Sanchez4, P. Marcellin5, D. Guyader6, S. Pol7, D. Larrey8, V. de Ledinghen9, D. Ouzan10, F. Zoulim11, J. P. zarski12, D. Roulot13, A. Tran14, J.P. Bronowicki15, G. Riachi16, P. Cales17, J. M. Péron18, L. Alric19, M. Bourlière20, P. Mathurin21, A. Sutton22, E. Letouze23, J. ZucmanRossi23, F. Roudot-Thoraval24, P. Nahon3 and ANRS. 1Hepatologie; 2 Santé publique, Hôpital Henri Mondor, Créteil; 3Hepatologie, Hôpital Jean Verdier, Bondy; 4ANRS, Paris; 5Hepatologie, Hôpital Beaujon, Clichy; 6 Hepatologie, Hôpital de Rennes, Rennes; 7Hepatologie, Hôpital Cochin, Paris; 8Heptologie, Hôpital de Montpellier, Montpellier; 9Hepatologie, CHU de Bordeaux, Bordeaux; 10Institut Arnault Tzanck, St Laurent du Var; 11Cancer Research Center of Lyon, Lyon; 12Hepatologie, CHU Grenoble, Grenoble; 13Hepatologie, Hôpital Avicennes, Bobigny; 14 Hépatologie, CHU Nice, Nice; 15Hépatologie, CHU Nancy, Nancy; 16 Hépatogastroentérologie, CHU Rouen, Rouen; 17 Hépatogastroentérologie, CHU Angers, Angers; 18Hépatologie; 19 Médecine Interne-Pôle Digestif, CHU Toulouse, Toulouse; 20Hépatogastroentérologie, Hôpital Saint Joseph, Marseille; 21Hépatologie, CHU Lille, Lille; 22Biochimie, Hôpital Jean Verdier, Bondy; 23Inserm U1162, CEPH - Fondation Jean Dausset, Paris; 24Public Health, Henri Mondor Hospital, Créteil, France E-mail: [email protected] Background and Aims: Semi-annual surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is recommended but has been challenged by registry studies. The aim of this work was to assess the impact of compliance to HCC screening on tumour stage at diagnosis, treatment procedures and survival in patients with compensated viral cirrhosis included in the ANRS CO12 CirVir prospective cohort. Methods: Patients with the following criteria were enrolled in 35 French centers: a) biopsy-proven HBV or HCV cirrhosis; b) Child-Pugh A; c) absence of previous liver complications. Patients were prospectively followed-up every 6 months. Compliance to screening guidelines was defined by a time frame between the HCC diagnostic imaging and the previous one inferior to 7 months. Ethnicity was assessed using a panel of 26 genetic variants. Results: A total of 1671 patients were enrolled between March 2006 and June 2012 [age 55, men 67.2%, HCV 1323, HBV 317, HCV-HBV 31]. During a median follow-up of 51 months, HCC was diagnosed in 187

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ORAL PRESENTATIONS patients [mean age 58 years, 162 (86.8%) HCV, 22 (11.8%) HBV, 3 (1.9%) HCV-HBV], among which, 141 (75%) fulfilled Milan criteria, 112 (83.6%) had AFP score ≤ 2 and 114 (68.7%) received curative treatment [transplantation (n = 15), resection (n = 21), percutaneous ablation (n = 76), resection + percutaneous ablation (n = 2)]. Compliance to screening concerned 113 (61.1%) patients. In multivariate analysis, the lack of compliance to screening (OR 2.46 [1.02–5.94]; p = 0.046) and Afr ethnicity (OR 4.09 [1.25–13.42]; p = 0.020) were associated with the probability of HCC at diagnosis outside Milan criteria. Absence of prior liver decompensation since inclusion (OR 8.02 [2.71–23.74]; p < 0.001), and compliance to screening (OR 2.85 [1.38–5.28]; p = 0.005) were the only independent factors associated with curative treatment implementation. Death occurred in 65 HCC patients, and was related to tumour progression in 35. After lead-time adjustment, overall survival was improved in patients with compliance to screening (3years overall survival: 54.2% vs. 45.7%, Log-rank = 0.040) and was impacted by the tumour stage at diagnosis and the type of treatment (curative vs. no) (Figure 1).

