10 de avondsymposium Groningen, 1 november Nieuwe ontwikkelingen in de behandeling van NSCLC Gevolgen van PATH project voor NSCLC

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1 10 de avondsymposium Groningen, 1 november 2017 Nieuwe ontwikkelingen in de behandeling van NSCLC Gevolgen van TH project voor NSCLC Hoe tillen we Moleculaire Diagnostiek van NSCLC naar hoger plan? Ed Schuuring KMBP (Klinisch Moleculair Bioloog in de ologie) voor ologie van UMCG, Friesland, Hoogeveen, Zwolle en Martini/Winschoten Head Laboratory Molecular ology, UMCG Groningen Disclosures Consultant/Advisory Board: AstraZeneca, Roche, Pfizer, Novartis, Amgen, BioCartis, QCMD, ESP, IQNTH, Cancer-ID Speaker s fee: Abbott, Novartis, Roche, Biocartis, Illumina Grants/Sponsoring: Pfizer, Biocartis, BMS, Roche, Boehringer Ingelheim Stock/Royalties: None All transferred to UMCG-account 1

2 Molecular profiling of lung cancer in 2017 Molecular ology Traditional histopathological classification >2009: Molecular Tumor Profiling Wild type del Li JCO 2013 To define which patients for what drug benefit most (personalised therapy) NGS analysis Today s tissue-management lung cancer (2017) 1st last 5% neoplastic cells This example represents a typical biopsy in our clinical practice (lung cancer) Images with courtesy of Erik Thunnissen, VUMC >50% neoplastic cells Presentation Ed Schuuring, 1 November 2017, Hoogkerk 2

3 More analysis from one biopsy? Today s tissue-management lung cancer (2017) HE first Diagnostic stain TTF1 Diagnostic stain mucin Diagnostic stain P63/p40 PD-L1 IHC ALK IHC NTRK FISH ROS1 FISH RET FISH MET FISH NGR1 FISH DNA isolation NGS mutation analysis RNA isolation MET exon skipping HE last Turn-around-time (TAT) and hands-on-time Presentation Ed Schuuring, 1 November 2017, Hoogkerk Molecular ology of lung cancer: Optimal molecular testing In Northern part of the Netherlands 3

4 Next Generation Sequencing: Ion Torrent Personal Genome Machine (PGM) >50 hotspot regions in 24 genes (83 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_ KIT_exon11 MET exon 14-intron 14 ALK_ GNA11_183 KIT_exon13 MET intron 13-exon 14 ALK_ GNA11_209 KIT_exon14 NRAS_ ALK_ GNAQ_183 KIT_exon17 NRAS_12-13 BRAF_600 GNAQ_209 KIT_exon18 NRAS_61 BRAF_exon11 GNAS_201 KIT_exon8 PDGFRA_exon12 EGFR_492 GNAS_227 KIT_exon9 PDGFRA_exon14 EGFR_exon18 H3F3A_27-36 KRAS_ PDGFRA_exon18 EGFR_exon19 H3F3B_35-37 KRAS_1213 PIK3CA_1047 EGFR_exon20 HRAS_ KRAS_61 PIK3CA_ EGFR_exon21 HRAS_1213 MAP2K1_ POLE_286 ERBB2_exon19 HRAS_61 MAP2K1_203 POLE_411 ERBB2_exon20 IDH1_132 MAP2K1_264 ROS1_2032 ERBB2_exon21 IDH2_ MAP2K1_382 ROS1_2155 ESR1_463 JAK2_617 MAP2K1_53 (inclusief MET-exon14-skipping en gatekeeper ROS/ALK mutatie) Molecular Oncological ology at UMCG: Predictive markers testing using in-situ-hybridization (FISH) ISH-based detection methods for rearrangements, deletions, CNV/amplication of clinical relevant targeted genes (UMCG/2016) Polysomy ALK Break-apart ALK Amplification FGFR1 Amplification HER2 Break-apart RET amplification MET BRISH HER2 Polysomy MET Break-apart ROS 4

