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Precision Oncology Decision Support Core
Funda Meric-Bernstam MD
ChairDepartment of Investigational Cancer Therapeutics
Medical DirectorSheikh Khalifa Ben Zayed Al NahyanInstitute for Personalized Cancer Therapy
Nellie B. Connally Chair in Breast Cancer Research
BRAFcKIT
cMET
CSFR1
EGFR
FGFR
FLT3HER2
HER3
MEK
NF1
NMYC
PDGFR
PIK3CA
PIK3R1
PTEN
RAFRAS
RET
TRK
RSPO VEGF
Genomically-Informed Targeted Therapy
RapidEvolutionofGenomicTesting
• Within each gene, hundreds of variants may be reported within different cancers.
• 29,459 genomic tests to date at MD Anderson• 2888 patients with solid tumors underwent next generation
sequencing on 50-134 gene panels in FY2017.
Medical Decision-Support
Doc,youmustknoweverything!
GettingtotheRightPatient,withtheRightDrugatthe
RightTime
PrecisionOncologyDecisionSupport(PODS)Core
Precision Oncology Decision Support
Selected publicationsMeric-Bernstam F and Mills, Nat Rev Clin Oncol. 2012 Chen K et al, Clin Chem. 2015Meric-Bernstam F et al. J Clin Oncol. 2013 Zhou W et al., Nat Methods. 2015Johnson A et al., Drug Discov Today.2015 Boland GM et al. Oncotarget.2015Meric-Bernstam F, J Natl Cancer Inst. 2015 Meric-Bernstam F et al, Ann Oncol.2016Meric-Bernstam F et al, J Clin Oncol. 2015 Johnson A et al, ASCO, 2016 Johnson A et al, J Clin Oncol Prec Onc, 2017 Kurnot K et al, Camcer Research 2017
What is an Actionable Genomic Alteration?
A genomic alteration can be considered “actionable” if it:
• predicts therapy response (sensitivity or resistance)• affects the function of a cancer-related gene, and can be targeted directly or
indirectly with approved or investigational therapies. • is a specific eligibility criteria for enrollment onto genotype-selected trials, • has demonstrated the ability to establish diagnosis or influence prognosis • is a germline alteration that predicts drug metabolism and/or adverse effects• is a germline alteration that predicts future risk of cancer or other diseases
(usually considered more “actionable” if prevention or screening with early treatment is feasible)
Meric-Bernstam, JNCI 2015
Confirm sequencing/variant calling quality;Identify mutations, copy number
changes, fusions
Relevant targeting drugs (direct and indirect)
Determine functional consequences of alterations: Clinical data (prognosis and response)Preclinical data/functional genomicsComputational functional predictionsPrediction of driver vs passenger
Assess evidence for using each drug in the context of altered gene/disease/molecular subtype
Prioritize mutations/targetsIdentify optimal treatment
Functional Alteration in Driver Gene?
Level I evidence Level II or III evidence
Retrieve clinical trials using genotype-
relevant drugs
Select optimal approved therapy:genomically-matched
or other approved therapy
Annotation of Variants of Known Functional Significance
Oncogene TumorSuppressor
Activating
Functional Significance
Inactivating
Yes
-------------------------------Actionable Variant Calls-------------------
No
Activating
Functional Significance
Inactivating InactivatingandNeomorphic*
Yes
• Yes: Literature based• Yes: Inferred• Yes: Functional Genomics
YesNo
LikelyBenign
No
Annotation of Variants of Unknown Functional Significance
Unknown
Functional Significance
• Confers drug sensitivity or resistance
Doesresearchshow:• Othervariantsofthecodonareactionable• Hot-spotarea• Functionallysignificantdomainw/other
actionablealterations• Splice-sitemutationsintumorsuppressors
PotentiallyYes
-------------------------------------Actionable Variant Calls---------------
Resources• UniProt• dbSNP
• Ensembl• ClinVar
• Published Literature
NO
Unknown
YES
• High-quality abstracts
FunctionalgenomicstoassessVUSsGordon Mills
287 31
152
19975
712
11
PODSSubmissions(N=1467)
InformativeResult Non-informativeResult
Dropped InProgress
TechnicalPending Pending
Moreinfoneeded
20% 7
45 2
222
6
AVcall:PODSSubmissionofUnknown/NotAnnotated(N=282)
Yes:Literaturebased Yes:FG Potentially No:FG No
282Resultsfrom271submissions
79%newnon-actionablealterations
16%newactionablealterations
FunctionalGenomicsUpdate
Web-basedAnnotationRequestForm
Currently:• Only directly accessible for MD
Anderson employees but with capability of providing annotations for patients treated outside of MD Anderson
• 3629 PODS annotation requests on 2741 patients with over 50 tumor types for 158 clinicians
Enhancements planned:• Accessibility beyond MD Anderson
• Pilot: UT Southwestern
PatientReports
ClearAlteration-LevelActionability Calls
AggregatedFrequencies
Emailed and Deposited into EHRClearFunctional
SignificanceCall
Patient Reports
Displayonlywhatisrelevanttopatient
Relevantdrugunderlined
Trials retrieved only if targets a potentially actionable or actionable alteration
Yes PotentiallyUnknown No9.4%29.7%
28.4% 32.5%
Actionable Variant Calls
Yes Potentially Unknown No
11.9%
36.1%
11.3%
40.7%
Actionable Variant Callsin Actionable Genes
Annotation of Actionability
Johnson and Khotskaya, JCO Prec Onc, 2017
Review of 1,669 requests for annotation of 4,084 alterations (2,254 unique) across 49 tumor types for 1,197 patients
Accrual of Genomically-Matched Trials
Johnson and Khotskaya, JCO Prec Onc, 2017
• Launched April 2014• All content publicly
accessible with free registration.
