Texas Collaborative Center for Hepatocellular Cancer

(TeCH)FUNDED BY CANCER PREVENTION AND RESEARCH INSTITUTE OF TEXAS (CPRIT)

RP190641AUGUST 31ST, 2019 – AUGUST 30TH, 2024

The goal of TeCH is to reduce HCC mortality in Texas by reducing the number of people who develop cancer or

detecting it early when it is curable.

To support and enhance research collaborations among CAP researchers by providing multiple levels of connectivity and necessary research support

To setup the framework to educate healthcare providers, researchers, and the public on best practices and to engage private and public entities in policy considerations

To engage all stakeholders and solicit strategies to improve HCC-related prevention and care and to best disseminate those improvements

To begin disseminating results on best practices and new opportunities that will impact HCC in Texas

Organizational Structure of TeCH

Oversight, Evaluation, and Coordination Research Support and Synergy Dissemination and Implementation

Steering Committee Scientific Committee Clinical Network Committee

Administrative Core Data and Biospecimen Core Community Outreach Committee

External Advisory Committee Annual Symposium Committee

Changing HCC Epidemiology in the United States and Texas

HASHEM B EL-SERAG, M.D. , M.P.H.

PROFESSOR AND CHAIR OF MEDICINE

BAYLOR COLLEGE OF MEDICINE

HOUSTON TEXAS

Gastroenterology 2017 152, 812-820

Age-adjusted HCC Incidence Rates in the United States between 2000 and 2012

White et al, 2017.

HCC Incidence Rates in Texas

0

5

10

15

20

25

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Age

-adj

uste

d in

cide

nce

rate

Hispanic, Texas

NH black, Texas

Hispanic, Nationwide

NH black, Nationwide

NH white, Texas

NH white, Nationwide

El-Serag et al 2019

HCV was the Dominant Risk Factor for HCC in the United States (1999)

(N=691)

Chart1

HCV

Both

HBV

Neither

Sales

0.47

0.05

0.15

0.33

Sheet1

Sales

HCV0.47

Both0.05

HBV0.15

Neither0.33

To update the chart, enter data into this table. The data is automatically saved in the chart.

Factors Associated With Increased HCC Risk in Patients with Active HCV Infection

Modifiable◦ Alcohol consumption◦ Nonalcoholic fatty liver disease◦ Obesity◦ Diabetes

Viral◦ Genotype 3◦ Coinfection with HBV or HIV

AASLD, IDSA, IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed July 15, 2015.

Non-modifiable• Older age at time of

infection• Male sex• Hispanic ethnicity

Antiviral Treatment with SVR

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

Cum

ulat

ive

inci

denc

e of

HCC

2982 2453(35) 1617(36) 636(14) 5(3) 0(0)No SVR19518 19372(85) 14364(68) 6128(29) 0(1) 0(0)SVR

N at risk (N HCC)

0 5 10 15 20 25Months after end of treatment

No SVR

SVR

Cumulative HCC incidence rates by DAA-related SVR

Kanwal F et al., Gastroenterology 2017

0.1 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8

OverallAgeYounger than 6565 year and olderRaceWhiteAfrican AmericanHispanicsDiabetes NoYes Alcohol useNoYes Drug useNoYes FIB-43.25

Incidence rate (per 100 person year)

Annual Incidence of HCC after SVR Stratified by Cirrhosis

Without cirrhosis With cirrhosis1.82%

(95% CI, 1.66-2.0%)

Kanwal F, Gastroenterology 2017

HCV-related HCC Has Started to Decline

HCV

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

HCV

ALD

HBV

NAFLD

Kim D et al. Gastroenterology 2020

National Vital Statistics System

2009-2018

HCC is Declining in Young Men

Females Males

Zhang X, El-Serag HB, Thrift AP. Cancer Epidemiol Biomarkers Prev. 2020 J

Viral factors Host Factors External Factors

HBV: Risk Factors for Progression to HCC

Persistently high HBV DNA levels

HBV CP variant

HBV genotype (C > B)

• Older age• Male gender• Asians??• Advanced fibrosis • Persistent ALT elevation• Recurrent hepatitis

flares• HDV, HCV coinfections• HIV coinfection • Family history of HCC

• Alcohol• Aflatoxin• Smoking

Antiviral Treatment

HBV Vaccination and HCC: Taiwan Experience

• HCC prevention extended from childhood to early adulthood• Failures: incomplete vaccination, maternal HBsAg or HBeAg

J Natl Cancer Inst 2009; 101:1348-1355

Globesity

Obesity and Risk of HCCMost—but not all—studies suggest a modest increase in the relative risk of HCC in obese persons