5 Predictive markers testing using immunohistchemistry Antibodies specific for clinical relevant proteins of mutated targeted genes (UMCG/2017) Specifiek anti- Specifiek anti- exon19-del IHC L858R-del IHC Kozu Lung cancer 2011 MET-IHC score Specifeke IHC voor ALK-breuk Positieve NSCLC FISH-ALKpositief FISH-ALKnegatief Specifiek IHC tegen BRAF-V600E Long AJSP 2012 Methods to detect predictive molecular aberrations in Molecular ology of lung cancer (2017) NGS-mutation: EGFR, ALK, ROS, RET, KRAS, BRAF, PIK3CA, MET, KIT FISH-rearrangement: ROS, RET, (ALK), NTRK1, NGR1 FISH-amplification/CNV: MET, HER2, FGFR1, EGFR1 IHC: HER2, ALK, ROS1, PD-L1 RTPCR: MET exon14-skipping Molecular Oncological ology at UMCG: 5

6 Molecular diagnostics of lung cancer for treatment planning using gene-targeted therapy in NL dutch guidelines In 2007: starting with EGFR-mutation screening In 2013: Dutch guideline in NSCLC Only EGFR-mutation analysis In 2013: ALK-translocation (Registration crizotinib July 2012) In July 2015: revisited Dutch guideline for NSCLC: (1) EGFR, ALK; (2) HER2, BRAF, RET and ROS1 Molecular diagnostics of lung cancer for treatment planning using gene-targeted therapy international guidelines Dutch Oncoline guideline for NSCLC (July 2015): (1) EGFR, ALK; (2) HER2, BRAF, RET and ROS1 CAP-IASLC-AMP guideline for NSCLC (Aug 2017) (Hanna JCO 2017) EGFR, ALK, ROS and PD-L1 (recommendation HER2, BRAF and RET) NCCN guideline for NSCLC (2016) for adca and never-smokers SCC (1) EGFR, ALK; (2) as part of broad profiling (HER2, MET, BRAF, RET, ROS1) ESMO guideline for NSCLC (2013/2016) (Kerr Ann Oncol 2013; Novello, 2016) co-testing EGFR and ALK (recommend KRAS, BRAF, HER2 and ROS1) 6

7 Nieuwe predicitieve biomarkers in kader van klinische trials bij longkanker in umcg ( Studie Fase Type tumor Doel NVALT 15 III plano - FGFR1 Stadium IIIB/IV met FGFR1 amp: nintedanib NVALT-17 III adeno - EGFR mut 1e lijn intercalated vs erlotinib NVALT-19 II mesothelioom 1e lijn maintenance gemcitabine na chemotherapie (cis/pem) IL-09 plano 1e lijn carbo/taxol/orale fosfoinositide 3-kinase remmer LO-41 II plano HER3 remmer + carbo/taxol LO-45 I/II SCLC - Extensive disease RP remmer + carbo/etoposide LO-24 II adeno - BRAF mutatie V600E 1e lijn stadium IV. BRAF/MEK remmer LO-27 III adeno - ALK translocatie 1e lijn LDK of cisplatine/pemetrexed LO-36 II adeno - ALK translocatie LO-36 II adeno - ALK translocatie LO-40 II adeno EGFR mutatie T790M+ 2e lijn: stadium IV bij EGFR resistentie: 3e generatie TKI LO-48 Ib/II adeno - EGFR + c-met amp.; geen 2e/3e lijn: c-met remmer + gefitinib T790M LO-54 III adeno - EGFR mutatie +/- T790M 3e en volgende lijnen; 3e generatie EGFR remmer vs chemotherapie, cross over mogelijk na chemotherapie Compassionate Use Ceritinib NSCLC EML4-ALK Bij resistentie voor crizotinib Alectinib NSCLC EML4-ALK Bij geen behandelopties meer voor ALK+ patienten Nivolumab NSCLC - plano & adenocarcinoom 2e lijns therapie na platinum doublet Sunitinib NSCLC - PDGFR mutatie indien PDGFR mutatie aanwezig na platinum doublet Sunitinib NSCLC - RET translocatie indien RET translocatie aanwezig na platinum doublet Bezocht op Molecular ology of lung cancer in UMCG and North-Netherlands (2017) NGS-mutation: EGFR, ALK, ROS, RET, KRAS, BRAF, PIK3CA, MET, KIT FISH-rearrangement: ROS, RET, (ALK), NTRK1, NGR1 FISH-amplification/CNV: MET, HER2, FGFR1, EGFR1 IHC: HER2, ALK, ROS1, PD-L1 RTPCR: MET exon14-skipping Molecular Oncological ology at UMCG: 7

