The Many Faces of Personalized Health Care: Pediatric and Medical Oncology Joshua D. Schiffman, MD Edward B. Clark, MD Chair in Pediatric Research Associate Professor, Pediatric Hematology/Oncology University of Utah School of Medicine April 01, 2014

The Cancer Challenge

• Second leading cause of death worldwide • 8 million deaths per year worldwide • 15 people die from cancer every minute • 1/2 of all men and 1/3 of all women will get cancer • Relapse is leading cause of cancer-related death

Translational Oncology Core Pilot Study

Huntsman Cancer Institute ARUP Laboratories

Translational Oncology Core Pilot Study

• • •

Enroll RELAPSED cancer patients (N=200) Pre- and post-test survey to clinician Sequenom Panel (OncoCarta Custom)

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277 mutation in 25 genes

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Return report to clinician

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OncoScan Array V3.0 (N=48)

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Genome-wide Copy Number/LOH

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74 Mutations in 9 Genes

Translational Oncology Core Pilot Study

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Sequenom:

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ABL1, AKT1, AKT2, BRAF, CDK4, CTNNB1, EGFR, ERBB2, FGFR1, FGFR3, FLT3, HRAS, JAK2, JAK3, KIT, KRAS, MET, MYC, NRAS, PDGFRA, PIK3CA, PTEN, RB1, RET, VHL

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OncoScan (Affy):

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BRAF, KRAS, EGFR, IDH1, IDH2, PTEN, PIK3CA, NRAS, TP53

…So what did we find?

Huntsman Cancer Institute: Molecular Diagnostic/Translational Oncology Core (TOC) Pilot Study

• Positive Mutation Frequency 48 out of 137 specimens were positive for ≥1 mutation (35%)

Huntsman Cancer Institute: Molecular Diagnostic/Translational Oncology Core (TOC) Pilot Study Tumor Types Analyzed by OncoScan (N=48) 15 ovarian/endometrial 15 colorectal tumors 12 melanoma 4 lung tumor 1 brain tumor 1 thyroid tumor

Clinically actionable/relevant copy number genes (N=100) ABL1, AKT1, AKT2, ALK, APC, AR, ARID1A, ASXL1, ATM, AURKA, BAP, BAP1, BCL2L11, BCR, BRAF, BRCA1, BRCA2, CCND1, CCND2, CCND3, CCNE1, CDH1, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CEBPA, CTNNB1, DDR2, DNMT3A, E2F3, EGFR, EML4, EPHB2, ERBB2, ERBB3, ESR1, EWSR1, FBXW7, FGF4, FGFR1, FGFR2, FGFR3, FLT3, FRS2, HIF1A, HRAS, IDH1, IDH2, IGF1R, JAK2, KDM6A, KDR, KIF5B, KIT, KRAS, LRP1B, MAP2K1, MAP2k4, MCL1, MDM2, MDM4, MET, MGMT, MLL, MPL, MSH6, MTOR, MYC, NF1, NF2, NKX2-1, NOTCH1, NPM, NRAS, PDGFRA, PIK3CA, PIK3R1, PML, PTEN, PTPRD, RARA, RB1, RET, RICTOR, ROS1, RPTOR, RUNX1, SMAD4, SMARCA4, SOX2, STK11, TET2, TP53, TSC1, TSC2, VHL

Ciriello et al., Nat Genet. (2013) / Frampton et al., Nat Biotechnol. (2013) Pritchard et al., J Mol Diagn. (2014) / Andre et al., Lancet Oncol. (2014)

TOC Colorectal Adenocarcinoma OncoScan Results (N=15)

Genome view (Nexus, BioDiscovery, Inc.)

Copy number aberrations in 15 colorectal adenocarcinoma cases

BMP-039

Metastatic tumor (left ovary) 90% tumor content by Sequenom KRAS G12S mutation

BMP-039

Metastatic tumor (left ovary) 90% tumor content by Sequenom KRAS G12S mutation

Focal CCND1 gain (4 copies) in LOH region in case BMP-18

Metastatic CRC (liver and bile duct) 50% tumor content by Sequenom KRAS G12D mutation

Focal CDK6 gain (7 copies) in BMP-46

Metastatic CRC (right colon) 30% tumor content by Sequenom KRAS G12C mutation

Next Study Design: 360 Degree Profiling Mutation Panel Genome-wide copy number Genome-wide transcriptome Genome-wide methylation

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Relapsed Pediatric Tumors Relapsed Colorectal Cancer Relapsed Ovarian/Endometrial Relapsed Melanoma Relapsed Sarcoma

Utah and Pediatric Cancer

Tumors found by early screening (Utah)

Grade II Glioma Grade III AA Lung Adenoca.

9 yo boy (TP53) Renal Cell Carcinoma 17 yo girl (TP53) 30 yo man (SDHB) 24 yo man (TP53) 41 yo woman (TP53) Carotid Body Tumor 51 yo woman (SDHB) Carotid Body Tumor 58 yo man (SDHB) Pheochromocytoma 34 yo man (SDHB)

Screening TP53 mutation carriers

100% Survival!

