molecular profiling of cholangiocarcinoma - milind javle, md

Molecular Profiling of Cholangiocarcinoma

Milind Javle, MDAssociate Professor

Department of GI Medical OncologyU.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 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

Churi et al, 2013; PROC AACR/ ASCO/ EORTC

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 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)

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 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