8 Uitdagingen mbt moleculaire pathologie in -labs in Nederland in 2017 Verschillende moleculaire predictieve markers Verschillende moleculaire detectiemethoden Geen/weinig informatie over huidige behandelmethoden Geen gestandaardiseerde verslaglegging Kosten spelen rol bij keuze (uitgebreidheid) testen 8

9 Project TH (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, LGA Goal: To introduce a NGS assay to create optimal and equal access to targeted therapies for all (lung, melanoma, GIST, CRC) cancer patients in the Netherlands elke patiënt de juiste uitslag en advies CALL ZONMW GGG: PERSONALISED MEDICINE ONCOLOGY Project TH (Predictive Analysis for THerapy) Optimizing access to personalized cancer therapy in the Netherlands; from tissue to therapy. Het doel van het TH-project: Optimalisatie van predictieve diagnostiek >> leren van best practices >> samen naar nog betere diagnostiek Standaardisatie van rapportage en interpretatie van moleculaire resultaten >> in LGA >> allemaal dezelfde taal spreken Inrichten van multidisciplinair expertise netwerk van moleculaire tumorboards >> samennaarbeterevertalingnaarde kliniek>> therapieop maat Opzetten infrastructuurvoor (toekomstig) Health Technology Assessment (HTA) onderzoek >> Effectiviteit organisatie van predictieve moleculaire diagnostiek >> Kosteneffectiviteit moleculaire testen 9

10 WP 2 Ed Schuuring, Petra Nederlof, Bastiaan Tops, Astrid Eijkelenboom WP 4 Stefan Willems; Henk-Jan van Slooten; Paul Seegers WP 1 Marjolijn Ligtenberg; Katrien Grünberg WP 3 Harry Groen; Hans Gelderblom; Katrien Grünberg Veerle Coupé; Eddy Adang; Erik Thunnissen List of predictive genetic biomarkers and accompanying targeted agents that are currently (2017) approved for treatment of solid tumours in The Netherlands Predictive gene Aberrations Cancer type Targeted agent ALK SNVs, Fusion-transcript Lung Crizotinib, Ceritinib BRAF SNVs Skin (melanoma) Vemurafenib EGFR SNVs Lung Gefitinib, erlotinib ERBB2 (Her2) amplification Breast Trastuzumab KIT SNVs GIST Imatinib, Sorafenib KRAS SNVs Colon Cetuximab, Panitumumab NRAS SNVs Colon Cetuximab, Panitumumab PDGFRA SNVs GIST Imatinib, Sorafenib ROS1 Fusion-transcript Lung Crizotinib, Ceritinib BRCA1 SNVs, CNVs Ovary Olaparib BRCA2 SNVs, CNVs Ovary Olaparib 10

