HCC screening and surveillance

HCC biomarkers and thecurrent role in patients at risk for hepatocellular carcinoma (HCC)Robert G. Gish MDSenior Medical Director Liver Program St Josephs Medical Center, Phoenix, AzClinical Professor of Medicine (Adjunct): University of Nevada, Las VegasMedical Director Hepatitis B Foundation, Doylestown, PA

HCC Biomarkers and Surveillance:OutlineBiomarkers for HCC are not being used primarily to establish a diagnosis of cancerHCC biomarkers can be used as risk tests in surveillance protocols to determine who may develop HCC and to guide changes in imaging method selection and timingAlpha beta-protein (AFP) is not FDA cleared as a single test for the diagnosis or risk of HCCDCP and AFPL3% are the only biomarkers that are cleared by the FDA with the intended use as risk markers for HCCAFP as a single test: for Diagnosis of HCC? (no): Poor Diagnostic Tool due toLow sensitivity and/or specificityTumor heterogeneityPatient heterogeneity

Combined use of AFP, AFP-L3 and DCP significantlyImproves the performance characteristics as risk markers for HCCKey Challenges and Uses of Biomarkers in Clinical PracticeCP1245754Roberts, LRmls/so10-9-2006Surveillance Guidelines for High-Risk Patients

Approval/Clearance And Reimbursement for HCC Biomarkers

USAFDA ClearanceCanada

Health CanadaEuropeCE MarkJapanMHLWAFPNot cleared for HCCReimbursedYesYes

YesReimbursedAFP-L3Yes ReimbursedYes

Yes

YesReimbursedDCPYesReimbursedYes

Yes

YesReimbursedThe biomarkers have been already approved in almost every region of the globe.Inclusion of AFP-L3 and DCP Biomarkers Enable More Comprehensive Surveillance StrategiesKumada T, et al. J Hepatol 1999;30:125-30.Makuuchi M, et al. Hepatol Res. 2008;38:37-51.Koike Y, et al. Cancer 2001;91:561-9.AFP-L3DCPAFP is a glycoprotein with a single asparagine-linked complex-type carbohydrate chain on each molecule.

AFP-L3 is an isoform of AFP which has an additional fucose residue.

Elevation of AFP-L3 is indicative of greater malignant potential of HCC and is correlated to shorter doubling time of tumor volume and increased hepatic arterial supply.1 DCP is a precursor form of prothrombin, a coagulation protein.

HCC cells lack the carboxylase protein to change DCP to prothrombin.

DCP has been reported to be a specific marker for microinvasion and a high DCP level is associated with development of portal vein invasion.2,3HCC biomarkers: Intended useAFP-L3 and DCP are intended for and FDA Cleared for in vitro diagnostic use as an aid in the risk assessment of patients with chronic liver diseases for development of HCC in conjunction with other laboratory findings, imaging studies, and clinical assessment. The combined use of these biomarkers has been shown to be more sensitive and effective for the early detection of HCC through surveillance.4-6

1. Shimauchi Y, et al. Oncol Rep.2000;7:249-56.2. Toyoda H, et al. Clin Gastroenterol Hepatol 2006;4:111-7.3. Volk ML, et al. Cancer Biomarkers 2007;3:79-87.Inclusion of AFP-L3 & DCP Improves Early DetectionPrimary ToolSensitivitySpecificityConclusionsColli et al (2006)1Ultrasound48%

(95% CI 34-62%)97%

(95% CI 95-98%)Ultrasound isinsufficiently sensitive to detect HCC in many cirrhotics or to support an effective surveillance program.Singal et al (2012)2Ultrasound43.9%91.5%Ultrasound is suboptimal when used aloneVolk et al (2007)3AFP, AFP-L3 & DCP 84%94%Combined use of AFP, AFP-L3 and DCP results in enhanced detection of HCC with minimal false positivesHann et al (2013)4AFP, AFP-L3 & DCP 83%91%Colli A, et al. Am J Gastroenterol 2006;101:513-23. Singal et al. Cancer Epidemiol Biomarkers Prev. 2012;21:793-9Volk ML, et al. Cancer Biomarkers 2007;3:79-87Hann HW, et al. DDW 2013 Poster Tu 1048Colli: Pooled 14 out of 2,524 studies using stringent criteria

Not suggesting that U/S be replaced by the biomarkers should be used in conjunction

Low sensitivity leads to patients who are not diagnosed, or who are diagnosed at a later stage. Low specificity leads to more false positives and additional expenses related to unnecessary testing.

