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02.1 kinkhabwala
1. UNIFYING STRATEGIES FOR THERAPEUTIC
INTERVENTION IN HEPATOCELLULAR
CARCINOMA
MILAN KINKHABWALA, MD
Professor of Surgery
Montefiore Einstein Liver
Center
2. Goals in Liver Cancer
• Using tumor biology to individualize
intervention for HCC
• Development of multimodality treatment
algorithms incorporating development of
molecular targets
• Development of novel locoregional therapy
3. Design of an Integrated Care System for Liver
Disease: Montefiore Einstein Liver Center
• Division of Transplantation/Hepatobiliary Surgery
• Division of Hepatology
• Marion Bessin Liver Research Center
4. Montefiore Einstein Liver Center
• Common inpatient and outpatient care system for medicine and
surgery
• Shared resources
• Protocolized care
• Common educational, clinical, and administrative meetings
• Integration of basic science and clinical faculty
5. Hepatobiliary cancer working group
• MELC core divisions
• Division of Oncology
• Department of Radiation Oncology
• Division of Interventional Radiology
Daily News
6. EPIDEMIOLOGY OF HCC
• Worldwide 6th most common
malignancy and 3rd leading cause
of cancer deaths
• HCC deaths are increasing the
U.S., as a complication of HCV
infection
8. BIOPSY IS GENERALLY NOT VALUABLE IN
HCC DIAGNOSIS
• 137 PATIENTS UNDERGOING BIOPSY FOR SUSPECTED HCC
(DURAND ET AL, J HEPATOLOGY 2001)
• 122 + BIOPSIES/SENSITIVITY OF BIOPSY 90%
• 13/15 PATIENTS WITH NEGATIVE BIOPSIES HAD HCC
NEGATIVE BIOPSY HAS LOW PREDICTIVE VALUE WHEN
INDEX OF SUSPICION IS HIGH
BIOPSY MAY NOT CHANGE MANAGEMENT OR
OUTCOME AND RISKS ARE HIGHER
NEEDLE TRACK SEEDING 2-10%
10. OPTIONS FOR THERAPEUTIC INTERVENTION
Potentially Curative
RESECTION
TRANSPLANTATION
ABLATION
Noncurative but prolong survival
TRANSCATHETER EMBOLIZATION
SYSTEMIC THERAPY
Efficacy and role still to be determined
RADIOSURGERY
11. RESULTS AFTER RESECTION FOR SMALL HCC :
GOOD EARLY LOCOREGIONAL CONTROL BUT LATE
RECURRENCE RATES > 50%
• MD ANDERSON, (Wayne et al, Annals of Surgery 2002).
N=249
Estimated survival 41% and 19% at 5 and 8 years
• PARIS VII UNIVERSITY (Belghiti, et al, Hepatogastroenterology 2002)
N=328 37% 5 year survival
• HONG KONG (NG, et al, Cancer 1995)
N-278
Overall 17% 5 year disease free survival (34% overall) after resection
12. Validation of Liver Transplantation (total
hepatectomy) as a Therapeutic Modality for HCC
• 4 year disease free survival of 92% can be achieved
for small unresectable HCC’s if specific imaging
based tumor criteria are met.
• Disease free survival was 59% if tumor exceed
criteria.
Mazaferro et al, 1996
14. LIMITATIONS OF TRANSPLANTATION
• RECURRENT HCV RESULTS IN STAGE 4 FIBROSIS IN 30-50%
BY YEAR 5 POST TRANSPLANT
• ACCESS TO ORGANS/WAITING TIME RELATED DISEASE
PROGRESSION (REQUIRES PRETRANSPLANT
LOCOREGIONAL CONTROL)
.25
.2
Cum. Hazar d
.15
.1 Cumulative hazard of tumor
.05
progression beyond acceptable
UNOS criteria after listing for OLT
0 COLUMBIA PRESBYTERIAN MEDICAL CENTER 1997-2003
0 200 400 600 800 1000
Time
15. • Is it better to resect or transplant patients
with HCV and early HCC?
