Schuuring

9e Leek avondsymposium
Nieuwe ontwikkelingen in de behandeling van NSCLC
Groningen, 9 november 2016
Vernieuwing en diagnostiek bij NSCLC
Disclosures
Consultant/Advisory Board:
AstraZeneca, Roche, Pfizer, Novartis, Amgen, Biocartis,
QCMD, ESP, IQNPATH
Ed Schuuring
Speaker’s fee:
Abbott, Novartis, Roche, Biocartis
Head Laboratory Molecular Pathology, UMCG Groningen
Coördinator Netwerk for Molecular Pathology North Netherlands
KMBP (Clinical Scientist in Molecular Pathology)
Professor in Molecular Oncological Pathology
Molecular profiling of lung cancer in 2016
Molecular Pathology
Traditional histopathological classification
Stock/Royalties:
None
Molecular diagnostics of lung cancer for treatment
planning using gene-targeted therapy in NL
international guidelines
Dutch Oncoline guideline for NSCLC (July 2015):
(1) EGFR, ALK; (2) HER2, BRAF, RET and ROS1
CAP-IASLC-AMP guideline for NSCLC (2013) (Lindeman 2013)
(1) EGFR, ALK; (2) HER2, BRAF, RET and ROS1
>2009: Molecular Tumor Profiling
Wild type
del746750
Li JCO 2013
ESMO guideline for NSCLC (2013) (Kerr, Ann Oncol 2014)
EGFR, ALK (recommend KRAS, BRAF, HER2 and ROS1)
To define which patients for what drug benefit most
(personalised therapy)
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De moleculaire diagnostiek van longkanker tbv
gen-mutatie-gerichte therapie
(Putative)
predictive biomarkers
Nieuwe predicitieve biomarkers in kader van klinische trials
Vanaf 2016 e.v. (verwachtte toepassingen):
New anticancer drugs
available
for gene-targeted therapy
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(~10% AC)
(100% AC)
(100% AC)
(~20% SCC)
(< 2% AC)
(~40% AC)
(4-20% AC)
(1.7% AC)
(<2% AC)
(2% AC)
(10% AC)
(<5% AC)
(~4% SCC)
> next-generation-TKI (afatinib)
> osimertinib, dacomitinib, afatinib/cetuximab, AUY922
> next-generation-TKI (ceritinib, alectinib)
> nintedanib
> vemurafinib, dafrafenib
> MET/MEK/RAF inhibitors
> crizotinib, cabozantinib, capmatinib
> crizotinib
> sunitinib, vandetanib, sorafinib
> herceptin, afatinib,
> cetuximab, erlotinib, …
> mTOR inhibitor, aspirine
> dasatinib
UMCG is longkanker-expertcentrum en participeert in vele (inter)nationale trials
Simon and Roychowdhury,
Nat Rev Drug Discov. 2013
Molecular tumor profiling 2016 Groningen:
Next Generation Sequencing
only predictive and diagnostic markers based on
current guidelines and ongoing clinical trial
Molecular status of key analytes in several diseases is already standard
of care:
Activerende EGFR mutaties
“resistente” EGFR mutaties
(“resistente”) ALK mutaties
FGFR1-amplificatie
BRAF-mutatie
KRAS-mutatie
MET-amplificatie/exon-skipping
ROS1-translocatie
RET/KIF5B-translocatie
HER2-mutatie
EGFR-amplificatie
PIK3CA-mutatie
DDR1-mutatie
Relevant predictive markers (UMCG 2014-2016)
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>30 hotspot regions in 11 genes (29 amplicon) (UMCG-PGM-v01 panel) for mutation
screening in lung cancer, melanoma, colon carcinoma, GIST
TAT: ~4-5 days (2 runs per week)
 Melanoma:
BRAF (NRAS, cKIT)
ALK codon 1174
GNA11 codon 209
 Lung cancer:
EGFR, ALK, ROS (RET, KRAS, BRAF, PIK3CA, MET, FGFR1)
ALK codon 1275
GNAQ codon 209
NRAS codon 117/146
 Colon cancer:
KRAS, NRAS, BRAF (PIK3CA)
