All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer...
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Advancing Cancer Genomics: The Impact of Personalized Genome SequencingAdvancing Cancer Genomics: The Impact of Personalized Genome Sequencing
PLEASE STAND BY… the webinar
will begin shortly…
Webinar SeriesWebinar SeriesScienceScience
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Advancing Cancer Genomics: The Impact of Personalized Genome SequencingAdvancing Cancer Genomics: The Impact of Personalized Genome Sequencing
Sponsored by:
Participating Experts:
Brought to you by the Science/AAAS Custom Publishing Office
Webinar SeriesWebinar SeriesScienceScience
25 February, 2013
Elaine Mardis, Ph.D.Washington University in St. LouisSt. Louis, MO
Michael Snyder, Ph.D.Stanford UniversityStanford, CA
Philip Stephens, Ph.D.Foundation MedicineCambridge, MA
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Next-Generation Sequencing: Translation to Cancer Prognosis, Diagnosis and Care
Elaine R. Mardis, Ph.D.Co-director, The Genome InstituteProfessor of GeneticsWashington University School of Medicine
Science/AAAS webinar February 2013
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Why is cancer WGS analysis “easy”?
• The comparison of a patient’s tumor to their normal genome • Provides an individualized comparison of what is truly somatic vs.
what is truly inherited (germline)• Existence of online information about frequently mutated genes in
cancer samples (COSMIC)• Large-scale efforts using NGS methods to catalogue mutated genes
(e.g. TCGA, ICGC)
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Why is cancer genome analysis challenging?
• In solid tumors, normal cells are present to differing degrees. Certain tumor types are quite diffuse (prostate, pancreas) and may require specific tumor cell isolation by LCM or flow sorting
• FFPE preparation from pathology (DNA/RNA degradation)• Aneuploidy and amplification of chromosomal segments
impacts the coverage model• Cellular heterogeneity: not all cells contain all mutations
and “druggable” mutations may be present at low levels (in a minor subclone)
• In blood or “liquid” tumors, a skin biopsy is taken for the normal but may contain high circulating tumor cells
• A cheek swab or mouthwash normal can be substituted, but lots of bacterial genomes get sequenced too…
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Every cancer genome is different…
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EGFR mutations in lung cancer
K DFG R Y
Tyrosine kinase
745 Y869
K DFG Y Y Y YTM
718 964
EGF ligand binding autophos
GXGXXG
835
R
776
H
858 947
MLREA
By directed PCR and capillary sequencing, we determined that ~80% of Iressaresponders have EGFR mutations in the tyrosine kinase domain
W. Pao et al., PNAS 2004
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Comprehensive Cancer Sequencing
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Read Alignment Enables Discovery and Integration
Whole genome sequencing
Exome or targeted sequencing
Whole transcriptome sequencing
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Annotating Somatic Alterations
Tier 1
Tier 2
Tier 3
Tier 4
8.6% (conserved/regulatory)1.3% (“the exome”)
41.4% other unique48.7%
(repetitive)
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Welch et al., JAMA 2011: 305(15): 1577-1584.
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Disease progression as an evolutionary process
Diagnosis: Multiple leukemic clones
present
Clinical remission: loss of most
leukemic clones
Relapse: Acquisition of new mutations in a pre-existing clone
• Multi-clonal or mono-clonal primary disease, wherein relapse always involvesnew mutations, some with unknown relevance
Ding et al., Nature 2012
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SNVs
Indels
SVs
CNVs
Fusions
DE genes
DE isoforms
Somatic/Germline Cancer Events
(DNA+RNA)
Drug-Gene interaction database-DGIdb
(24 database sources)
Filtered (activating/drivers)
Candidate genes/pathways
Clinically actionable events
Clinically actionable events
Functional annotation
DrugBank
TTD
clinicaltrials.gov
PharmGKB
STICH2
Kinases
RTKs
NetMHCPan
Clinical prioritization and reporting
Clinical Genome Analysis/Interpretation Pipeline
Malachi & Obi Griffith, Scott Smith
**
****
**
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Therapeutic Predictions for NSCLC Mutations
Govindan et al., Cell 2012
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Before AfterMost NSCLC patients with mutations in the epidermal growth factor receptor (EGFR) gene are exquisitely sensitive to tyrosine kinase inhibitors (TKIs) These patients often achieve remarkable relief from their tumor burden, but most progress to metastatic disease while on therapy, due to acquired resistance.
