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Molecular Profiling of Cholangiocarcinoma
Milind Javle, MD
Associate Professor
Department of GI Medical Oncology
U.T. M.D. Anderson Cancer Center
mjavle@mdanderson.org
Cholangiocarcinoma Foundation
Stakeholder Meeting
February 28, 2014
Molecular Profiling: Study Hypothesis
Identify novel biomarkers and targets that can be used
to improve the outcome:
These targets can be explored for their therapeutic
value using novel inhibitors
Stratification into subgroups with prognostic implications
Recent Successes: Targeted Therapy
Cancer Genetic
Aberration
Targeted Agent
Clear cell renal
carcinoma
VHL Bevacizumab,
Sunitinib, Sorafenib
NSCLC ALK Crizotinib
Basal cell
carcinoma
PTCH1 Hedgehog
Inhibitors
Melanoma B-RAF Vemurafenib
Hotspot Somatic Mutation Detection
using Sequenom MassARRAY
Advantages
 Can be used with a small FFPE sample
 Can test multiple genes at the same time
 Can test 384 samples at the same time
 Can detect a mutation even if present in only
5% of the sample
 Relatively cheap
Disadvantages
 Not useful for detection of fusion genes or
for discovering novel targets
Targeted Next Generation Sequencing
 Ability to fully sequence large numbers of
genes in a single test.
 Panel is scalable: pharma requirements
 Detect deletions, insertions, copy number
alterations, translocations and exome-wide
base substitutions in known cancer-related
genes
 Tissue requirement<50 ng DNA: critical in
biliary cancers
Patient Population (n=158)
GB Cancer
N=83
• 34 Primary; 49 Metastatic
• NGS of 236 cancer-related genes
Cholangioca
N=75
• 55 intrahepatic; 13 had surgical
resection
• NGS of 236 cancer-related genes
Molecular Profiling of Cholangiocarcinoma - Milind Javle, MD
Churi et al, 2013; PROC AACR/ ASCO/
EORTC
Molecular Profiling of Cholangiocarcinoma - Milind Javle, MD
Somatic Mutations: Biliary Cancer
Intrahepatic
Cholangio
(N=55)
Extrahepatic Cholangio
(N=20)
Mutation %
TP53 34%
KRAS 24%
IDH1/2 24%
ARID1A 20%
CDKN2 16%
MCL1 16%
PBRM1 11%
BAP1 9%
Mutation %
TP53 45%
KRAS 40%
ERBB2* 25%
SMAD4 25%
CDKN2 15%
PIK3CA 15%
FBXW7 15%
BRCA1/2,
PALB2
15%
ERBB2* GVs were mutations
Mutation %
TP53 63%
KRAS 5%
ERBB2 17%
SMAD4 11%
CDKN2 49%
ARID1A 18%
NRAS 5%
Gallbladder Cancer
(N=83)
ERBB2* GVs amplifications
ERRFI-1: ERBB receptor feedback
inhibitor-1
EGFR Targeting in
Cholangiocarcinoma
2/2008 9/2012
Cholangiocarcinoma: Pazopanib + Trametinib
Baseline
8
weeks
Cholangiocarcinoma
BAP1: relation to survival
BAP1(BRCA Associated Protein-1)
 Germline BAP1 mutations: uveal melanoma
and mesothelioma (Science 2010, Nat Gen
2011)
 Somatic BAP1 mutations: prostate, ovarian,
colon, breast, lung cancers, mesothelioma +
intrahepatic cholangiocarcinoma
 BAP1 loss is associated with an aggressive
metastatic phenotype in uveal melanoma,
renal cancer + cholangiocarcinoma
BAP1(BRCA Associated Protein-1) Mutation:
CCA
Clinical phenotype:
Advanced disease at presentation
High proportion of bony metastases
Early PD post chemotherapy
Early recurrence post operatively.