11 TH-WP2 task force gene-panel (2017 for implementation) Clinical relevant: direct impact on targeted therapy: > Dutch (concept) onco-guidelines > Ongoing Dutch clinical trials > Information from pharma (2017/drup-study) > literature Lung cancer, CRC, GIST and melanoma Variants (mutations, deletions, fusions, CNV) Design mutation/gene panel: Leon van Kempen, Leonie Kroeze, Bas Tops, Arja ter Elst, Ed Schuuring smmip-design/validation: Leonie Kroeze, Astrid Eijkelenboom, Marjolijn Ligtenberg TH-v02D DNA gene panel (Oct 2017: implementatie in 4 centers using smmip-ngs) Predictive gene Aberrations Predictive gene Aberrations AKT1 SNV JAK2 SNV AKT2 SNV KIT SNV + CNV AKT3 SNV KRAS SNV + CNV ALK SNV + CNV MAP2K1 SNV ARAF SNV MDM2 CNV BRAF SNV + CNV MET SNV + CNV DDR2 SNV MTOR SNV EGFR SNV + CNV NRAS SNV ERBB2 SNV + CNV PDGFRA SNV + CNV FGFR1 CNV PIK3CA SNV FGFR2 CNV POLE SNV FGFR3 CNV PTEN SNV GNAS SNV RAF1 SNV GNAQ SNV ROS1 SNV GNA11 SNV TP53 SNV + CNV HRAS SNV IDH1 SNV MSI IDH2 SNV AMELX/Y Consortium (Dutch University Laboratories of Molecular ology) Consensus on NGS mutation panel > each patient in NL receives same opportunities for therapy 11

12 Single molecule Molecular Inversion Probes for NGS TH-panel Single molecule tag to identify independent biological template molecules: Higher specificity Higher sensitivity single molecule tag Hiatt JB, et al. Genome Res May;23(5): Molecular ology of lung cancer in UMCG and North-Netherlands (2017) NGS-mutation: EGFR, ALK, ROS, RET, KRAS, BRAF, PIK3CA, MET, KIT FISH-rearrangement: ROS, RET, (ALK), NTRK1, NGR1 FISH-amplification/CNV: MET, HER2, FGFR1, EGFR1 IHC: HER2, ALK, ROS1, PD-L1 RTPCR: MET exon14-skipping Molecular Oncological ology at UMCG: 12

13 TH-RNA-gene panel: gene-composition (in development) Predictive gene NTRK1 MET EGFR ALK FGFR3 BRAF RET ROS1 PDGFRA NRG1/FGFR1? Aberrations Fusion-transcript Exon 8/14 skipping Viii deletion Fusion-transcript Fusion -transcript Fusion-transcript Fusion-transcript Fusion-transcript Fusion-transcript Fusion-transcript Consortium (Dutch University Laboratories of Molecular ology) Consensus on NGS mutation panel > each patient in NL receives same opportunities for therapy RNA-based assays to detect fusions commercial kits becoming available now ALK RGQ RT-PCR kit (Qiagen) Ion AmpliSeq RNA fusion Lung Cancer Panel (Life Techn) (RUMC, DNA, LUMC) EML4-ALK Fusion Gene Detection Kit (Amoy Diagnostics) EML4-ALK Fusion Gene Detection Kit (Entrogen) RNA-seq (NGS-approach;???) ncounter Nanostring Lung Panel (UMCG/NKB) RNA SPET Panel Nugen (UMCG/NKB) Archer Fusionplex CTL Panel (NKI, Erasmus, LUMC)Lung Cancer Lung Cancer Qiaseq Targeted RNAscan panel (RadboudMC) Validated in 4 TH-labs on same samples (what test should we use?) in single run all fusions tested (cost-effective) possibility to add targets (NGR1, MET-skipping) Validate predictive value to select good responders RNA vs DNA from FFPE-tissue 13

14 RNA-based assays to detect fusions for ALK, RET, NTRK AND ROS nanostring UMCG (first data) 2/2 RET-fusions; 3/3 ALK-fusions; 3/3 ROS-fusions; 4/4 negative controls Next-step: ad NGR1 and MET-exon14 skipping Molecular results might as well be hieroglyphs ALK, APC, ASXL1, ATM, BAP1, BCR-ABL, BRAF, BRCA1, BRCA2, CEB, CRAF (RAF1), CSF1R, CTLA4,CTNNB1, DDR1, DNMT3A, ERBB1 (EGFR), ERBB2 (HER2), ESR1, FGFR4, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MAP2K1 (MEK1), MAP2K2 (MEK2), MAPK3 (ERK1), MET, MLL (KMT2A), MPL (TPOR), MYC, MYD88, NOTCH1, NPM1, NRAS, RP1, PDGFRA, PDGFRB, PIK3CA, PML, PTEN, PTPN11, RARA, RB1, RET (MEN2), RUNX1, TET2, TP53, VEGFA, VEGFR1 (FLT1), VEGFR2 (KDR), VEGFR3 (FLT4), VHL, WT1, mtor List of actionable cancer biomarkers, 2015 AD Hieroglyphs on stone tablet, 5000 BC Courtesy of Mark Bogulski, MD, Genome Health Solutions University of Alabama Comprehensive Cancer Center Research Retreat, Birmingham, AL, October 6,