Targeted Therapies Often Lead to Therapy Resistance
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A reality for targeted therapy prediction: Off-label FDA
We predicted Lukas’ 2nd relapse ALL would respond to Sutent due to FLT3 over-expressionSutent is not FDA approved for use in ALL treatmentPfizer twice rejected compassionate use requests from Lukas
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Personalized Immunotherapy
• Identifying the most highly expressed tumor‐specific neo‐antigens present in each patient’s tumor requires an algorithmic evaluation of their genic missense mutations with the HLA class 1 subtype • This approach generates a prioritized list of neo‐antigens that can be used either to generate a DNA‐based vaccine or a mature dendritic cell‐based vaccine that is highly personalized to their tumor cell antigens• Our early work in this approach is establishing a workflow and tractable clinical timeframe for neo‐antigen identification, vaccine production and in vitro functional evaluation prior to the patient’s receipt of the vaccine
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Advancing Cancer Genomics: The Impact of Personalized Genome SequencingAdvancing Cancer Genomics: The Impact of Personalized Genome Sequencing
Sponsored by:
Participating Experts:
Brought to you by the Science/AAAS Custom Publishing Office
Webinar SeriesWebinar SeriesScienceScience
25 February, 2013
Elaine Mardis, Ph.D.Washington University in St. LouisSt. Louis, MO
Michael Snyder, Ph.D.Stanford UniversityStanford, CA
Philip Stephens, Ph.D.Foundation MedicineCambridge, MA
![Page 19: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/19.jpg)
Cancer Genomics
Michael Snyder
February 25, 2013
Conflicts: Personalis, Genapsys, Illumina
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• Whole genome sequencing from archival cancer samples (formalin fixation and paraffin embedding).
• Illumina sequencing with 100 base paired end reads using a HiSeq 2000 system.
• Analysis of copy number aberrations and other genetic aberrations
Two Examples Metastatic Colorectal Cancer Genome Sequencing Analysis
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Patient 2382 – Metastatic colorectal cancerChromosome 7: Two amplification regions
Chr 7p arm Chr 7q armLog 2 ratio‐
genomic copy
number
Chromosome 7 coordinates (Mb) NCBI 37
• Both loci > 10 copy number showing statistical significance.
• EGFR amplification is in ~3% of colorectal cancers (Cancer Genome Atlas)
CEN
Normal diploid copy numberEGFR CDK6
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• FFPE 5 micron sections of primary tumor
• Gene amplification containing a CDK8 on Chr 13.
Patient 2222 – metastatic colorectal cancer
CDK8
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Identifying novel driving variations in complex cancer genomes remains
challenging, especially in a personalized manner?
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Integrative Profiling of Esophageal Cancer
• Used laser‐capture microdissection to isolate tumor and paired normal tissue• LCM critical for transcriptome analysis of normal tissue
• Complete Genomics whole genome sequencing• HiSeq 2x101 bp paired‐end RNA‐sequencing• Nimblegen 2.1M CNV array
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How to find potential driver mutations‐ RNA Sequencing
Deep genome sequencing>20,000 SNVs and Indels>1000 Structural Variants
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Copy number is concordant with gene expression changes
Could refine CNV list by looking for enrichment of concordant gene expressionOutliers could be interesting cases
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CNVs with concordant gene expression
(number of overlapping genes)
Amplifications containing more up regulated genes are enriched in genes annotated with GO terms related to cell cycle and division
GO Enrichment
UpregulatedGenes
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GO enrichment on specifically induced genes: Metastasis
OFF ON genes
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GO enrichment on down regulated genes:Cell differentiation
≥2x Down genes
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Expression can also be used to prioritize single nucleotide variant lists
• Examined RNA‐seq data to look for evidence of genomically called somatic SNVs
• As others have observed about a third of nonsynonymous (NS) variants are expressed
• Known TP53 (Y220C) loss‐of‐function, mutation that destabilizes protein
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Conclusions:
1) Druggable targets can be readily found by WGS
