molecular profiling of cholangiocarcinoma - milind javle, md
DESCRIPTION
From the 2014 Cholangiocarcinoma Foundation's Stakeholders Meeting. February 27-28, 2014 at the Huntsman Cancer Institute, University of UtahTRANSCRIPT
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Molecular Profiling of Cholangiocarcinoma
Milind Javle, MDAssociate Professor
Department of GI Medical OncologyU.T. M.D. Anderson Cancer Center
Cholangiocarcinoma Foundation Stakeholder Meeting
February 28, 2014
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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
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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
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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
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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
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Patient Population (n=158)
GB Canc
erN=8
3
• 34 Primary; 49 Metastatic• NGS of 236 cancer-related
genes
CholangiocaN=7
5
• 55 intrahepatic; 13 had surgical resection
• NGS of 236 cancer-related genes
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Churi et al, 2013; PROC AACR/ ASCO/ EORTC
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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
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ERRFI-1: ERBB receptor feedback inhibitor-1
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EGFR Targeting in Cholangiocarcinoma
2/2008
9/2012
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Cholangiocarcinoma: Pazopanib + Trametinib
Baseline
8 weeks
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Cholangiocarcinoma BAP1: relation to survival
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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
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BAP1(BRCA Associated Protein-1) Mutation: CCA
Clinical phenotype:
Advanced disease at presentationHigh proportion of bony metastasesEarly PD post chemotherapyEarly 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)
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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)
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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
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Acknowledgements
Biliary Cancer Working GroupThomas 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 ProgramsIvan Roa (Santiago, Chile)
Juan Carlos Roa (Santiago, Chile)
VK Kapoor (Lucknow, India)
S Tanasanvimon (Bangkok, Thailand)
Funding SupportGAP: SINFCholangiocarcinoma FoundationDonor funds