BRAF exon 15
KIT exon 11
NRAS codon 12/13
 GIST:
cKIT, PDGFRA (NRAS)
EGFR exon 18
KIT exon 13
NRAS codon 61
EGFR exon 19
KIT exon 14
PDGFRA exon 12
EGFR exon 20
KIT exon 17
PDGFRA exon 14
EGFR exon 21
KIT exon 8
PDGFRA exon 18
ERBB2 exon 19
KIT exon 9
PIK3CA exon 20
ERBB2 exon 20
KRAS codon 117/146
PIK3CA exon 9
ERBB2 exon 21
KRAS codon 12/13
BRAF exon 11
 Breast cancer:
HER2, BRCA1
Molecular Oncological Pathology at UMCG: www.MolOncoPath.nl
KRAS codon 61
Molecular Oncological Pathology at UMCG: www.MolOncoPath.nl
Presentation Ed Schuuring, 12th May 2016 Barcelona
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Next Generation Sequencing: Ion Torrent
Personal Genome Machine (PGM)
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Other methods to detect predictive molecular aberrations in
Molecular Pathology of lung cancer (2016)
>50 hotspot regions in 24 genes (85 amplicons) (UMCG-PGM-v02b panel) for mutation
screening in lung cancer, melanoom, colon carcinoma, GIST
TAT: ~4-5 days (2 runs per week)
AKT1_17
ESR1_534-537
KIT_exon11
MET exon 14-intron 14
ALK_1151-1156
ALK_1174-1206
ALK_1269-1275
BRAF_600
BRAF_exon11
EGFR_492
EGFR_exon18
EGFR_exon19
EGFR_exon20
EGFR_exon21
ERBB2_exon19
ERBB2_exon20
ERBB2_exon21
ESR1_463
GNA11_183
GNA11_209
GNAQ_183
GNAQ_209
GNAS_201
GNAS_227
H3F3A_27-36
H3F3B_35-37
HRAS_117-146
HRAS_1213
HRAS_61
IDH1_132
IDH2_140-172
JAK2_617
KIT_exon13
KIT_exon14
KIT_exon17
KIT_exon18
KIT_exon8
KIT_exon9
KRAS_117-146
KRAS_1213
KRAS_61
MAP2K1_111-124
MAP2K1_203
MAP2K1_264
MAP2K1_382
MAP2K1_53
MET intron 13-exon 14
NRAS_117-146
NRAS_12-13
NRAS_61
PDGFRA_exon12
PDGFRA_exon14
PDGFRA_exon18
PIK3CA_1047
PIK3CA_542-549
POLE_286
POLE_411
ROS1_2032
ROS1_2155
FISH-rearrangement: ALK, ROS, RET, NTRK1
FISH-amplification/CNV: MET, HER2, FGFR1
IHC: HER2, ALK, ROS1
RTPCR: MET exon14-skipping
Underlined targets are under validation
(inclusief MET-exon14-skipping en gatekeeper ROS/ALK)
Molecular Oncological Pathology at UMCG: www.MolOncoPath.nl
Molecular Oncological Pathology at UMCG: www.MolOncoPath.nl
Challenges/pitfalls in 2016/2017
• Different predictive markers in other centers
(not the same or less markers for all cancer patients in NL)
• Different molecular methods
Presentation Ed Schuuring, 12th May 2016 Barcelona
Project PATH (Predictive Analysis for THerapy)
Optimizing access to personalized cancer therapy in
the Netherlands; from tissue to therapy.
national consortium of >38 pathology-labs, medical oncologists,
pulmonologists, NVALT, NVMO, NVVP, PALGA
Goal: To introduce a NGS panel to create optimal and equal access
to targeted therapies for all (lung, melanoma, GIST, CRC) cancer patients
in the Netherlands
• Lack of information on current treatment options
2016-2020: 37 predictive and diagnostic genes based on
current guidelines and ongoing clinical trial (updated Feb 2016)
CALL ZONMW GGG: PERSONALISED MEDICINE – ONCOLOGY
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Project PATH (Predictive Analysis for THerapy)
Project PATH (Predictive Analysis for THerapy)
Optimizing access to personalized cancer therapy in
the Netherlands; from tissue to therapy.
Optimizing access to personalized cancer therapy in
the Netherlands; from tissue to therapy.