2) Transcriptome sequencing of both matched normal and tumor samples can be use as an effective filter for novel somatic variation discovered by cancer genome sequencing
3) Given the low recurrence rates of most novel variants, functional characterization of these variants in relevant models will become increasing important
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Acknowledgements
CRC: Hanlee Ji, Hassan Chaib, George Fisher
Esophageal Cancer: Jason Reuter
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Advancing Cancer Genomics: The Impact of Personalized Genome SequencingAdvancing Cancer Genomics: The Impact of Personalized Genome Sequencing
Sponsored by:
Participating Experts:
Brought to you by the Science/AAAS Custom Publishing Office
Webinar SeriesWebinar SeriesScienceScience
25 February, 2013
Elaine Mardis, Ph.D.Washington University in St. LouisSt. Louis, MO
Michael Snyder, Ph.D.Stanford UniversityStanford, CA
Philip Stephens, Ph.D.Foundation MedicineCambridge, MA
![Page 34: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/34.jpg)
‹›
Advancing Cancer Genomics: The Impact of Personalized Genome Sequencing
Phil Stephens, Head of R&D, Foundation Medicine Inc, Cambridge, MA
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‹›
Therapies targeting the alterations that drive an individual patient’s disease can be very effective
Matching the correct targeted therapy to the correct patient is diagnosticallychallenging as the number of “clinically relevant” genomic alterations increases
Pre‐therapy Post‐therapy
Patient with BRAF V600E mutated malignant melanoma treated with selective inhibitor of BRAF (Vemurafenib)
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‹›
The complexity of solid cancer genomes poses significant diagnostic challenges
Pre-cancerous In situ Invasive Metastaticlesion cancer cancer cancer
Mutagenic exposureGenetic InstabilityGenomic instability
Genomic alterations NumberTotal 10,000sClinically relevant 1‐2
Number of “clinically relevant” alterations in a single patient is LOW, buried amongst 1,000s of total genomic alterations
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‹›
• Number of clinically relevant genomic alterations across a disease indication (e.g. Lung cancer) is HIGH
• The five clinically relevant types of genomic alterations (base sub, indel, amplification, homozygous deletion and gene fusion) each pose different diagnostic challenges
• Low tumoral purity in many clinical specimens requires diagnostic tests with extremely high accuracy
• Many clinical cancer specimens are FFPE which can damage DNA and include needle biopsies which are tiny
• The clinical report must be comprehensive but easily interpretable by a busy community oncologist
Diagnostic challenge: Translating NGS from the research setting into the clinic
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‹›
• Number of clinically relevant genomic alterations across a disease indication (e.g. Lung cancer) is HIGH
• The five clinically relevant types of genomic alterations (base sub, indel, amplification, homozygous deletion and gene fusion) each pose different diagnostic challenges
• Low tumoral purity in many clinical specimens requires diagnostic tests with extremely high accuracy
• Many clinical cancer specimens are FFPE which can damage DNA and include needle biopsies which are tiny
• The clinical report must be comprehensive but easily interpretable by a busy community oncologist
Diagnostic challenge: Translating NGS from the research setting into the clinic
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‹›
• Number of clinically relevant genomic alterations across a disease indication (e.g. Lung cancer) is HIGH
• The five clinically relevant types of genomic alterations (base sub, indel, amplification, homozygous deletion and gene fusion) each pose different diagnostic challenges
• Low tumoral purity in many clinical specimens requires diagnostic tests with extremely high accuracy
• Many clinical cancer specimens are FFPE which can damage DNA and include needle biopsies which are tiny
• The clinical report must be comprehensive but easily interpretable by a busy community oncologist
Diagnostic challenge: Translating NGS from the research setting into the clinic
![Page 40: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/40.jpg)
‹›
• Number of clinically relevant genomic alterations across a disease indication (e.g. Lung cancer) is HIGH
• The five clinically relevant types of genomic alterations (base sub, indel, amplification, homozygous deletion and gene fusion) each pose different diagnostic challenges
• Low tumoral purity in many clinical specimens requires diagnostic tests with extremely high accuracy
• Many clinical cancer specimens are FFPE which can damage DNA and include needle biopsies which are tiny
• The clinical report must be comprehensive but easily interpretable by a busy community oncologist
Diagnostic challenge: Translating NGS from the research setting into the clinic
![Page 41: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/41.jpg)
‹›
• Number of clinically relevant genomic alterations across a disease indication (e.g. Lung cancer) is HIGH
• The five clinically relevant types of genomic alterations (base sub, indel, amplification, homozygous deletion and gene fusion) each pose different diagnostic challenges
• Low tumoral purity in many clinical specimens requires diagnostic tests with extremely high accuracy
• Many clinical cancer specimens are FFPE which can damage DNA and include needle biopsies which are tiny
• The clinical report must be comprehensive but easily interpretable by a busy community oncologist
Diagnostic challenge: Translating NGS from the research setting into the clinic
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‹›
FoundationOne™: Comprehensive NGS‐based cancer genomic profiling assay specifications
• One comprehensive genomic profile to detect all clinically relevant genomic alterations in a single assay
• Focused on the 236 known clinically & biologically relevant cancer genes
• Validated high accuracy from routine clinical specimens with ≥20% tumor nuclei
• Requires small amounts of tissue from routine FFPE samples including needle biopsies (≥50ng of DNA)
• Customized computational biology algorithms validated for high sensitivity and specificity in samples with low purity
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‹›
FoundationOne™: Comprehensive NGS‐based cancer genomic profiling assay specifications
• One comprehensive genomic profile to detect all clinically relevant genomic alterations in a single assay
• Focused on the 236 known clinically & biologically relevant cancer genes
• Validated high accuracy from routine clinical specimens with ≥20% tumor nuclei
• Requires small amounts of tissue from routine FFPE samples including needle biopsies (≥50ng of DNA)
• Customized computational biology algorithms validated for high sensitivity and specificity in samples with low purity
![Page 44: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/44.jpg)
‹›
FoundationOne™: Comprehensive NGS‐based cancer genomic profiling assay specifications
• One comprehensive genomic profile to detect all clinically relevant genomic alterations in a single assay
• Focused on the 236 known clinically & biologically relevant cancer genes
• Validated high accuracy from routine clinical specimens with ≥20% tumor nuclei
• Requires small amounts of tissue from routine FFPE samples including needle biopsies (≥50ng of DNA)
• Customized computational biology algorithms validated for high sensitivity and specificity in samples with low purity
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‹›
FoundationOne™: Comprehensive NGS‐based cancer genomic profiling assay specifications
• One comprehensive genomic profile to detect all clinically relevant genomic alterations in a single assay
• Focused on the 236 known clinically & biologically relevant cancer genes
• Validated high accuracy from routine clinical specimens with ≥20% tumor nuclei
• Requires small amounts of tissue from routine FFPE samples including needle biopsies (≥50ng of DNA)
• Customized computational biology algorithms validated for high sensitivity and specificity in samples with low purity
![Page 46: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/46.jpg)
‹›
FoundationOne™: Comprehensive NGS‐based cancer genomic profiling assay specifications
• One comprehensive genomic profile to detect all clinically relevant genomic alterations in a single assay
• Focused on the 236 known clinically & biologically relevant cancer genes
• Validated high accuracy from routine clinical specimens with ≥20% tumor nuclei
• Requires small amounts of tissue from routine FFPE samples including needle biopsies (≥50ng of DNA)
• Customized computational biology algorithms validated for high sensitivity and specificity in samples with low purity
![Page 47: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/47.jpg)
‹›
FoundationOne™: Comprehensive NGS‐based genomic profiling assay workflow (14‐21 days)
Sample preparation:
Analysispipeline:
Pre‐Analytic Process(Pre‐Sequencing)
Post‐Analytic Process(Post‐Sequencing)
Translating research grade NGS to a clinical cancer diagnostic assayrequires extensive optimization and investment