8Biomarkers Supplement Ultrasound and Provide an opportunity for earlier HCC detection Surveillance strategyCost per test1AdvantagesDisadvantagesNo surveillance $0No expenditureNo chance of diagnosisUltrasound$185Widely used , low costPoor sensitivityUltrasound + AFP$216Widely usedPoor sensitivity, particularly in early stage HCCUltrasound + AFP, AFP-L3, DCP$361Earlier and more sensitive detection of HCCAdditional costs of AFP-L3 and DCPCT$640High sensitivityHigh cost, limited accessYu NC, et al. Clin Gastroenterol Hepatol 2011;9:161-7.Semiannual CT is sensitive in HCC detection but costs are very high. Adding AFP-L3 and DCP to regular practice is not very expensive but is very effective to aid in early diagnosis of HCC. Detecting HCC early enough to undergo resection improves incremental cost-effectiveness of HCC treatments.

9Earlier Detection of HCC May Improve Opportunity for Cost-Effective InterventionsTreatments (Stage I)Mean years survivedMean cumulative expendituresICERs (Incremental cost-effectiveness ratios)No treatment 1.06$35,390N/AChemotherapy1.29$68,824Insignificant difference Radiation1.47$65,09874,404Liver directed (Ablation and/or TACE )2.67$95,56625,345Resection4.51$123,80715,303Transplant5.98$207,47355,066Shaya FT, et al. Pharmacoeconomics. 2013 Nov 29.Resection, classified by the AASLD Guidelines as curative therapy, is also the most cost effective.Shaya et al. reported that resection at an earlier stage was the most effective for incremental cost-effectiveness ratios (ICERs) considering life years and cumulative medical expenditures.

10Costs and Performance of HCC Surveillance ToolsSurveillance testsCost per test1ReferencesSensitivitySpecificityUltrasound $185Singal, et al. (2012)244%92%AFP only$31Volk, et al. (2007)369%91%3 biomarkers (AFP, AFP-L3, DCP)$176

$88 (AFP, AFP-L3) + $88 (DCP)Volk, et al. (2007)388%91%Hann, et al. (2013)483%91%Yu NC, et al. Clin Gastroenterol Hepatol 2011;9:161-7.Singal et al. Cancer Epidemiol Biomarkers Prev. 2012;21:793-9Volk ML, et al. Cancer Biomarkers 2007;3:79-87Hann HW, et al. DDW 2013 Poster Tu 1048Costs1 : CT, $640; MRI, $140011AFP-L3 and DCP Are Reimbursed By Various Insurance Providers AFP-L3 and DCP are covered by a number of public and commercial payers (data on file)

Medicare Clinical Laboratory Fee Schedule1 AFP-L3 (CPT 82107): $88.54DCP (83951): $88.54

