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Molecular Phenotype Guided Therapy for Pancreatic Cancer

David Chang Clinical Senior Lecturer Wolfson Wohl Cancer Research Centre ECMC Annual Network Meeting 14th May 2014

Outline

•  Cancer is heterogeneous �  APGI sequencing project (mutational landscape) �  Therapeutic implications �  DNA-damaging agents responsive phenotype

•  Lesson learnt so far and challenges ahead

Cancer is complex & Heterogeneous

International Cancer Genome Consortium (ICGC)

CANADA• Pancreatic cancer (Ductal adenocarcinoma)• Pediatric brain tumors (Medulloblastoma)• Prostate cancer (Adenocarcinoma)

GERMANY• Lung cancer (Multiple rare subtypes) • Malignant lymphoma (Germinal center B-cell derived lymphomas)• Pediatric brain tumors (Medulloblastoma and Pediatric pilocytic astrocytoma)• Prostate cancer (Early onset)

UNITEDKINGDOM

• Bone cancer (Osteosarcoma/ chondrosarcoma/ rare subtypes)• Breast cancer (Triple negative/lobular/ other)• Chronic Myeloid Disorders (Myelodysplastic syndromes, myeloproliferative neoplasms and other chronic myeloid malignancies) • Esophageal cancer (Esophageal adenocarcinoma) • Prostate cancer

EU / UNITEDKINGDOM

• Breast cancer (ER positive, HER2 negative)

• Bladder cancer• Blood cancer (Acute lymphoblastic leukemia/ Acute myeloid leukemia) • Brain cancer (Glioblastoma multiforme/ Lower grade glioma)• Breast cancer (Ductal & lobular)• Cervical cancer (Squamous) • Colorectal cancer (Adenocarcinoma)• Endometrial cancer (Uterine corpus endometrial carcinoma)• Gastric cancer (Adenocarcinoma)• Head and neck cancer (Squamous cell carcinoma/ Thyroid carcinoma)• Liver cancer (Hepatocellular carcinoma)• Lung cancer (Adenocarcinoma/ Squamous cell carcinoma)• Ovarian cancer (Serous cystadenocarcinoma)• Pancreatic cancer (Adenocarcinoma)• Prostate cancer (Adenocarcinoma)• Renal cancer (Renal clear cell carcinoma/ Renal papillary carcinoma)• Skin cancer (Cutaneous melanoma)

UNITED STATES ITALY• Rare pancreatic tumors (Enteropancreatic endocrine tumors and rare pancreatic exocrine tumors)

CHINA• Bladder cancer (Urothelial carcinoma)• Blood cancer (Acute myeloid leukaemia and Chronic myelogenous leukaemia)• Brain cancer (Glioblastoma multiforme)• Breast cancer (Triple negative)• Colorectal cancer (Adenocarcinoma, non-Western)• Esophageal cancer (Squamous carcinoma)• Gastric cancer (Intestinal- and diffuse-type)

• Liver cancer (Hepatocellular carcinoma, HBV-associated)• Lung cancer (Squamous cell carcinoma)• Nasopharyngeal cancer (Nasopharyngeal carcinoma, Asia)• Ovarian cancer• Pancreatic cancer (Ductal adenocarcinoma) • Prostate cancer• Renal cancer (Clear cell renal cell carcinoma)• Thyroid cancer (Papillary carcinoma)

• Thyroid cancer (Papillary carcinoma)

SAUDI ARABIA

• Blood cancer (Acute myeloid leukaemia)• Breast cancer (Asian phenotype)• Lung cancer (Adenocarcinoma/ Squamous cell carcinoma)

SOUTH KOREA

Grey = Collaboration

EU / FRANCE• Renal cancer (Renal cell carcinoma) (Focus on but not limited to clear cell subtype)

MEXICO• Blood cancer (Diffuse large B-cell lymphoma)• Breast cancer (Ductal carcinoma)• Cervical cancer • Head and neck cancer (Squamous cell carcinoma of oral cavity/oropharynx/ sinonasal cavity/ hypopharynx/larynx)• Pediatric solid tumors

SPAIN• Chronic lymphocytic leukemia (CLL with mutated and unmutated IgVH) FRANCE

• Breast cancer (Subtype defined by an amplification of the HER2 gene)• Ewing sarcoma • Liver cancer (Hepatocellular carcinoma) (Secondary to alcohol and adiposity)• Prostate cancer (Adenocarcinoma)

AUSTRALIA• Ovarian cancer (Serous cystadenocarcinoma)• Pancreatic cancer (Ductal adenocarcinoma/ Neuroendocrine tumors)• Prostate cancer

JAPAN• Liver cancer (Hepatocellular carcinoma) (Virus-associated)

SINGAPORE• Biliary tract cancer (Gall bladder cancer/ Cholangiocarcinoma)

BRAZIL• Skin cancer (Melanoma)

INDIA• Oral cancer (Gingivobuccal)

Australian Pancreatic Cancer Genome Initiative (APGI)

Prospective observational cohort study design (350 PDAC)

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Genomic Landscape of PDAC

•  KRAS (93%), •  TP53 (42%), •  SMAD4 (20%) •  MLL3 (8%) •  PCDH15 (7%) •  TGFBR2 (6%) •  SF3B1 (5%) •  ARID1A (5%) •  ATM (5%) •  CDKN2A (4%)