• First 32 genes with dozens of individual aberrations annotated.
• Therapeutic implications
• Relevant trials
• New gene-level variants added continuously.
Personalizedcancertherapy.orgPCT.mdanderson.org
Kurnitt et al Cancer Research Nov 2017
ClinicalTrialEmailAlerts
BasedonVariantActionability
On-demandlinkforscreening
Alertstriggeredonlyifactionable/potentiallyactionablealterationisselectedtrials
Recruiting Basket Trials
or TAPUR
Akt AZD5363,MSC2363318A,BAY1125976,ARQ751,Temsirolimus
PTEN Buparlisib,MSC2363318A,Talazoparib,ARQ751,Temsirolimus
PIK3R1/2
PIK3CAGDC-0032,MSC2363318A,PQR309,ARQ751Temsirolimus
PIK3CB/D Temsirolimus,TAK228
PTPN11
Temsirolimus,TAK228
Temsirolimus,TAK228STK11
TSC1/2 Temsirolimu,TAK228s
Temsirolimus,TAK228MTOR
NF1/2 Temsirolimus,LXH524,LLT462
GNA11 LXH524,LLT462,Selumetinib*
GNAQ LXH524,LLT462,Selumetenib*
LXH524,LLT462,RegorafenibRAF1
ARAF LLT462
HRAS LLT462,Selumetinib*
NRAS Bimetinimeb,LXH524,Selumetinib*
KRASSelumetinib*,ABBV-75,CB839,Ribociclib,LXH524,MLN2480
BRAF
Dabrafenib+Trametinib,LGK974,Sorafenib,LXH524,Vemurafenib/cobimetinib,BVD-523,PLX8394,MLN2480,RXDX-105,INCAGN01949,Selumetinib*,Regorafenib
MYC AZD1775
N-MYC GSK525762,
ROS
Erlotinib,KBP-5209,Neratinib,CB-1158(EGFRWT)EGFR
RON Crizotinib
HER2 Neratinib,Pertuzumab,Trastuzumab,ZW25,KBP-5209,Afatinib
ABT-348,PalbocicliibCDKN2
A
Dasatinib,MGCD516DDR2
MET Crizotinib,INC280,MGCD265,SYM015,MGCG516
SMO Vismodegib
PTCH Vismodegib
MK-3475,PDR001,MEDI4736,AtezoPD-L1
TP53 COTI-2:TP53mt/ALRN-6924:TP53WT
KIT Imatinib,MGCD516
IDH1
IDH2 LY3200882
SRC
KIT Dasatinib, DCC-2618, regorafenib,sunitinib
RNF43 LGK974
RSPO LGK974
MRCA1
ATM/ATR
Veliparib/olaparib/Talazoparib
Talazoparib
FANCs TalazoparibVeliparib
IDH305,AG-221,AG120
EMSY Talazoparib
MRE11A
Talazoparib
NBS1 Talazoparib
PALB2 Talazoparib
Talazoparib,Veliparib
RAD50RAD51
C
MAP2K1/3 BVD-523,LXH524
NTRK1/2/3
LOXO-101,RXDX-101,MGCD516
ROS1 Ceritinib,Crizotinib,RXDX-101
ALK
NOTCH1
AXL MGCD516
PDGFRA/B
MGCD516,Dasatinib,Regorafenib,DCC-2618,sunitinib
MGCD516,RXDX-105,Regorafenib,sunitinib
RET
VEGFR1
(FLT1)VEGFR2
(KDR)
CCNE1 AZD1775
VEGFR3
(FLT4)
FGFR1/2/3
TAS-120,Debio1347INCB054828,PRN1371
FGFR4 FGF401,TAS-120,PRN1371
FGFs FGF401,INCB054828
Biomarker-Selected Trials in ICT
~ 100 targets; over 70 drugs, over 60 trials
MSC2363318A,Temsirolimus
BRCA1BRCA2
Olaparib,Talazoparib,Lurbinectedin,MPDL3280A,MEDI4736
Alectinib,Ceritinib,Crizotinib,RXDX-101,X-396
Axitinib<regorafnib,sunitinib
Axitini,regorafenib,sunitinib
Axitinib,regorafnib,sunitinib
Crizitinib
Dasatinib
EPHA2
