the many faces of personalized health care: pediatric and medical oncology
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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. - PowerPoint PPT PresentationTRANSCRIPT
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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
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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
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Huntsman Cancer Institute
ARUP Laboratories
Translational Oncology Core
Pilot Study
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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
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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
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…So what did we find?
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Huntsman Cancer Institute: Molecular Diagnostic/Translational Oncology Core (TOC) Pilot Study
• Positive Mutation Frequency48 out of 137 specimens were positive for ≥1 mutation (35%)
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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
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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)
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TOC Colorectal Adenocarcinoma OncoScan Results (N=15)
Genome view(Nexus, BioDiscovery, Inc.)
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Copy number aberrations in 15 colorectal adenocarcinoma cases
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BMP-039 Metastatic tumor (left ovary) 90% tumor content by SequenomKRAS G12S mutation
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BMP-039 Metastatic tumor (left ovary) 90% tumor content by SequenomKRAS G12S mutation
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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
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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
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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
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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
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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
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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
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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
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• 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
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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
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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.”
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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
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• 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)
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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
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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
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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