20% Survival

P=0.0056

8 LFS families

−33

TP53

mut + −18 surveillance −12 no surveillance

Surveillance

− 10 tumors, 7 pts − All pts alive

No Surveillance

− 12 tumors, 10 pts − 2 alive (20%)

Villani et al. Lancet Oncology (2011)

Cancer Genetics Study (CGS)

• Familial cancer syndrome global registry and biospecimen bank • Enroll children and families at high risk for cancer • • DNA, cell lines, and tumor samples Biology and clinical data linked to family pedigrees • Participants linked to UPDB

Bella Johnson, Anne Naumer, Wendy Kohlmann

Cancer Genetics Study

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Data collection

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Cancer history

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Medical history

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Genetic testing

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Cancer screening

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Patient reported family history

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Linked to UPDB genealogy records Databases

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CCR, Subject, itBioPath, Progeny

Cancer Genetics Study

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Sample collection

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1ACD tube for cell lines (limited availability)

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1 EDTA tube for DNA and plasma

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1 Red top tube for serum

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1 PAXgene tube for RNA

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1 CPT tube for PBMC

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Archived tissue or excess tissue from surgery if not already in TRAC

PCH Pediatric Cancer Program

• • Life Course Health Care Complications and Costs – Anne Kirchhoff, PhD • Value-Based Pediatric Clinical Cancer Care –

Richard Lemons, MD PhD

• Advanced Therapeutic Approaches to Pediatric Cancer – Mike Spigarelli, MD PhD Identifying New Genes and Novel Screening Approaches for Pediatric Cancer –

Joshua Schiffman, MD

DICER1 Family

“I’m not sure that you guys are really going to be able to find anything with this study if you are stupid enough to drive out here in this weather.”

Summary 1. Precision Oncology is happening now at University of Utah 2. Early tumor surveillance in patients at genetic risk for cancer saves lives 3. PCH Pediatric Cancer Program identifying late effects, toxicities, pharmaco dynamics, and genetic risks 4. UGP is finding cancer-associated genes

Questions?

[email protected]

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Schiffman Lab

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Lisa Abegglen

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Christin Christensen Ashley Chan Marcus Stucki Jamie Gardiner Tonya Santoro Kristy Lee Sharanya Raghunath Clint Mason ARUP

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Sarah South, Xinjie Xu, Erica Andersen, Reha Toydemir Nexus (BioDiscovery)

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Soheil Shams, PhD

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RESEARCH SUPPORT:

ASH Scholar Fellowship Award Curesearch Foundation (Children’s Oncology Group) St. Baldrick’s Foundation Alex’s Lemonade Stand Foundation SARC Career Development Award Children’s Health Research Career Development Award (5K12HD001410-09) Damon Runyon Clinical Investigator Award Leukemia & Lymphoma Society 1R01CA161780-01 (NCI/NIH)

Colorectal Cancer Mutation Summary

Sample ID

BMP-002

BMP-006 BMP-015 CNA/LOH

+++

+ + +++ Sequenom

No mutations

KRAS G12D BRAF V600E KRAS G12C PIK3CA E542K

OncoScan

No mutations

KRAS G12D (6.59) BRAF V600E (9.31)

KRAS G12 D/V

(8.83) PIK3CA E542K (41.22) BMP-018

BMP-025

BMP-036

BMP-047

++ +++

++ ++

+

KRAS G12D

KRAS

No mutations

KRAS G12D/V (10.21) KRAS G12D/V (12.44)

No mutations

PIK3CA

KRAS G12V

mutations KRAS G12D/V (11.36) BMP-040

BMP-041 +++

1/15 (7%) = BMP-043 BMP-046 ++ ++ ++ BRAF mutations KRAS G12C/S (46.16) JAK3 mutation

PIK3CA C420R BRAF V600E KRAS G12C

No mutations

PTEN K267fs*9 (128.56)

(not included in panel)

BRAF V600E (57.54) KRAS G12C/S (21.45)

++

JAK3 V7221

(not included in panel)

Ovarian and Endometrial Samples (N=15): Mutation Summary Sample CNA Sequenom OncoScan

BMP 1 Yes No Mutations No Mutations

BMP 4 Yes PIK3CA p.E545K

PIK3CA p.E545K

BMP 5 Yes No Mutations No Mutations BMP 8 BMP12 Yes Yes No Mutations No Mutations

TP53 p.R273H/L

No Mutations BMP20 BMP23 Yes Yes

PIK3CA p.R88Q

No Mutations

PIK3CA

BMP26 Yes Yes

PTEN p.N323fs*2

No Mutations

PTEN BMP28

BMP29

Yes

No

PIK3CA p.H1047R

No Mutations

TP53 TP53 p.R248Q/L mutations KRAS p.G12D/V

(Score:8.32)

PIK3CA p.H1047R mutations

BMP42 Yes No Mutations No Mutations

BMP44

BMP45

Yes

Yes

PIK3CA p.Q546K

No Mutations

PIK3CA p.Q546K

No Mutations BMP48 Yes No Mutations No Mutations

Metastatic Melanoma (N=12): Mutation Summary Case ID BMP-009 CNAs Yes By Sequenom NRAS Q61K Mutation By OncoScan NRAS Q61K Mutation

BMP-037 Yes Yes No Mutations No Mutations No Mutations

BMP-013

BMP-019

Yes Yes

Yes

Yes

BMP-024 BMP-030 Yes Yes

NRAS G12C Mutation NRAS G12C Mutation NRAS

No Mutations

BRAF

No Mutations

PTEN mutation BRAF V600E Mutation

No Mutations

NRAS Q61R mutation

No Mutations No Mutations

BMP-031

BMP-034

Yes

Yes

NRAS Q61K Mutation PIK3CA NRAS Q61K Mutation mutation BMP-035 Yes PTEN R130fs*4 mutation PTEN R130fs*4 mutation

(CCND1 amplification)