Saunders D, et al. APT 2010.Gupta A et al. Am J Clin Oncol. 2018

DiabetesN=173,643

No Diabetes N=650,620

P

Obesity/Diabetes and HCCDistal vs. Proximal Associations

Obesity/Diabetes

Distal associations

HCC

Proximal associations• Abdominal obesity• Humoral Mechanisms• Medications• NAFLD/NASH• Genetic Factors

Natural History of NAFLD

NAFLD

Isolated Fatty Liver

NASH

NASH Cirrhosis

HCC

Decompensation

~70-75%

~11% over 15 years, but significant variability

1. ↑ risk of death compared with general population1. Cardiovascular2. Malignancy3. Liver-related

2. NASH with fibrosis portends worse prognosis 1. Fibrosis progression a/w DM, severe IR, weight

gain >5kg, rising ALT, AST

~7.2% over 6.5 years

19-45% over 7-10 years

1. None to very minimal progression to fibrosis

2. No ↑ risk of death compared with the general population

Fatty Liver with Mild Inflammation

Possible sampling variability withsome risk of progression

~20-25%

Modified from Torres DM et el. Features, diagnosis, and treatment of NAFLD. Clin Gastro Hepatol 2012;10:837-858.

HCC in Patients with (Biochemical) NAFLD452,767 with NAFLD and 450,627 w/o NAFLD

0.35

0.30

0.25

0.2

0.15

0.1

0.05

0Ann

ual H

CC in

cide

nce/

1000

PY

NAFLD Controls

Hazard ratio7.5 (95% CI=6.05-9.23 )

Mean 9.1 (SD 2.9) year follow-up

NAFLD: 727 HCC = 0.20/1000 PYNon-NALFD: 87 HCC = 0.02/1000 PY

Kanwal F et. al. Gastroenterology 2018

HCC Incidence in Subgroups Of Patients with NAFLD

0.2 0.4 0.6 0.8 1.0 8.0 10.0 12.0 20.0Incidence rate per 1000 person-years

DiabetesNo

Yes

Age (year)65

Race BlackWhite

Hispanic

Cirrhosis Diagnosis, high FIB-4Diagnosis, low FIB-4

High FIB-4No diagnosis, low FIB-4

Kanwal F, et. al. Gastroenterology 2018.

Dyslipidemiaalone

10.0

8.0

6.0

5.0

4.0

3.0

2.0

1.0

0

Dyslipidemia & hypertension

Adju

sted

haz

ard

ratio

Dyslipidemia & diabetes

Dyslipidemia, hypertension &

diabetes

BMI 30

Stratified Analyses in 208,403 Patients with Dyslipidemia

Factors Associated with Risk of NAFLD Progression to Cirrhosis or HCC

Multivariate Analyses (Joint Effects)

Kanwal F, et al. Hepatology 2019

1500 VA patients & HCC (2005- 2010) Patients without cirrhosis 13%Risk of HCC in absence of cirrhosis NAFLD:

OR: 5.4; 95% CI (3.4–8.5) Metabolic Syndrome:

OR: 5.0; 95% CI (3.1–7.8)

HCC in the Absence of Cirrhosis

Mittal A et al Clinical Gastroenterology and Hepatology 2015

• NAFLD and Metabolic Syndrome are main risk factors for HCC in the absence of cirrhosis

Chart1

NAFLDNAFLD

HCVHCV

HBVHBV

Alcohol abuseAlcohol abuse

IdiopathicIdiopathic

Cirrhosis

No cirrhosis

65.4

34.6

91.1

8.9

92.3

7.7

88.9

11.1

66.2

33.8

Sheet1

NAFLDHCVHBVAlcohol abuseIdiopathic

Cirrhosis65.491.192.388.966.2

No cirrhosis34.68.97.711.133.8

Sheet1

Cirrhosis

No cirrhosis

Sheet2

Sheet3

Metabolic Associated Fatty Liver Disease (MAFLD)

Eslam M, et al. Gastroenterology 2020

Prevalence of Risk Factors vs Risk of HCC

Previous State Present/Future State

Prevalence of Risk Factor

HCC

Risk

Disease typePrevalence in

general population

Risk estimate of HCC

Population attributable

fraction

HBV 0.5-1% 20-25 5-10%HCV 1-2% 20-25 20-25%Alcoholic liver disease 10-15% 2-3 20-30%

Metabolic syndrome 30-40% 1.5-2.5 30-40%

MAFLD 70-80% 1.5 70-80%

HCC Risk FactorsPrevalence, Relative Risk Estimates, and

Population Attributable Fraction

Drop Decline Drop

El-Serag HB, et al. Gastroenterology 2018.