FYN
FYN
LCK
YES1Dasatinib
Dasatinib
Dasatinib
Dasatinib
Dasatinib
CCND1 Palbociclib
FLT3 Sunitinib
VHL Sunitinib
CDK4 Palbociclib
Successes in Precision Oncology Basket Trials
BRAF V600E NSCLC Vemurafenib
BRAF V600 Anaplastic Thyroid Cancer
N/A
KIF5-RET CCDC6-RET Other aberrations
KDR,PIK3CA
RETFISH
+NF
1,PIK3CA
EGFRL8
61Q
NF1,PIK3CA,
RETFISH
+
KIF5B-RET
KIF5
B-R
ET
CC
DC
6-R
ET
CC
DC
6-R
ET
KIF5
B-R
ET
KIF5
B-R
ET
Hyman*, Puzunov*, Subbiah* et al, NEJM, 2015 Cascone and Subbiah, ASCO, 2016
Vivek Subbiah
RET fusion NSCLCVandetinib+everolimus
Subbiah JCO in press
• Dabranib/trametinib• Sixteenpatientswith
BRAFV600E-mutatedanaplasticthyroidcancerwereevaluable
• Overallresponseratewas69%
HER2 as a TargetSUMMIT trial: Neratinib for HER2 mutant, HER2 nonamplified BCSingle agent ORR 8 weeks 33%; confirmed ORR 25% CBR 42%: Combination ORR at 8 weeks 42%, confirmed ORR 25%, CBR 58%
Hyman, Piha Paul et al SABCS 2016
HER2mutations
HER2amplification
HER2amplifiedCRC;Hurvitz,ASCOGI2017HER2amplifiedsalivaryca;KurzrockASCO2017
Conclusions
• Genomic sequencing is increasingly prevalent
• Its utility is dependent on:• likelihood of truly actionable alterations • Available therapies• Whether therapeutic intervention is feasible/appropriate
• Multianalyte analysis and combinatorial therapy is likely to enhance driver identification and responses
Acknowledgements ICT•David Hong•Sarina PihaPaul•Vivek Subbiah•Siqing Fu•Filip Janku•Lia Tsimberadou•Aung Naing•Dan Karp•Shubham Pant•Tim Yap•Jordi Rodon
Oncology Champions•Debu Tripathy, Stacy Moulder and
Naoto Ueno, Senthil Domodoran- breast•Cathy Eng and Scott Kopetz- CRC•Mike Davies-melanoma•John de Groot- neurooncology•Ravi Vinod sarcoma•John Heymach- lung•Faye Johnson •and William William-head and neck•Shannon Westin /Rob Coleman- gyn onc
Molecular Diagnostic Lab• Stan Hamilton• Raja Luthra• Russel lBroaddus• Mark Routbort• Keyur Patel• Sinchita Roy-ChowduriPath• Aysegul Sahin• Dipen Maru• Alex Lazar• Victor Prieto• Coya TapiaClinical Cancer Genetics• Molly Daniels• Louise Strong• Karen Lu • Banu Arun• Jenniifer Litton
Funding: Bosarge Foundation,Khalifa Foundation,U01 CA180964,NCATS UL1 TR000371; CCSG P30 CA 016672
CPRIT
IPCT Admin TeamGordon MillsJohn MendelsohnKenna Shaw
Decision Support TeamAmber JohnsonAnn Bailey Jia ZengVijay HollaBeate LitzenburgerNora SanchezYekarterina Khotskoya
Univ Texas School of Biomedical InformaticsElmer BernstamTrevor CohenHua XuJim ZhengZhongming Zhao
Bioinformatics/StatsKen ChenHao ZhaoYuan QiXiaoping SuHan LiangLi Zhang