15 Nation wide Digital ology Database (since 1991) Courtesy of S. Willems, UMCU Standarization of molecular data (NGS) reporting > launching first molecular-module (KRAS, EGFR, BRAF) (dec 2015) > launching molecular-module for NGS data (oct 2017) > linking to clinical databases and registries (2018) Options for Quality-control, TAT, identifying rare mutation, etc 15

16 Reporting Mutation Analysis data Handling of unexpected, difficult, rare mutations? Treatment options? 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% tumortype B A C D C D genenset A B C D NGS analyse analyse en en moleculaire interpretatie tumorspecifieke verandering gen a gen b gen c, mut X gen b behandeling op maat Regulier MDO moleculaire tumor board 16

17 tumortype B A C D C D genenset A B C D NGS analyse analyse en moleculaire interpretatie tumorspecifieke verandering gen a gen b gen c, mut X gen b behandeling op maat Regulier MDO Moleculaire Tumor Board Interpretation of Mutation Analysis Data Handling of unexpected, difficult, rare mutations? Treatment options/advice? (1) KMBP/pathologist search for information on general treatment advice and interpretation in -report (2) assistance with specific treatment advice via the Molecular Tumor Board Groningen (every Friday MTB-meeting) (3) Using databases, variant calling, 3-D modelling Using 3D-modeling, drug design and predicting interaction Groningen Research Institute for Pharmacy (drug design) 17

18 Every Friday from hrs we discuss requests for advice (since Nov 2014) Molecular Tumor Board Groningen (in dutch) Prof dr Ed Schuuring, KMBP Dr Arja ter Elst, KMBP Prof dr Anke van den Berg, KMBP Dr Nils t Hart, lungpathologist Prof dr Wim Timens, lungpathologist Prof dr Harry Groen, pulmonologist Dr Jeroen Hiltermann, pulmonologist Dr Anthonie van der Wekken, pulmonologist Prof dr Geke Hospers, medical oncologist Dr Hilde Jalving, medical oncologist Dr Matthew Grover, drug-design pharmocologist Dr Leon van Kempen, KMBP-trainee Dr Maarten Niemantsverdriet, KMBP-trainee This expert forum combines the expertise of clinical molecular biologists in pathology, pathologists, medical oncologists, molecular pharmacologist and pulmonologists Verslaglegging mutatieanalyse moleculaire interpretatie Materiaal (FFPE-blokje) ontvangen voor consult van MZH (MZH:T II1). Moleculaire interpretatie (UMCG): Er is een mutatie aangetoond in EGFR: c.2573t>g; p.(l858r). Er zijn geen mutaties waargenomen in de andere mutatie-hotspots in EGFR, BRAF, KRAS, ERBB2 (HER2), KIT, ALK, NRAS, PDGFRA en PIK3CA. Klinische interpretatie: Longcarcinomen (met name NSCLC) met een activerende mutatie in EGFR reageren in het algemeen goed op therapie gericht tegen EGFR. Indien u een behandeladvies of informatie wenst over lopende trials, kunt u contact opnemen met onze Moleculaire Tumor Board via MoleculaireTumorBoard@path.umcg.nl (zie 18