Some Examples of Health Plan CoverageMedicareMedicaidTricareHighmark Blue Cross Blue ShieldEmblemHealthCapital Blue CrossTufts Health PlanBlue Cross Blue Shield of DelawarePriority Health Centers for Medicare and Medicaid Services. Clinical Laboratory Fee Schedule. 2013.Liver Dedicated Surveillance Ultrasound (US)+ HCC biomarkers in at-risk patients*Poor/Fairquality USOr abnormal biomarkersGood/Excellent quality US and normal HCC biomarkers#gadoxetate disodium MRI (Or dynamic CT)US surveillance q6 months with biomarkersNegative MRIAbnormal US orincreasing biomarkersblood tests AFP-L3%/DCP (HCC serum biomarkers); *AASLD Guidelines 2009; # see LI-RADS.AASLD = American Association for the Study of Liver Diseases; AFP = alpha-fetoprotein; CT = computed tomography;DCP = des-gamma-carboxy prothrombin; HCC = hepatocellular carcinoma; LI-RADS = Liver Imaging Reporting and Data System;MRI = magnetic resonance imaging; US = ultrasound.Proposed Liver Ultrasound AlgorithmGish, R. ,Gastroenterology & Hepatology, 2014; 10;2:121-123. Gish RG. Early Detection of Hepatocellular Carcinoma Through Surveillance Using Biomarkers. Gastroenterology and Hepatology, 2014. Volume 10, Issue 2; 121-123.http://www.gastroenterologyandhepatology.net/index.php/archives/february-2014/early-detection-of-hepatocellular-carcinoma-through-surveillance-using-biomarkers/.13HCC Biomarkers Utility ExamplesRemember: Not all HCC make all biomarkersPatient number of AFP-L3, DCP and AFP in those with known HCC (n=685)Toyoda et al. Clin Gastro and Hep 2006;4:111-117AFP > 20 ng/mLDCP > 40mAU/mLAFP-L3 > 10%9611093153451415159 (23%) all negative15Combined Biomarker Testing Identifies a Greater Number of Positive tests in Patients with Known HCC1AFP-L3 Positive15(20.3%)DCP Positive3(4.1%)AFP Positive8(10.8%)7(9.5%)15(20.3%)4(5.4%)15(20.3%)All Negative7(9.5%)FDA submission data for uTASWako i30 If HCC biomarkers are used prior to imaging: In this study of 74 patients, the use of AFP alone would have detected 45 HCC cases and missed 29 cases of HCCCut-off pointPositive casesAFP 20 ng/mL45 (60.8%)AFP-L310 %49 (66.2%)DCP 7.5 ng/mL

29 (39.2%)Combination ofAFP, AFP-L3, and DCPSame as above67 (90.5%)Cant predict in advance which biomarker will be most effective, so need to run all three tests.

Both biomarkers are highly specific for HCC and complement each other.15 Therefore, when both markers are measured in tandem, the sensitivity is improved while the high specificity is maintained.16,17 In other words, the combination measurement of three HCC biomarkers will identify a greater number of patients at risk of developing HCC during surveillance than with each marker alone.

The diagram shows that if you were to run AFP alone, you would miss:7 patients that were DCP positive but not AFP positive 19 patients that were AFP-L3 positive but not AFP positive 4 patients that were positive for both DCP and AFP-L3, but negative for total AFP - Of the 74 patients in this study, 26 patients with HCC would have been missed if only AFP were used16Utility when biomarkers are used in combination in patients without HCC: False Positives, True Negative, True Positives (in the colored circles)AFP-L3%DCPAFP2 (0.5%)3 (0.7%)9 (2.2%)15 (3.7%)26 (6.5%)81(20.2%)True Negative258 (64%)7 (1.7%)False PositiveAFP: 25%AFP-L3%: 7%DCP: 9%N = 401FDA submission data for LiBASys17This is looking at G4 (no HCC) but they tested positive for the marker (false positives). If using only AFP there is a 24.6% false positive rate. That is the highest of all three markers. By adding in the other markers you lower the possibility of having false positives. There is only a 0.5% chance that someone without HCC would test positive for all three markers.

But lets keep looking at AFP since it is the bench mark. If a doctor adds in DCP- only 7 out of 401 pts tested positive for both of these. Or L3 + AFP- only 9 out of 401 tested positive for both of these. All the more reason to use- there is such a low likelihood of false positives when more than one marker is elevated. rule out the possibility of a false positive.Predictors of HCC Development in Patients with Chronic Hepatitis CEl-Serag, et al. 2014

The development of HCC in patients with HCV and cirrhosis can be predicted based on: high AFP levels high ALT levels low platelet levels older age at AFP testAFP = -fetal protein; ALT = alanine aminotransferase.El-Serag HB, Kanwal F, Davila JA, Kramper J, Richardson P. Laboratory-based algorithm to predict development of hepatocellular carcinoma in patients with hepatitis C and cirrhosis. Gastroenterol. 2014;146;1249-1255.

18Case 1 Risk assessment of HCC development by AFP-L3

0.17 ng/mLAFP-L3 Normal: