The Many Faces of Personalized Health The Many Faces of Personalized Health Care: Pediatric and Medical OncologyCare: Pediatric and Medical Oncology

Joshua D. Schiffman, MDEdward 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

Huntsman Cancer Institute

ARUP Laboratories

Translational Oncology Core

Pilot Study

Translational Oncology Core

Pilot Study

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

– 277 mutation in 25 genes– Return report to clinician

• OncoScan Array V3.0 (N=48)– Genome-wide Copy Number/LOH– 74 Mutations in 9 Genes

Translational Oncology Core

Pilot Study

• Sequenom:– 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

• OncoScan (Affy):– 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 Frequency48 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/endometrial15 colorectal tumors

12 melanoma4 lung tumor1 brain tumor

1 thyroid tumor

Tumor Types Analyzed by OncoScan (N=48)

15 ovarian/endometrial15 colorectal tumors

12 melanoma4 lung tumor1 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

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,

VHLCiriello 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 SequenomKRAS G12S mutation

BMP-039 Metastatic tumor (left ovary) 90% tumor content by SequenomKRAS G12S mutation

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

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

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

Focal CDK6 gain (7 copies) in BMP-46

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

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

Next Study Design:

360 Degree Profiling

Mutation PanelGenome-wide copy numberGenome-wide transcriptomeGenome-wide methylation

360 Degree Profiling

Mutation PanelGenome-wide copy numberGenome-wide transcriptomeGenome-wide methylation

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

Utah and Pediatric Cancer

Tumors found by early screening (Utah)

9 yo boy (TP53)

17 yo girl (TP53)

24 yo man (TP53)

41 yo woman (TP53)

30 yo man (SDHB)

51 yo woman (SDHB)

58 yo man (SDHB)

34 yo man (SDHB)

Grade II Glioma

Grade III AA Lung Adenoca.

Renal Cell Carcinoma

Carotid Body Tumor

Carotid Body Tumor Pheochromocytom

a

Villani et al. Lancet Oncology (2011)

100% Survival!

P=0.0056P=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%)

Screening TP53 mutation carriers

20% Survival

Bella Johnson, Anne Naumer, Wendy KohlmannBella Johnson, Anne Naumer, Wendy Kohlmann

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

Cancer Genetics Study• Data collection

– Cancer history– Medical history– Genetic testing– Cancer screening– Patient reported family history– Linked to UPDB genealogy records

• Databases– CCR, Subject, itBioPath, Progeny

• Sample collection– 1ACD tube for cell lines (limited availability)– 1 EDTA tube for DNA and plasma– 1 Red top tube for serum– 1 PAXgene tube for RNA– 1 CPT tube for PBMC– Archived tissue or excess tissue from surgery if

not already in TRAC

Cancer Genetics Study

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.”

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

Summary

Questions?

Joshua.Schiffman@hci.utah.edu

• Schiffman Lab– Lisa Abegglen– Christin Christensen– Ashley Chan– Marcus Stucki– Jamie Gardiner– Tonya Santoro– Kristy Lee– Sharanya Raghunath– Clint Mason

• ARUP– Sarah South, Xinjie Xu, Erica

Andersen, Reha Toydemir

• Nexus (BioDiscovery)– Soheil Shams, PhD

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 SummarySample ID CNA/LOH Sequenom OncoScan

BMP-002 +++ No mutations No mutations

BMP-006 + KRAS G12D KRAS G12D (6.59)

BMP-015 + BRAF V600E BRAF V600E (9.31)

BMP-017 +++ KRAS G12C PIK3CA E542K

KRAS G12D/V (8.83) PIK3CA E542K (41.22)

BMP-018 ++ KRAS G12D KRAS G12D/V (10.21)

BMP-022 +++ KRAS G12D KRAS G12D/V (12.44)

BMP-025 ++ No mutations No mutations

BMP-033 ++ No mutations No mutations

BMP-036 + KRAS G12V KRAS G12D/V (11.36)

BMP-039 ++ KRAS G12S KRAS G12C/S (46.16)

BMP-040 ++ KRAS G12D KRAS G12D/V (12.47)

BMP-041 +++ No mutations No mutations

BMP-043 -PTEN K267fs*9 PIK3CA C420R

BRAF V600E

PTEN K267fs*9 (128.56)(not included in panel)

BRAF V600E (57.54)

BMP-046 ++ KRAS G12C KRAS G12C/S (21.45)

BMP-047 ++ JAK3 V7221 (not included in panel)

14/15 (93%) = Copy Number Present

8/15 (53%) = KRAS mutations

2/15 (13%) = PIK3CA mutations

2/15 (13%) = BRAF mutations

1/15 (7%) = JAK3 mutation

Sample CNA Sequenom OncoScanBMP 1 Yes No Mutations No Mutations

BMP 4 Yes PIK3CA p.E545K PIK3CA p.E545K

BMP 5 Yes No Mutations No Mutations

BMP 8 Yes No Mutations TP53 p.R273H/L

BMP12 Yes No Mutations No Mutations

BMP20 Yes PIK3CA p.R88Q TP53 p.R248Q/L

BMP23 Yes No Mutations No Mutations

BMP26 Yes PTEN p.N323fs*2 KRAS p.G12D/V (Score:8.32)

BMP27 Yes No Mutations No Mutations

BMP28 Yes PIK3CA p.H1047R PTEN p.R130G

PIK3CA p.H1047R PTEN p.R130G

BMP29 No No Mutations No Mutations

BMP42 Yes No Mutations No Mutations

BMP44 Yes PIK3CA p.Q546K PIK3CA p.Q546K

BMP45 Yes No Mutations No Mutations

BMP48 Yes No Mutations No Mutations

Ovarian and Endometrial Samples (N=15):Mutation Summary

14/15 (93%) = Copy Number Present

4/15 (27%) = PIK3CA mutations

2/15 (13%) = PTEN mutations

2/15 (13%) = TP53 mutations

Metastatic Melanoma (N=12):Mutation Summary

Case ID CNAs By Sequenom By OncoScan

BMP-009 Yes NRAS Q61K Mutation NRAS Q61K Mutation

BMP-010 Yes No Mutations No Mutations

BMP-013 Yes NRAS G12C Mutation NRAS G12C Mutation

BMP-014 Yes BRAF V600E Mutation BRAF V600E Mutation

BMP-019 Yes No Mutations No Mutations

BMP-021 Yes NRAS Q61R mutation NRAS Q61R mutation

BMP-024 Yes No Mutations No Mutations

BMP-030 Yes PIK3CA H701P mutation No Mutations

BMP-031 Yes NRAS Q61K Mutation NRAS Q61K Mutation

BMP-034 Yes BRAF K601E Mutation No Mutations

BMP-035 Yes PTEN R130fs*4 mutation PTEN R130fs*4 mutation

BMP-037 Yes No Mutations (CCND1 amplification)

12/12 (100%) = Copy Number Present

4/12 (33%) = NRAS mutations

2/12 (17%) = BRAF mutations

1/12 (8%) = PTEN mutation

1/12 (8%) = PIK3CA mutation