Library Construction, Hybrid Capture: Clinical report:
Extensive optimization
Resource intensive
Extensive optimization
Advanced computational biology
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‹›
Rigorous analytical validation essential prior to clinical use: Approach used for base substitutions
Mutant Allele Frequency
Number of Subs
Pool 1 Pool 2 Total
<5 % 206 201 407
5 ‐10% 314 300 614
10‐15% 130 103 233
15‐20% 75 77 152
20 ‐ 100 % 332 318 650
Total 1,057 999 2,056Pool 2
Pool 1
Pooling HapMap cell lines generates 2,056 base substitutions (subs) at a range of allele frequencies across the entire assay
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‹›
Analytical validation results demonstrate the high accuracy and reproducibility required for clinical use
Sample prep and algorithms optimized to detect genomic alterations with high accuracy from clinical specimens with ≥20% tumor nuclei
Base substitutions (MAF 5-100%)
Sensitivity: >99% PPV: >99%
Insertions/deletions (1-40bp, MAF 10-100%)
Sensitivity: >98% PPV: >99%
Copy number alterations (zero or ≥8 copies)
Sensitivity: >95% PPV: >99%
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‹›
Analytical validation results demonstrate the high accuracy and reproducibility required for clinical use
Sample prep and algorithms optimized to detect genomic alterations with high accuracy from clinical specimens with ≥20% tumor nuclei
Base substitutions (MAF 5-100%)
Sensitivity: >99% PPV: >99%
Insertions/deletions (1-40bp, MAF 10-100%)
Sensitivity: >98% PPV: >99%
Copy number alterations (zero or ≥8 copies)
Sensitivity: >95% PPV: >99%
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‹›
Sample prep and algorithms optimized to detect genomic alterations with high accuracy from clinical specimens with ≥20% tumor nuclei
Base substitutions (MAF 5-100%)
Sensitivity: >99% PPV: >99%
Insertions/deletions (1-40bp, MAF 10-100%)
Sensitivity: >98% PPV: >99%
Copy number alterations (zero or ≥8 copies)
Sensitivity: >95% PPV: >99%
Analytical validation results demonstrate the high accuracy and reproducibility required for clinical use
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‹›
Overview statistics of first consecutive 2,221 cases profiled in our CLIA certified, CAP accredited lab
Number of samples 2,221*Number of failed samples 109 (4.9%)
Samples with at least one actionable alteration 1,614 (76.4%)
Mean number of alterations per sample 3.06 [0-23]Mean number of actionable alterations per sample 1.57 [0-16]*Number excludes the ~10% of samples with insufficient material
Actionable definitionFDA approved targeted therapy in tumor typeFDA approved targeted therapy in another tumor typeOpen clinical trial of therapy targeting alteration
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‹›
Overview statistics of first consecutive 2,221 cases profiled in our CLIA certified, CAP accredited lab
Number of samples 2,221*Number of failed samples 109 (4.9%)
Samples with at least one actionable alteration 1,614 (76.4%)
Mean number of alterations per sample 3.06 [0-23]Mean number of actionable alterations per sample 1.57 [0-16]*Number excludes the ~10% of samples with insufficient material
Actionable definitionFDA approved targeted therapy in tumor typeFDA approved targeted therapy in another tumor typeOpen clinical trial of therapy targeting alteration
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‹›Tumor types that comprise the 2,221 clinical cases
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‹›
Actionable alterations identified in the 2,221 clinical cases
Hotspot includes alterations detectable by a hypothetical test
combining SNaPshot, OncoCarta, OncoMap and HER2, EML4-ALK,
(assumes 100% sensitivity)
Identifies nearly four times the number of actionable alterations than a hypothetical panel combining multiple Hotspot assays
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‹›
0
500
1000
TP53
KRAS
PIK3
CACD
KN2A APC
MYC
MCL1
CDKN
2BEG
FRPTEN
ARID1A RB1
CCND1 NF1
ERBB
2MDM
2FG
FR1
BRAF
CDK4
SMAD
4BR
CA2
PTPR
DAT
MSTK1
1CC
NE1
FBXW
7CT
NNB1
BRCA
1NOTC
H1RICT
OR
LRP1
BNRA
SDN
MT3A
KDM6A
FGFR3
SMAR
C…SO
X2AK
T2PIK3
R1CD
H1RP
TOR
IDH1 NF2
AKT1
BAP1
CCND3
CDK6
MET
CCND2
TET2
AURK
AFG
FR2
MAP
2K4
NKX
2_1
PDGFRA
VHL
TSC2
RUNX1 ALK
KIT
MSH
6EW
SR1
Most frequently altered genes
76.4% of specimens harbored ≥1 actionable alteration*62/155 most commonly altered genes displayed
Long tail of somatically altered genes accounts for majority of actionable alterations
Num
ber o
f alte
red
case
s
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‹›
• KIF5B‐RET expression led to oncogenic transformation
