molecular subtypes: not quite ready for prime time
DESCRIPTION
Molecular Subtypes: Not Quite Ready for Prime Time. Scott Kopetz, MD, PhD. Department of GI Medical Oncology MD Anderson Cancer Center. Individual Biomarkers versus Molecular Subtypes. YES. Individual biomarkers: Microsatellite instability in all patients - PowerPoint PPT PresentationTRANSCRIPT
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Molecular Subtypes:Not Quite Ready for Prime Time
Scott Kopetz, MD, PhD. Department of GI Medical Oncology
MD Anderson Cancer Center
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NOT YET
YES
Individual Biomarkers versus Molecular Subtypes
• Individual biomarkers:– Microsatellite instability in all patients
• For adjuvant decisions in Stage II and screening for HNPCC– KRAS, NRAS, BRAF in all metastatic patients
• For consideration of EGFR sensitivity and prognosis
• Molecular subtypes– 200 gene…400 gene…whole exome sequencing– Gene expression profiles– Proteomic panels
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Why not yet….?
• We need studies to evaluate the benefit from extended molecular testing (beyond KRAS, NRAS, BRAF)
• We need to define the molecular subtypes by gene expression
• We need validated assays to move into the clinic
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Why not yet….?
• We need studies to evaluate the benefit from extended molecular testing (beyond KRAS, NRAS, BRAF)
• We need to define the molecular subtypes by gene expression
• We need validated assays to move into the clinic
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“My panel is bigger than yours…”
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Integrating into Clinical Trials:Increase in Prospective Enrichment
Unen-riched
EGFR en-
riched
Novel enriched
13%
3%
Kopetz, et al JCO ‘08, updated from clinicaltrials.gov
Unen-riched
EGFR en-
riched
Novel enriched
9%
40%
2007-08 2011-12
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Paucity of High-Frequency Targets Means Large Screening Efforts Needed
Currently “actionable”
Not actionableScreening size for a 20 patient
proof-of-principle study
100’s <3% frequency
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Consent Tissue Acquisition
Block Selection, Extraction
Testing Completed
Results Relayed
Timeline for Biomarker Testing
6 calendar days28 calendar days
33 calendar days
Median Time:
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ATTACC Program: Assessment of Targeted Therapies Against Colorectal
Cancer
• 5-FU refractory disease• ECOG PS 0-1• Tissue available for molecular testing
Eligibility
• Patients undergo biomarker assessment• CLIA-certified assaysScreening
• Based on biomarker, patients allocated to one of several treatment protocols
• Patients not expressing biomarker of interest are treated in unenriched protocols
Allocation
S. Kopetz, PI
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CpG Island Methylation Demethylator Azacitadine + XELOXMitotic inhib Nab-paclitaxel
BRAF Mutation BRAF+EGFR+irino Vemurafenib +cetux+ irino
MD
Ande
rson
ATT
ACC
Prog
ram
: Bi
omar
ker S
cree
ning
for 5
-FU
Re
frac
tory
Met
asta
tic C
RCPTEN Loss or PIK3CAmut Akt inhibitor MK-2206
Exon 3,4 KRAS or NRAS mutant RAF inhibition LY3009120ERK inhibition Biomed Valley
HER2 overexpression HER2 inhibition Trastuzumab +/- EGFR HER2 mutation ERB family inhib TBA
Enrichment Therapeutic Agent(s)Mechanism
PTEN Loss/KRAS WT PI3K-beta inhibitor SAR26031
Aquired RAS mutation MEK + EGFR inhibition Panitum + Trametinib
EGFR ectodomain mutation Alternate EGFR Panitumumab
KRAS and PIK3CA mutation Dual MEK, PI3K BYL719 and MEK162
MSI High CTLA4 and PD1 Nivolumumab, Ipilumumb
Triple KRAS/BRAF/NRAS WT EGFR+HER2 Cetuximab + trastuzumab
N=550enrolled
Current Screening Panel
IonTorrent 50 gene panel
-IonProton 400 gene
CpG Methylation Panel
Immunohistochemistry
-PTEN, MET, HER2 expression
KRAS, NRAS, EGFR ectodomain mutation in
cfDNA/plasma
Microsatellite instability panel
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42%
10%4%
20%
13%
2% 9%
Allocated to Study
Regorafenib
Poor PS/Death
Treatment at home
Treatment off protocol
Ineligibility
Withdrew consent
The Reality of Screening Studies1 in 5 Patients Allocation to Enrichment Study
Through 3/1/13, N=250, first new treatment on ATTACC
19% enriched companion study
Overall, 42% study enrollment, including 23% unenriched study
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Practical Considerations for Enrichment Studies
• Enrichment strategies require…– Consenting patients for screening– Explaining the study– High research staff utilization per “screen failure”
• Patient-satisfaction is very dependent on biomarker turn-around time– Obtaining outside paraffin blocks is rate-limiting step– How long should one delay treatment waiting for a 5%
frequency biomarker? • Other experimental options need to be available
– Enrichment study is hard to justify to patients in isolation
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Example: 19124802
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BOTH
Pails
Kras
Braf
PIK3CAPTENAKT
WT/WT
STUDY DESIGN
DNA-based Screening Trial, based on NCI MATCH study
5-FU/Bev + drug A
Chemo + drug B
5-FU/Bev + drug C
5-FU/Bev + drug D
5-FU/Bev + drug E
FOLFOX/Bev x 8then
Maintenance
Endpoint PFSN = TBD but likely3000 – 5000Slide from P. O’Dwyer
ASSIGN Study:COLON CANCER TASK FORCE , NCI GI STEERING COMMITTEE
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Flexibility & Centralization
Providing clinical data
Sending gDNA/cDNA
Sending Tumor tissue
Providing results
BIOBANKING
Centralizing and storing samplesExtracting gDNA/RNA
CLINICAL CENTERS
Treating and recruiting patients
EORTC Headquarters
Maintaining Sample Tracking tool, eCRF and results database
DIAGNOSTICS LABORATORIES
Performing BM analyses
Answering if patient eligible for study
Screening Effort ProtocolsEnrollmentSPECTAColorGoal: 600 pts/yearEnroll: 10-15% of screened
Slide from S. Tejpar
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To date… Limited Prospective Biomarker Success in CRC
New or Anticipated Agents/Indications
– Bevacizumab (2nd line)– Ziv-aflibercept– Regorafenib– TAS-102
No new biomarker-directed therapy
Wrong premise, wrong implementation, or still too early?