Conclusions: In this prospective cohort of patients with compensated viral cirrhosis, compliance to screening guidelines for HCC improved the probabilities to diagnose liver cancer at an earlier stage, to the implementation of first-line curative treatments and improved survival. PS117 INTEGRATION OF THE CANCER-RELATED PRO-INFLAMMATORY RESPONSE AS A STRATIFYING BIOMARKER OF SURVIVAL BENEFIT WITH SORAFENIB IN HEPATOCELLULAR CARCINOMA J. Howell1, D. Pinato2, R. Ramaswami2, T. Arizumi3, C. Ferrari4, A. Gibbin4, M. Burlone4, G. Guaschino4, J. Black5, L. Sellers5, M. Kudo6, M. Pirisi4, R. Sharma5. 1Hepatology; 2Oncology, Imperial College, London, United Kingdom; 3Hepatology, Kinki University School of Medicine, Osaka, Japan; 4Translational Medicine, Università degli Studi del Piemonte Orientale, Novara, Italy; 5Surgery and Cancer, Imperial College London, London, United Kingdom; 6Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan E-mail: [email protected]

Background and Aims: Response to sorafenib is highly variable in hepatocellular carcinoma (HCC) and stratifying prognostic markers of survival in patients on sorafenib are an unmet clinical need. The study aim was to assess the prognostic relationship between baseline inflammatory parameters and treatment-related toxicities as biomarkers to predict sorafenib-induced survival benefit in a large mixed-race prospective cohort of patients with advanced HCC. Methods: Patients with HCC were consecutively recruited from three tertiary centres (Japan, Italy and UK) and clinical data were prospectively collected. The primary study endpoint was overall survival (OS) after commencing sorafenib. Results: 442 patients with advanced stage HCC on sorafenib were recruited (follow-up 5096 person-months at risk). 88% had BCLC stage B or greater HCC and 72.3% had Child-Pugh A cirrhosis. On Cox multivariate regression, previously-treated HCC (HR 0.579, 95% CI 0.385–0.872, p = 0.009), CLIP score (HR 1.723, 95% CI 1.462–2.047, p < 0.0001), baseline red cell distribution width (RDW; HR 1.234, 95% CI 1.115–1.290, p < 0.0001) and neutrophil to lymphocyte ratio (NLR; HR 1.218, 95% CI 1.108–1.322, p < 0.0001) were significant independent risks for shorter survival, whilst sorafenib-related diarrhoea was associated with prolonged survival (HR 0.533, 95% CI 0.373– 0.763, p = 0.001). RDW, CLIP score and sorafenib-related diarrhoea were the strongest predictors of 3 month and 12 month survival on sorafenib and were therefore combined into an optimised logistic regression model for 3 month and 12 month survival endpoints. RDCLIP score (CLIP score multiplied by RDW) ≥70 and absence of treatment-related diarrhoea had good utility for predicting 3-month survival (AUC of 0.808 (95% CI 0.734–0.882), PPV of 86.4% and NPV of 83.3%), compared with CLIP (AUC = 0.642) or BCLC score alone (AUC = 0.579). Median survival time was 2.1 months (IQR 2–2.2 months) compared with 8.4 months (IQR 4.23–16.8 months) in patients who did not fulfil these criteria. RD-CLIP score ≥ 35 and no treatmentrelated diarrhoea had an AUC of 0.787 for predicting 12-month survival (PPV 55.6%, NPV 79.0%; median survival 5.6 months (IQR 2.9–7.6 months) compared with 10.3 months (IQR 4.3–20 months). Conclusions: The novel prognostic index RDCLIP, combining CLIP score with inflammatory marker RDW and treatment-related diarrhoea has good accuracy for predicting overall, 3 month and 12 month survival in patients on sorafenib. PS118 HIGH SERUM SOLUBLE INTERCELLULAR ADHESION MOLECULE 1 (ICAM-1) CONCENTRATION IS ASSOCIATED WITH HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT IN HBV, HCV, AND NON-VIRAL LIVER DISEASE: MULTIPLEX ANALYSIS OF 51 CYTOKINES AND OTHER SERUM MARKERS V.L. Chen1, O. Podlaha2, J. Estevez3, B. Li2, A. Le3, P. Vutien4, E. Chang5, S. Pflanz2, Z. Jiang2, D. Ge2, A. Gaggar2, M. Nguyen3. 1Medicine, Stanford University Medical Center, Stanford, CA; 2Gilead Sciences, Foster City; 3Medicine, Stanford University Medical Center, Palo Alto; 4 Medicine, Rush University Medical Center, Chicago; 5Health Research and Policy (Epidemiology), Stanford University, Palo Alto, United States E-mail: [email protected] Background and Aims: HCC is a serious complication of chronic liver disease and a leading cause of cancer mortality worldwide. Conventional risk factors such as cirrhosis, age, and ethnicity have limited ability to predict HCC risk. Our goal was to examine serum cytokine/marker profiles to identify biomarkers that can predict HCC development in patients with underlying liver disease. Methods: We performed a prospective cohort study of 284 patients with chronic liver disease (106 HBV, 114 HCV, and 64 non-viral) who did not have HCC at baseline at a US medical center. Patients were enrolled from 2000–2007 and followed until HCC development (median follow-up = 155.3 months, IQR = 45.8–210.8 months). Serum samples were obtained at baseline, and microplex analysis (Luminex 200 IS) was used to measure serum levels of 51 common cytokines and other serum markers. We used Lasso regression to screen for

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