• KIF5B‐RET transformed cells are sensitive to RET inhibitors
RET fusions identified in 8/367 (2.2%) NSCLC patients, TWO NSCLC patients with RET fusions demonstrated good response to RET inhibitors
KIF5B RETExons 1-15 Exons 12-20
Kinesin Coiled coil Tyrosine kinase
KIF5B-RET fusion TKI sensitivity
• Screening ~600 patients revealed KIF5B‐RET fusions ~1% in Caucasians and 6.3% in Asian patients without known driver mutations
Translation
Novel KIF5B‐RET fusion identified in first clinical case
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‹›
ERBB2 amplification and overexpression routinely tested for in breast and gastroeosphageal cancers
% T
umor
s
0%
5%
10%
15%
20%
ERBB2 alterations by type and site of origin
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‹›
0%
5%
10%
15%
20%
• ERBB2 alterations identified in 110 specimens across 13 tumor types (4.8% total cases)
ERBB2 alterations by type and site of origin
• 42.3% of ERBB2 alterations were mutation/fusion (in non‐ERBB2 amplified specimens)
% T
umor
sERBB2 amplification and overexpression routinely tested for in breast and gastroeosphageal cancers
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‹›
ERBB2mutations in breast cancer cluster in the kinase domain
Distribution of ERBB2 mutations on ERBB2 protein
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‹›
ERBB2mutations in breast cancer cluster in the kinase domain
Distribution of ERBB2 mutations on ERBB2 protein
ERBB2 GRB7
ERBB2 mutation/fusion enriched in CDH1 mutated in 5/22 invasive lobular cancer (22.7%) vs CDH1 WT invasive breast cancer 8/286 (2.8%) p=0.0006
ERBB2-GRB7 fusion identified invasive lobular breast cancer
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‹›
ERBB2mutations in breast cancer cluster in the kinase domain
Distribution of ERBB2 mutations on ERBB2 protein
Invasive lobular breast cancer patient with ERBB2 mutation known to have had a good response to ERBB2 targeted therapy
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‹›
0%10%20%30%40%50%60%
EGFR alterations by site of origin
EGFR alterations were identified in 151 cases across 13 different tumor types (6.8% total cases)
% T
umor
s
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‹›
6/32 NSCLCs harbored EGFR alterations missed by other diagnostic assaysBreast cancer patient with EGFR mutation had good response to EGFR TKI
Distribution of EGFR mutations on EGFR protein
EGFR alterations were identified in 151 cases across 13 different tumor types (6.8% total cases)
![Page 65: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/65.jpg)
‹›Conclusions
• Translating research grade NGS to a clinical cancer diagnostic assay requires extensive optimization and investment
• Rigorous analytical validation to determine test accuracy and reproducibility is required prior to clinical use
• Complex information must be conveyed in an easily interpretable, comprehensive report to maximize utility for busy oncologists
• Initial clinical results are encouraging, 76.4% of clinical cases harbored at least one actionable genomic alteration
• Comprehensive profiling can identify four times the number of targeted treatment options compared to “Hotspot” tests
• Patients who have exhausted treatment options may show dramatic responses to targeted therapies identified as rational candidates in clinical reports
![Page 66: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/66.jpg)
‹›Conclusions
• Translating research grade NGS to a clinical cancer diagnostic assay requires extensive optimization and investment
• Rigorous analytical validation to determine test accuracy and reproducibility is required prior to clinical use
• Complex information must be conveyed in an easily interpretable, comprehensive report to maximize utility for busy oncologists
• Initial clinical results are encouraging, 76.4% of clinical cases harbored at least one actionable genomic alteration
• Comprehensive profiling can identify four times the number of targeted treatment options compared to “Hotspot” tests
• Patients who have exhausted treatment options may show dramatic responses to targeted therapies identified as rational candidates in clinical reports
![Page 67: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/67.jpg)
‹›Conclusions
• Translating research grade NGS to a clinical cancer diagnostic assay requires extensive optimization and investment
• Rigorous analytical validation to determine test accuracy and reproducibility is required prior to clinical use
• Complex information must be conveyed in an easily interpretable, comprehensive report to maximize utility for busy oncologists