WP2: Predictive testing: Nation-wide used consensus panel with relevant mutations
WP3: Expert Network: Molecular tumor board and national platform
WP4: Synoptic reporting in PALGA: consensus in reporting molecular results in Pathology report
WP5: Economic evaluation: organisation efficacy and cost-effectiveness of predictive diagnostics
Goal: To introduce a NGS panel to create optimal and equal access
to targeted therapies for all cancer patients in the Netherlands
Executive board:
focus on integration scientific efforts
Coordinator/management (principal investigator)
– WP1: Marjolijn Ligtenberg, Katrien Grünberg
4 Work Package-leaders:
– WP2: Ed Schuuring, Bas Tops, Petra Nederlof
– WP3: Katrien Grünberg, Harry Groen, Hans Gelderblom
– WP4: Stefan Willems, Henk-Jan van Slooten, Paul Segers
– WP5: Erik Thunnissen, Eddy Adang
Consortium (Dutch University Laboratories of Molecular Pathology)
Consensus on NGS mutation panel > each patient in NL receives same opportunities for therapy
PATH-targeted gene panel (implementatie in 2017)
Predictive gene
Aberrations
Predictive gene
Aberrations
AKT1
SNVs, CNVs
KRAS
SNVs, CNVs
AKT2
CNVs
IDH1
SNVs
AKT3
CNVs
IDH2
SNVs
ALK
SNVs, Fusion-transcript
JAK2
SNVs
ARAF
SNVs, CNVs
MAP2K1 (MEK1)
SNVs
BRAF
SNVs, CNVs
MDM2
CNVs
CCND1
CNVs
MET
SNVs, CNVs
CCND3
CNVs
MTOR
SNVs
CDK4
CNVs
NRAS
SNVs
CDK6
CNVs
NTRK1
Fusion-transcript
CDKN2A (p16)
SNVs, CNVs
PDGFRA
SNVs
DDR2
SNVs
PIK3CA
SNVs, CNVs
EGFR
SNVs
PTEN
SNVs, CNVs
ERBB2 (Her2)
SNVs, CNVs
RET
SNVs, Fusion-transcript
FGFR1
SNVs, CNVs
ROS1
SNVs, Fusion-transcript
FGFR2
SNVs, CNVs
SMO
CNVs, SNVs
FGFR3
SNVs, CNVs, fusion-transcript
SRC
CNVs, SNVs
HRAS
SNVs, CNVs
TP53
CNVs, SNVs
KIT
SNVs
Consortium (Dutch University Laboratories of Molecular Pathology)
Consensus on NGS mutation panel > each patient in NL receives same opportunities for therapy
Single molecule Molecular Inversion Probes for NGS PATH-panel
(smMIP-NGS)
single molecule tag
Single molecule tag to identify independent biological template molecules:
Higher specificity
Higher sensitivity
Hiatt JB, et al. Genome Res. 2013 May;23(5):843-54
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Project PATH (Predictive Analysis for THerapy)
Optimizing access to personalized cancer therapy in
the Netherlands; from tissue to therapy.
NGS analysis
Today’s tissue-management lung cancer (2016)
“1st”
Moleculaire Pathologie in de regio Noord
PA
UMCG
Groningen
PA
PA
Friesland
Martini
Groningen
Leeuwarden
“last”
Noord-oost
HUB
5% neoplastic cells
management
UMCG
PA
PA
TREANT
Isala
Hoogeveen
Zwolle
PA
This example represents a typical biopsy
in our clinical practice (lung cancer)
Enschede
Images with courtesy of Erik Thunnissen, VUMC
• Sufficient DNA for NGS
• >20% neoplastic cells
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Today:
Panel-Ion Torrent: 10 ng (~1600 cells)
Panel-Miseq: 50 ng
WES: ~500 ng
WGS: ~500ng
• Not enough tumour DNA
• 5 neoplastic cells (<1%)
Standard lung cancer biopsies are not (yet) suitable for WES/WGS
Prefered: the use of small gene-panel (1600 neoplastic cells)
Images courtesy of Erik Thunnissen, VUMC
>50% neoplastic cells
Presentation Ed Schuuring, 12th May 2016 Barcelona
More analysis from one biopsy?