BAP1 is a deubiquitylase +
multiprotein complexes:
Regulates cell cycle, cellular
differentiation, cell death,
gluconeogenesis and the DNA
damage response
(Carbone, Nat Rev Cancer, March
2013)
Targeting Based on Molecular Profile
 Phase I Pazopanib + Trametinib (Zinner)
 BGJ398-FGFR inhibitor for patients with biliary cancer
FGFR-fusions or mutations (Javle)
 BYL719 + Gemcitabine and Cisplatin (Shroff)
 Phase I BKM120: PIK3CA for cases with mutation
(Piha-Paul)
 Phase I Neratinib: ERBB2 mutations (Piha-Paul)
 Phase I Vemurafenib with Irinotecan and Cetuximab
(Hong)
Conclusions
 Somatic mutation profiling is feasible in
biliary tract cancers and has clinical
utility
 Distinct pattern of genetic changes
depending upon site of tumor (intra vs
extrahepatic vs GB cancer)
 Therapeutic and prognostic implications
require prospective investigation
Acknowledgements
Biliary Cancer Working Group
Thomas Aloia
Chaitanya Churi
Claudius Conrad
Christopher Crane
Milind Javle
Harmeet Kaur
Evelyne Loyer
Anirban Maitra
Armeen Mahvash
Rachna Shroff
Jean Nicholas Vauthey
Mingxin Zuo
FOUNDATION MEDICINE
Boston, MA
Gordon Mills, MDACC
Waun Ki Hong
Global Academic Programs
Ivan Roa (Santiago, Chile)
Juan Carlos Roa (Santiago, Chile)
VK Kapoor (Lucknow, India)
S Tanasanvimon (Bangkok, Thailand)
Funding Support
GAP: SINF
Cholangiocarcinoma
Foundation
Donor funds

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Molecular Profiling of Cholangiocarcinoma - Milind Javle, MD

  • 1. Molecular Profiling of Cholangiocarcinoma Milind Javle, MD Associate Professor Department of GI Medical Oncology U.T. M.D. Anderson Cancer Center mjavle@mdanderson.org Cholangiocarcinoma Foundation Stakeholder Meeting February 28, 2014
  • 2. Molecular Profiling: Study Hypothesis Identify novel biomarkers and targets that can be used to improve the outcome: These targets can be explored for their therapeutic value using novel inhibitors Stratification into subgroups with prognostic implications
  • 3. Recent Successes: Targeted Therapy Cancer Genetic Aberration Targeted Agent Clear cell renal carcinoma VHL Bevacizumab, Sunitinib, Sorafenib NSCLC ALK Crizotinib Basal cell carcinoma PTCH1 Hedgehog Inhibitors Melanoma B-RAF Vemurafenib
  • 4. Hotspot Somatic Mutation Detection using Sequenom MassARRAY Advantages  Can be used with a small FFPE sample  Can test multiple genes at the same time  Can test 384 samples at the same time  Can detect a mutation even if present in only 5% of the sample  Relatively cheap Disadvantages  Not useful for detection of fusion genes or for discovering novel targets
  • 5. Targeted Next Generation Sequencing  Ability to fully sequence large numbers of genes in a single test.  Panel is scalable: pharma requirements  Detect deletions, insertions, copy number alterations, translocations and exome-wide base substitutions in known cancer-related genes  Tissue requirement<50 ng DNA: critical in biliary cancers
  • 6. Patient Population (n=158) GB Cancer N=83 • 34 Primary; 49 Metastatic • NGS of 236 cancer-related genes Cholangioca N=75 • 55 intrahepatic; 13 had surgical resection • NGS of 236 cancer-related genes
  • 8. Churi et al, 2013; PROC AACR/ ASCO/ EORTC
  • 10. Somatic Mutations: Biliary Cancer Intrahepatic Cholangio (N=55) Extrahepatic Cholangio (N=20) Mutation % TP53 34% KRAS 24% IDH1/2 24% ARID1A 20% CDKN2 16% MCL1 16% PBRM1 11% BAP1 9% Mutation % TP53 45% KRAS 40% ERBB2* 25% SMAD4 25% CDKN2 15% PIK3CA 15% FBXW7 15% BRCA1/2, PALB2 15% ERBB2* GVs were mutations Mutation % TP53 63% KRAS 5% ERBB2 17% SMAD4 11% CDKN2 49% ARID1A 18% NRAS 5% Gallbladder Cancer (N=83) ERBB2* GVs amplifications
  • 11. ERRFI-1: ERBB receptor feedback inhibitor-1
  • 13. Cholangiocarcinoma: Pazopanib + Trametinib Baseline 8 weeks
  • 15. BAP1(BRCA Associated Protein-1)  Germline BAP1 mutations: uveal melanoma and mesothelioma (Science 2010, Nat Gen 2011)  Somatic BAP1 mutations: prostate, ovarian, colon, breast, lung cancers, mesothelioma + intrahepatic cholangiocarcinoma  BAP1 loss is associated with an aggressive metastatic phenotype in uveal melanoma, renal cancer + cholangiocarcinoma
  • 16. BAP1(BRCA Associated Protein-1) Mutation: CCA Clinical phenotype: Advanced disease at presentation High proportion of bony metastases Early PD post chemotherapy Early recurrence post operatively. BAP1 is a deubiquitylase + multiprotein complexes: Regulates cell cycle, cellular differentiation, cell death, gluconeogenesis and the DNA damage response (Carbone, Nat Rev Cancer, March 2013)
  • 17. Targeting Based on Molecular Profile  Phase I Pazopanib + Trametinib (Zinner)  BGJ398-FGFR inhibitor for patients with biliary cancer FGFR-fusions or mutations (Javle)  BYL719 + Gemcitabine and Cisplatin (Shroff)  Phase I BKM120: PIK3CA for cases with mutation (Piha-Paul)  Phase I Neratinib: ERBB2 mutations (Piha-Paul)  Phase I Vemurafenib with Irinotecan and Cetuximab (Hong)
  • 18. Conclusions  Somatic mutation profiling is feasible in biliary tract cancers and has clinical utility  Distinct pattern of genetic changes depending upon site of tumor (intra vs extrahepatic vs GB cancer)  Therapeutic and prognostic implications require prospective investigation
  • 19. Acknowledgements Biliary Cancer Working Group Thomas Aloia Chaitanya Churi Claudius Conrad Christopher Crane Milind Javle Harmeet Kaur Evelyne Loyer Anirban Maitra Armeen Mahvash Rachna Shroff Jean Nicholas Vauthey Mingxin Zuo FOUNDATION MEDICINE Boston, MA Gordon Mills, MDACC Waun Ki Hong Global Academic Programs Ivan Roa (Santiago, Chile) Juan Carlos Roa (Santiago, Chile) VK Kapoor (Lucknow, India) S Tanasanvimon (Bangkok, Thailand) Funding Support GAP: SINF Cholangiocarcinoma Foundation Donor funds