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Why not yet….?
• We need studies to evaluate the benefit from extended molecular testing (beyond KRAS, NRAS, BRAF)
• We need to define the molecular subtypes by gene expression
• We need validated assays to move into the clinic
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Two Approaches to Biomarker Integration
• Individual Biomarker Perspective– Biomarkers are paired with individual drugs
• Taxonomy Perspective– Move to a “Taxonomy” Perspective
Drug X Biomarker A
Drug X
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Two Approaches to Biomarker Integration
• Individual Biomarker Perspective– Biomarkers are paired with individual drugs
• Taxonomy Perspective– Move to a “Taxonomy” Perspective
Drug X Biomarker A
Drug X
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Definitions
Taxidermy = Stuffing Taxonomy = Grouping based on common patterns
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CRC Taxonomy Hasn’t Been Defined To Date
Sotiriou et al NEJM, 2009; Alizadeh et al, Nature 2000
Bas
al
Lum
inal
A
Lum
inal
B
Her
2-po
s
?Breast Cancer Lymphoma Colorectal Cancer
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Gene Expression Tests are “Fit for Purpose”
Prognostic Assays Taxonomy / Molecular Classification Assays
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0%5%
10%15%20%25%30%35%40%45%
0 10 20 30 40 50 60 70
3-ye
ar R
ecur
renc
e Ri
sk
Recurrence Score
≠
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KRAS Poorly Recapitulates Taxonomy
Budinska et al ASCO ‘12
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Stem-like (18%): MSS, Wnt high, crypt base, benefit CT and FOLFIRI, worse survival
MelbourneT:209 V:443128 genes
AgendiaT:188 V:54332/53/102 genes
FrenchT:443 V:105857 genes
AMC-AJCCII-90T:90 V:1074146 genes
PETACC3T:1113 V:72054 genes
TCGAT:220
Good prognosis (40%) Poor prognosis (60%): immune down/ cell signaling, ECM and focal adhesion pathways up
A-type (22%): BRAFm, MSI/dMMR, epithelial proliferative
A-type (62%): low mutation, MSS, epithelial proliferative, benefit adjuvant CT C-type (16%): mesenchymal, no benefit CT
CIN immune down (20%): conventional precursor
dMMR (20%): sessile serrated precursor, BRAFm, immune up
CSC (10%): serrated, poor survival
CIN Wnt up (30%): conventional precursor
CIN normal (10%): serrated, poor survival
KRASm (10%): serrated, CIMP+
CCS1 (50%): CIN+, KRASm and TP53m, left colon, Wnt high CCS2 (25%): MSI, CIMP+, BRAFm, right colon
CCS3 (25%): poorly dif, EMT, invasion, migration and TGF-β signaling, no benefit cetuximab
MSI/CIMP (30%): BRAFm, hypermutated
CIN (30%) Invasive (40%)
Surface crypt (26%): KRASm, EMT low, Wnt low, papillary or serrated phenotype
Lower crypt (30%): EMT low, Wnt high, tubular phenotype
Mesenchymal (19%): EMT/ CSC high Wnt low, poor prognosis, BRAFm, desmoplastic
CIMP+ (11%): MSI, BRAFm, immune up, mucinous
Mixed (14%): Wnt high, CSC high, tubular
SwissT:445 V:77430 genes
Goblet (14%): MSI, crypt top, Wnt low, no benefit adj CT, good prognosis
Inflammatory (18%): MSI, benefit FOLFIRI
Enterocyte (18%): crypt top ,Wnt low
TA cetux sensitive (18%): MSS, high EGFR ligands, good prognosis
TA cetux res (14%): MSS, stem cell, MET-inh sensitive, worse survival
Published Molecular Subtypes of Colorectal Cancer
Slide from Rodrigo Dienstmann
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PIs: Justin Guinney Rodrigo Dienstmann
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CLUSTER 2CLUSTER 3
CLUSTER 4
CLUSTER 1
Consensus clusters
ASCO 2014 Clinical Symposium: Colorectal Cancer: Not Just One Disease
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Why not yet….?
• We need studies to evaluate the benefit from extended molecular testing (beyond KRAS, NRAS, BRAF)
• We need to define the molecular subtypes by gene expression
• We need validated assays to move into the clinic
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Development of Validated Assay is Nontrivial
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“The same rigor that we use for development of the drug has to go into the biomarker development” R. Pazdur (FDA)
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Conclusion
• Everyone should be testing for MSI and KRAS, NRAS, BRAF
• We need to do the studies to demonstrate benefit of more extended molecular profiling– Low yields for actionable mutations– Need more and better novel therapies
• A consensus is building for defining the subsets• The assays need to be built, and moved into
clinical labs.
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