Texas HCC Consortium (THCCC) Accrual as of October 12, 2020

Institution Name Start Date* Total Accrual % of Total Registered

Michael E DeBakey VAMC Dec. 21, 2016 630 25.1%

UT Southwestern Medical Center at Dallas Jan. 9, 2017 435 17.4%

Parkland Health and Hospital System Jan. 10, 2017 493 19.7%

Baylor College of Medicine Feb. 9, 2017 525 20.9%

The Texas Liver Institute Apr. 20, 2017 140 5.6%

Baylor Scott & White Research Institute Jun. 14, 2019 172 6.9%

Doctor’s Hospital at Renaissance Oct. 8, 2019 93 3.7%

Baylor All Saints Medical Center Jun. 4, 2020 18 0.7%

Total 2506 100%

*Start date is defined as the date that the first subject was enrolled.

THCCC: Cirrhosis Risk Factors in the Main Racial/Ethnic Groups

(El-Serag HB et al. Gastroenterology; 2020 accepted)

HCC Incidence Rate as of February 19, 2020

Abbreviations:OSD: Off-study dateDD: Death dateHCC: HCC date

†Whichever occurs first

𝐻𝐻𝐻𝐻𝐻𝐻 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐼𝐼𝐴𝐴𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐴𝐴𝐼𝐼𝐼𝐼 𝑅𝑅𝐴𝐴𝑅𝑅𝐼𝐼 =75

𝑂𝑂𝑂𝑂𝑂𝑂,𝑂𝑂𝑂𝑂,𝐻𝐻𝐻𝐻𝐻𝐻, 𝑜𝑜𝑜𝑜 𝐻𝐻𝐴𝐴𝑜𝑜𝑜𝑜𝐼𝐼𝐴𝐴𝑅𝑅 𝑂𝑂𝐴𝐴𝑅𝑅𝐼𝐼† − 𝑅𝑅𝐼𝐼𝑅𝑅𝐼𝐼𝑅𝑅𝑅𝑅𝑜𝑜𝐴𝐴𝑅𝑅𝐼𝐼𝑜𝑜𝐴𝐴 𝑂𝑂𝐴𝐴𝑅𝑅𝐼𝐼365.24

= 𝟏𝟏.𝟗𝟗𝟗𝟗%

SummaryChanging HCC Risk Factors◦ Less active HCV and HBV◦ More Metabolic Syndrome

Changing in HCC Risk◦ Lower individual risk but more individuals at risk

Metabolic Syndrome and HCC Risk◦ Relative risk of HCC is modestly elevated but absolute risk is low◦ Factors influencing HCC risk: abdominal obesity, diabetes, NAFLD, PNPLA3

Knowledge Needed◦ Risk stratification◦ Mechanisms◦ Treating metabolic syndrome

AcknowledgmentsCollaborators:

• David Davila, PhD

• Jennifer Kramer, PhD

• Donna White, PhD

• Fasiha Kanwal, MD

• Aaron Thrift, PhD

Funders:• NIH NCI• NIH NIDDK• VA HSRD• CPRIT

����Texas Collaborative Center for Hepatocellular Cancer� (TeCH)�The goal of TeCH is to reduce HCC mortality in Texas by reducing the number of people who develop cancer or detecting it early when it is curable.�Organizational Structure of TeCHChanging HCC Epidemiology in the United States and TexasSlide Number 5Slide Number 6HCC Incidence Rates in TexasHCV was the Dominant Risk Factor for HCC in the United States (1999)Factors Associated With Increased HCC �Risk in Patients with Active HCV InfectionSlide Number 10Annual Incidence of HCC after SVR Stratified by CirrhosisHCV-related HCC Has Started to DeclineHCC is Declining in Young MenHBV: Risk Factors for Progression to HCCHBV Vaccination and HCC: �Taiwan ExperienceGlobesityObesity and Risk of HCCDiabetes Is Associated with a Two-fold Increase in Risk of HCCObesity/Diabetes and HCC�Distal vs. Proximal AssociationsNatural History of NAFLDHCC in Patients with (Biochemical) NAFLD�452,767 with NAFLD and 450,627 w/o NAFLDSlide Number 23�Factors Associated with Risk of NAFLD Progression to Cirrhosis or HCC �Multivariate Analyses (Joint Effects)  Metabolic Associated Fatty Liver Disease (MAFLD)Prevalence of Risk Factors vs Risk of HCCHCC Risk Factors�Prevalence, Relative Risk Estimates, and Population Attributable Fraction�Texas HCC Consortium (THCCC) �Accrual as of October 12, 2020THCCC: Cirrhosis Risk Factors in the Main Racial/Ethnic Groups �(El-Serag HB et al. Gastroenterology; 2020 accepted)HCC Incidence Rate as of February 19, 2020SummaryAcknowledgments