•  Whole Exome Capture and Sequencing + CNV (n=142) (Biankin et al., Nature 2012)

•  38 of 79 (> 1 mutations) identified by Jones et al. (2008 n=24) •  186 of 998 of Jones et al. (2008) •  19% overlap •  1456 novel genes mutated

Ave Coverage: 68 - 200x 90% > 15 independent reads CNV: 10% of Genome

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Known oncogenes: KRAS: 93% GNAS: 7% SF3B1: 4% Known TSG: TP53 70% CDKN2A 24% SMAD4 22% ARID1A 16% BRCA1 4% SLIT2 4%

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Non-Silent Point Mutations in PDAC (WGS)

Waddell, Pajic, Patch, Chang et al, in submission

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Multiple Subtypes : Implications for Development of Therapeutic Strategy Heterogeneity = Therapeutic development implications

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Fool’s Gold or Lost Treasures??

Stewart & Kurzrock, BMC Cancer 2013

Not Approved Approved

Target in 15% Target in 16.7%

P = 0.06 P = 0.04

(Exceptional) Responders

n = 11

Simulation of 334 NSCLC patients (actual survival) in each arm (668 in total)

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Waddell, Pajic, Patch, Chang et al, in submission

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Chang et al, Nat Rev Cancer, 2014

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Pajic & Chang et al, in preparation

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HER2 Amplified (2%): GEM + Trastuzumab KRAS wild type (5%): GEM + Erlotinib BRCA2 Germ Line mutant (3%): MMC + Capecitabine

Initially direct recruitment of ICGC patients Then panel-based screening

•  Logistically demanding: tissue acquisition, QC, drugs •  Patients randomised to standard of care withdraw and buy

drug themselves •  Screening time (main problem is sample delivery) •  Sample variability (different path labs) •  Low prevalence phenotypes (need to screen large numbers) •  Screening cost (genome maybe cheaper, bioinformatics still

the same)

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•  Patients without an actionable phenotype (what is best SOC?) •  Social and ethical implications with sequencing (framework for

return of results) •  Change of technology (re-validation) •  Lots more to be learnt & lots more challenges ahead

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Biobanking & QC

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1. Independent Pathological review in Australia, Italy and USA.

2. 5mm3 frozen blocks of Tumour are sectioned to locate non-tumour tissue.

3. Tumour rich regions are dissected form block and DNA/RNA extracted

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How to integrate detailed molecular information into clinical practice: Molecular MDT

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ABCC9,ADAMTS20, AMAC1L2,, BLID, BRCC3, CACNA1C, CAPN11, CENPE, COLEC11, CTCF, FRMD6, GPR137B, LEMD2, PIK3CD, PXDN, RPA1..

Mutation burden

Mutational Signature

Breakpoint Signature

Telomere status

Mutations

Genome organization

Ploidy

Clonality

Germline/Inheritance

Comprehensive Cancer Genome analysis:

(<3 days)

Evolution

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Cost of Sequencing is dropping dramatically (technology is here!!)

Green & Guyer, Nature 2011

Harness the Technology: From Base Pairs to Bedside

Knowledge Bank Approach

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Data Sharing at a Global Scale

http://genomicsandhealth.org/

185 organisations, 26 countries 1st meeting March 2014

Jeff Evans Juan Valle Andrew Biankin Sean Grimmond and more��

Smarter and more Nimble Trial Designs

Better Integration between Key Elements

Translate Research Medicine to Routine Patient Care�

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QCMG: Sean Grimmond Garvan: Andrew Biankin

Emily Colvin Amanda Mawson Johana Susanto Marina Pajic Mona Martyn-Smith Lorraine Chantrill Adnan Nagrial Venessa Chin

Bioinformatics: John Pearson Lynn Fink Darrin Taylor David Wood Conrad Leonard Oliver Holmes Christina Xu Matthew Anderson Scott Wood Sarah Song Felicity Newell

GenomeSeq: David Miller Tim Bruxner Craig Nourse Ehsan Nourbakhsh Suzanne Manning Angelika Christ Ivon Harliwong Senel Idrisoglu

Genome Biology: Nic Waddell Karin Kassahn Ann-Marie Patch Katia Nones Nicole Cloonan Anita Steptoe Shivangi Wani Keerthana Krishnan Jason Steen Muhammad Fadlullah Kelly Quek

Rob Sutherland Liz Musgrove Roger Daly James Kench

Chris Scarlett Marc Jones David Chang Jianmin Wu Anthony Gill Page Tobelman Jeremy Humphris Mark Pinese Mark Cowley Angela Chou Lorraine Chantrill Adnan Nagrial Venessa Chin

Amber Johns Scott Mead Michelle Thomas Chris Toon Mary-Anne Brancato Cathy Axford

QCMG: Sean Grimmond Garvan: Andrew Biankin

APGI collaborators & patients

Acknowledgements

Verona: Aldo Scarpa Claudio Bassi Paolo Pederzoli Rita Lawlor

Johns Hopkins: Ralph Hruban Jim Eshleman Anirban Maitra Chris Iacobuzio-Donahue

Sanger: Ludmil Alexandrov Serena Nik-Zainal Peter Campbell Mike Stratton

Glasgow: Ross Carter Colin Mackay Nigel Jamieson Euan Dickson Mark Duxbury Karin Oien Jane Hair Fraser Duthie Jeff Evans

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