Today’s tissue-management lung cancer (2016)
HE first
Diagnostic stain TTF1
Diagnostic stain mucin
Diagnostic stain P63/p40
ALK IHC
ALK FISH
ROS1FISH
RET FISH
MET FISH
FGFR1 FISH (SCC)
DNA isolation mutation analysis
RNA isolation MET exon skipping
HE last
Turn-around-time (TAT) and hands-on-time
Presentation Ed Schuuring, 12th May 2016 Barcelona
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Liquid biopsy:
Samples that can not be analysed
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bloed als bron om longkanker te diagnostiseren
Neoplastic cell percentage too low
Low amount of tissue
Low amount of DNA
Bad quality of DNA (high background)
Representing ~20% of all our requests for NGS mutation analyses
in our routine diagnostic testing in Molecular Pathology
Mutatie testen UMCG (nieuwe diagnostische test)
Circulerend tumor DNA in celvrij plasma
EGFR-T790M bij resistentie TKI (tagrisso/osimertinib)
• FDA-approved for EGFR-T790M-positive cases ( nov 2015)
• EU-approved for EGFR-T790M-positive cases (feb 2016)
• FDA-approved T790M-test cobas-EGFR-mutation test v2 (nov 2015; available in NL in jan 2016;
UMCG only)
EGFR-del19/L858R voor behandelkeuze
• Dutch onco-guideline (july 2015)
• UMCG-ISO15189-validated ddPCR EGFR mutation test
BRAF-V600E voor behandelkeuze/monitorig therapie
KRAS-common voor behandelkeuze/monitoring therapie (bv respons bij immunotherapie)
KIT-exon 11 voor behandelkeuze/monitoring therapie in GIST
extra kosten, snellere TAT, meer biopten met uitslag (beperkt genen), andere logistiek
EGFR-plasmatest: logistiek aanvragen binnenkort op www.moloncopath.nl
(tot dat moment direct contact met Ed Schuuring)
Reporting Mutation Analysis data
Handling of unexpected, difficult, rare mutations?
Treatment options ?
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Example: NSCLC with EGFR: c.2281G>A; p.(D761N)
Example: NSCLC with PIK3CA: c.3140A>G; p.(H1047R)
Example: NSCLC with PIK3CA: c.3140A>G; p.(H1047R) 80% and p(L858R) 35%.
Example: AKT3 amplificatie 80%, EGFR amplificatie 50%, KRAS amplificatie 20%, TSC1
A944T mutatie 10%, MDM2 amplificatie 7%, MCL1 amplificatie 3%, TP53 Y234C mutatie
2%, EPHA5 A454N mutaties 1%, MYST3 amplificatie 1%
(1) KMBP/pathologist search for information on general treatment
advice and interpretation in PA-report
(2) assistance with specific treatment advice via the Molecular Tumor
Board Groningen (every Friday MTB-meeting)
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www.moloncopath.nl
Molecular Pathologie UMCG-team
MD-technicians:
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Ingrid de Boer-Huitema
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Annelies ten Caat
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Erik Nijboer
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Paskal van Norel
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Rianne Pelgrim
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Inge Platteel
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Martin Schipper
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Jantine Sietzema
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Klaas Kooistra
KMBP:
•Elise van der Logt
•Arja ter Elst
•Anke van den Berg
•Ed Schuuring
•Maarten Niemantsverdriet (KMBPio 2016-2020)
•Leon van Kempen (KMBPio 2016-2018)
Pathologists:
•Wim Timens
•Nils ‘t Hart
•Arjan Diepstra
Molecular Tumor Board Groningen (in dutch)
Ed Schuuring, KMBP
Arja ter Elst, KMBP
Anke van den Berg, KMBP
Nils ’t Hart, lungpatholoog
Wim Timens, lungpatholoog
Harry Groen, pulmonologist
Jeroen Hiltermann, pulmonologist
Anthonie van der Wekken, pulmonologist
Geke Hospers, medisch oncologist
Lucy Hijmering-Kappelle, pulmonologist
Hilde Jalving, medisch oncoloog
Sjoukje Oosting, medisch oncoloog
Mathew
Maarten Niemantsverdriet, KMBPio
Leon van Kempen, KMBPio
Saskia Offermans, pathologist Isala
Clemens Prinsen, KMBP Isala
Jos Stigt, pulmonologist Isala
Gallop-studie: Pieter Boonstra, Marco Tibbesma, Arja ter Elst, Ed Schuuring, An Reyners
PATH-consortium
NVALT-plasma-studies: Lisestte Bosman, Arja ter Elst, Harry Groen, Ed Schuuring
Dank voor uw aandacht
[email protected]
www.MolOncoPath.nl
Leek-meeting 9 november 2016
Recente literatuur te lezen in oratie van prof dr Ed Schuuring:
http://www.rug.nl/news-and-events/promotioninauguration/2013/06_oratie-schuuring.pdf
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