16. Models of Hepatic Oncogenesis
I. Adenoma II. Chronic inflammation
Type 1:
HNF1a mutation Chronic viral hepatitis
HBV
Type 2: HCV
Wnt/bCatenin activation Inherited metabolic disorders
Wilsons
Hemachromatosis
Type 3:
Noninherited metabolic disorders
No HNF or bCatenin mutations
NAFLD
III. Toxin/environmental
carcinogens
Aflatoxin B1
17. Pathogenesis of HCC
• Heterogenous group of carcinomas with diverse molecular
alterations
• Continuous inflammation and regeneration of hepatocytes
• Multistep accumulation of genetic/chromosomal alterations over
years-decades
– Hyperplastic change/macrogenerative nodules
– Low grade to High grade Dysplasia
– Early HCC
– Advanced HCC
• Upregulation of growth factors, inactivation of tumor suppressor
genes, microsatellite instability
18. Hepatitis B Virus: direct and indirect
oncogenic effects
– Viral DNA integration into the genome causing disruption of
chromosomal stability or tumor suppressor genes and/or
activation of protooncogenes
– Direct oncogenic effect of viral protein HBx (16.5kDa) which may
regulate a number of viral and cellular genes:
• Basal transcription machinery (TFIIB, TBP, RPB5)
• Src pathway
• Ras/Raf signaling
• Amplification of TGFb
– Indirect effects mediated by cellular immune responses
19. HCV
• Mostly indirect effects (HCV viral DNA is never
integrated into the genome)
• Viral proteins (core protein in particular) may
interfere with intracellular signalling resulting in
inhibition of apoptosis
22. Molecular targeted therapy for HCC
Drug Type of Drugs Molecular Targets Affected Signaling Pathways FDA Approval
Sorafenib Tyrosine kinase inhibitor VEGFR, PDGFR, RAF VEGFR, PDGFR, RAS/MAPK yes
Sunitinib Tyrosine kinase inhibitor VEGFR, PDGFR, c-kit VEGFR, PDGFR, c-kit No, phase II or 3 trials
Bevacizumab Monoclonal antibodies to ligand VEGFR VEGFR No, phase II or 3 trials
Cetuximab Monoclonal antibodies to ligand EGFR EGFR No, phase II or 3 trials
Erlotinib Tyrosine kinase inhibitor EGFR EGFR No, phase II or 3 trials
Gefitinib Tyrosine kinase inhibitor EGFR EGFR No, phase II or 3 trials
Lapatinib Tyrosine kinase inhibitor Her-2/neu Her-2/neu No, phase II or 3 trials
Rapamycin ST kinase inhibitor mTOR PIK3/Akt/mTOR No, phase II or 3 trials
Everolimus ST kinase inhibitor mTOR PIK3/Akt/mTOR No, phase II or 3 trials
XL-765 ST kinase inhibitor PI3K PIK3/Akt/mTOR No, phase II or 3 trials
Trastuzumab monoclonal antibodies to receptor Her-2/neu Her-2/neu No, phase II or 3 trials
23. Survival Signatures and Survival Curves in the Training Set
Gene Expression in HCC:
Differential gene expression in
nontumoral tissue predicts
outcome:
Opportunity for individualizing
therapeutic intervention?
Hoshida Y et al. N Engl J Med 2008;359:1995-2004
24. Kaplan–Meier curves showing the correlation between mTOR
dysregulation and recurrence post resection for HCC
Villanueva et al, Gastroenterology 2008
25. Can we use proteomics to discover a serum marker for
early stage (curable) or occult HCC?
• IRB approval obtained:
– Blood from 10 patients with
HCV cirrhosis with no HCC
– Blood from 10 patients with
HCV cirrhosis and known
HCC
– If surgery is performed, blood
also collected from the hepatic
vein effluent
• Perform proteomic analysis
Wolkoff, Angeletti, Kinkhabwala
26. MELC Projects
Active tissue capture protocol Gaglio
Prospective data collection using OTTR Kinkhabwala
Clinical trials:
Sorafenib v. Sunitinib Kaubisch
Hepatitis C / Vertex Reinus
RAD-001 (Phase II) Kaubisch
Outcomes research in Hepatitis C Reinus
Downstaging of HCC:
Radiosurgery (Pilot) Gabeau
Proteomic profiling of HCC
Wolkoff/Kinkhabwala/Angeletti
Biology of Liver Radiation Guha
Hinweis der Redaktion
Figure 2. Survival Signatures and Survival Curves in the Training Set. Curves are shown for survival according to the association of the gene signature with survival, based on leave-one-out cross-validation testing (Panel A), and for overall survival according to the level of expression of the 186 signature genes (Panel B); of these, 113 were associated with a good prognosis and 73 with a poor prognosis. Panel C shows the expression pattern of the survival signature (comprising 186 genes). The 20 genes most closely associated with a poor prognosis are listed on the left, and the 20 most closely associated with a good prognosis on the right. Red indicates high expression; blue indicates low expression. Panel D shows representative photomicrographs of sections of liver tissue adjacent to tumor that were profiled in this study; there were no histologic correlates with survival. Staining was with hematoxylin and eosin.