• Initial clinical results are encouraging, 76.4% of clinical cases harbored at least one actionable genomic alteration
• Comprehensive profiling can identify four times the number of targeted treatment options compared to “Hotspot” tests
• Patients who have exhausted treatment options may show dramatic responses to targeted therapies identified as rational candidates in clinical reports
![Page 68: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/68.jpg)
‹›Conclusions
• Translating research grade NGS to a clinical cancer diagnostic assay requires extensive optimization and investment
• Rigorous analytical validation to determine test accuracy and reproducibility is required prior to clinical use
• Complex information must be conveyed in an easily interpretable, comprehensive report to maximize utility for busy oncologists
• Initial clinical results are encouraging, 76.4% of clinical cases harbored at least one actionable genomic alteration
• Comprehensive profiling can identify four times the number of targeted treatment options compared to “Hotspot” tests
• Patients who have exhausted treatment options may show dramatic responses to targeted therapies identified as rational candidates in clinical reports
![Page 69: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/69.jpg)
‹›Conclusions
• Translating research grade NGS to a clinical cancer diagnostic assay requires extensive optimization and investment
• Rigorous analytical validation to determine test accuracy and reproducibility is required prior to clinical use
• Complex information must be conveyed in an easily interpretable, comprehensive report to maximize utility for busy oncologists
• Initial clinical results are encouraging, 76.4% of clinical cases harbored at least one actionable genomic alteration
• Comprehensive profiling can identify four times the number of targeted treatment options compared to “Hotspot” tests
• Patients who have exhausted treatment options may show dramatic responses to targeted therapies identified as rational candidates in clinical reports
![Page 70: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/70.jpg)
‹›Conclusions
• Translating research grade NGS to a clinical cancer diagnostic assay requires extensive optimization and investment
• Rigorous analytical validation to determine test accuracy and reproducibility is required prior to clinical use
• Complex information must be conveyed in an easily interpretable, comprehensive report to maximize utility for busy oncologists
• Initial clinical results are encouraging, 76.4% of clinical cases harbored at least one actionable genomic alteration
• Comprehensive profiling can identify four times the number of targeted treatment options compared to “Hotspot” tests
• Patients who have exhausted treatment options may show dramatic responses to targeted therapies identified as rational candidates in clinical reports
![Page 71: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/71.jpg)
‹›Acknowledgements
www.foundationmedicine.com, www.foundationone.com
Foundation Medicine Foundation Medicine AlumniAmy Donahue Kai Wang Maureen CroninAlex Parker Kiel Iwanik Mirna JaroszAlex Fichtenholtz Kristen MahoneyChristine Hiemstra Lazaro Garcia
Christine Vietz Mandy Zhao Dana Faber Cancer InstituteDoron Lipson Mario Alfano Pasi A. JänneEmily White Matt Hawryluk Marzia CapellettiFrank Juhn Michelle Nahas Dalia ErcanJames Sun Norma PalmaJared White Roman YelenskyGarrett Frampton Sean DowningGary Palmer Selmira BeckstromGeneva Young Siraj AliGeoff Otto Sohail BalasubramanianJared White Tina Brennan Jeff Ross Vera Banning John Curran Vincent MillerJie He Zac Zwirko
![Page 72: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/72.jpg)
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Advancing Cancer Genomics: The Impact of Personalized Genome SequencingAdvancing Cancer Genomics: The Impact of Personalized Genome Sequencing
Webinar SeriesWebinar SeriesScienceScience
25 February, 2013
Elaine Mardis, Ph.D.Washington University in St. LouisSt. Louis, MO
Michael Snyder, Ph.D.Stanford UniversityStanford, CA
Philip Stephens, Ph.D.Foundation MedicineCambridge, MA
![Page 73: All slides Cancer Genomics webinar on 25 Feb 2013 Final3 ... slides_Cancer... · Advancing Cancer Genomics: ... ScienceWebinar Series 25 February, 2013 Elaine Mardis, Ph.D. ... •](https://reader036.fdocuments.net/reader036/viewer/2022062917/5ed8ae516714ca7f47685fe3/html5/thumbnails/73.jpg)
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Advancing Cancer Genomics: The Impact of Personalized Genome SequencingAdvancing Cancer Genomics: The Impact of Personalized Genome Sequencing
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