19 Moleculaire Tumor Board in UMCG en regio-noord Jos Stigt, Saskia Offermans, Clemens Prinsen (Isala, Zwolle) TH Expert netwerk Netwerk van Moleculaire Tumorboards (MTBs) Vertaling moleculaire info naar behandeladviezen Terugkoppeling naar moleculaire database Faciliteert toegang tot klinische trials Nationaal expert platform Casusoverleg ICT infrastructuur voor delen van informatie en decision support tools Contact met farma, CPCT, gezondheidsautoriteiten, etc Harmonisatie mbt interpretatie, advies en rapportage Gedeelde database (variant/advies/respons) Landelijke database (overview observed variants and biology) 19

20 Proposal to organise national program for optimal targeted treatment To exchange info on experience, training, education, ongoing trials Trial alert CPCT Pharma Scientific socs LGA Hub Hub Noordwe st Noordoos t Hub Midden Hub Zuidwest Landelijk platform predictieve diagnostie k Hub Middenw est Hub Zuid Hub Oost All hospitals Regional hubs Interaction with important stakeholders Regional Molecular Tumor Boards National tumor board Forum Linking with clinical databases Farma CPCT CMDP NVALT BOM Project TH (Predictive Analysis for THerapy) Optimizing access to personalized cancer therapy in the Netherlands; from tissue to therapy. Moleculaire ologie in de regio Noord UMCG Groningen Friesland Leeuwarden TREANT Hoogeveen Noord-oost HUB management UMCG Martini Groningen Isala Zwolle Enschede 20

21 Moleculaire ologie in de regio Noord UMCG Noordelijk Netwerk voor Moleculaire ologie: Friesland Leeuwarden TREANT Hoogeveen Groningen Noord-oost HUB Coordination UMCG Martini Groningen Isala Zwolle Afstemming met pathologen en oncologen Zelfde pakket aan MD-testen Vergelijkbare zorg voor elke patient Centrale MD-testen (complexe assays) Lokale testen (voor lage TAT) Kosten-effectiviteit Kwaliteit Regionaal overleg, bijscholing met oncologen Scholing voor AIOS Enschede 2017: UMCG centrale Moleculaire Tumor Board (nov 201 Lokale boards binnen netwerk Bij-/nascholing pathologen/oncologen Predictive molecular testing anno 2017 Molecular profiling diagnosis Molecular profiling diagnosis tissue biopsy Patient with cancer? liquid biopsy 21

22 Can peripheral blood be used to determine the presence of the tumor? Plasma: * DNA and circulating tumor DNA (ctdna) * RNA and circulating tumor RNA (ctrna) * Proteomic/immunological tumor markers * Pharmacokinetics ([drug]) Leukocytes and circulating tumor cells (CTC) Platelets and tumor RNA Mutatie testen UMCG FFPE-biopten met >2% neoplastische cellen 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; UMCG ref-lab for NL) EGFR-del19/L858R voor behandelkeuze Dutch onco-guideline (july 2015) UMCG-ISO15189-validated ddpcr EGFR mutation test BRAF-V600E voor behandelkeuze/monitorig melanoom KRAS-common voor behandelkeuze/monitoring CRC KIT-exon 11 voor behandelkeuze/monitoring GIST extra kosten, snellere TAT, meer biopten met uitslag (beperkt genen), andere logistiek EGFR-plasmatest: logistiek aanvragen op Via apart extern plasma-aanvraagformulier Op verzoek versturen we pakket met info, formulier en bloedbuizen) 22

23 MD-technicians: Ingrid de Boer-Huitema Annelies ten Caat Erik Nijboer Paskal van Norel Rianne Pelgrim Inge Platteel Martin Schipper Jantine Sietzema Tom Artz Frank Scherpen Klaas Kooistra Molecular ologie UMCG-team KMBP: Elise van der Logt (F, UMCG) Arja ter Elst Anke van den Berg Ed Schuuring (UMCG, HGV, MZH, F, Isala) Maarten Niemantsverdriet (KMBPio ) (Isala, UMCG) Leon van Kempen (KMBPio ) ologists: Wim Timens Nils t Hart Arjan Diepstra (moleculaire patholoog) 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 Glover, drug-design (GRI of Pharmacy) 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 TH-consortium NVALT-plasma-studies: Lisestte Bosman, Arja ter Elst, Harry Groen, Ed Schuuring 23