Different drug regularity bodies in different countries.
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
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
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