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Molecular subtyping in colorectal cancer: implications for therapeutic decisions
Josep Tabernero, MD PhD Medical Oncology Department Vall d’Hebron University Hospital & Vall d’Hebron Institute of Oncology Barcelona, Spain Great Debates & Updates in GI Malignancies New York, March 27th 2015
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Advances in the treatment of mCRC
5-FU Capecitabine, S-1 Irinotecan Oxaliplatin 2000 More options RR ≈ 45-50% mTTP 8−9 months mOS months Optimal regimens Sequencing Treatment duration 1995 One option RR 50-60% mTTP 9+ months mOS months Cure 5-FU Capecitabine, S-1 Irinotecan Oxaliplatin Cetuximab, Panitumumab Bevacizumab, Aflibercept Regorafenib, TAS-102 2014 Many options Optimal regimens Correct sequencing & dosing Cost Biomarkers Patients’ selection 5-FU EGFR inh. Angiogenesis inh. First-line efficacy RR 20% mTTP 5−6 months mOS 10−12 months Issues Low efficacy
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Outline Molecular determinants of primary and secondary resistance to EGFR inhibitors in mCRC Unsupervised genotyping of CRC Genotype-driven targeted treatment combinations in mCRC: BRAF and RAS mutant populations
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Outline Molecular determinants of primary and secondary resistance to EGFR inhibitors in mCRC Unsupervised genotyping of CRC Genotype-driven targeted treatment combinations in mCRC: BRAF and RAS mutant populations
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Targeting the EGFR pathway in CRC
TGF-α Amphiregulin Epiregulin Anti-EGFR MoAbs: Cetuximab Panitumumab (RAS inh.) RAF inh. MEK inh. ERK inh. Inhibitors EGFR expression 27–99% KRAS mutation 45–50% NRAS mutation 5-8% KRAS EGFR Sos Grb2 BRAF BRAF mutation 5-10% EGFR mutation 1-2% MEK MAPK 5
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Primary resistance to anti-EGFR therapy in colorectal cancer
Responder (15%) KRAS/PIK3CA/PTEN KRAS amplification (1%) BRAF/PIK3CA/PTEN KRAS-NRAS (35-45%) MET amplification (2%) BRAF (5-10%) HER2 amplification (3%) Non responder (16%) PIK3CA and/or PTEN (15%) Modified from Bardelli, J Clin Oncol 2010 6
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Multiple mechanisms of acquired resistance to EGFR inhibition in CRC
Hobor S et al, Clin Cancer Res 2014; Salazar R & Tabernero J, Clin Cancer Res 2014
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Liquid biopsies to monitor gene amplification associated with acquired resistance
Bardelli et al., Science Discovery, 2014
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Potential biomarkers in mCRC for EGFR inhibitors
On/Off marker Threshold marker RAS mut BRAF mut PIK3CA mut cMET & HER2 amplifications TP53 mut PTEN mut EGFR mut EGF & EGFR polymorphisms Genomic/Proteomic COX-2 PTEN EGF Epiregulin Amphiregulin EGFR expression DUSPs Mitogen-activated protein kinase phosphatase-1 (MKP-1) (-) predictive biomarkers Signatures
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Outline Molecular determinants of primary and secondary resistance to EGFR inhibitors in mCRC Unsupervised genotyping of CRC Genotype-driven targeted treatment combinations in mCRC: BRAF and RAS mutant populations
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Genomic Landscape of CRC… 2012
Hypermutated tumors 16% Non-hypermutated tumors 84% Facts: 224 T/N pairs Next-Generation Sequencing – Whole Exome Seq >20X coverage 32 somatic recurrent mutations per tumor Cancer Genome Atlas Network, Nature 2012
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Somatic mutations in different tumor types
Lawrence et al. Nature 2013
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Genomic Landscape of CRC… 2012
Hypermutated tumors 16% Non-hypermutated tumors 84% Facts: 224 T/N pairs Next-Generation Sequencing – Whole Exome Seq >20X coverage 32 somatic recurrent mutations per tumor Cancer Genome Atlas Network, Nature 2012
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Molecular Classification of CRC… 2012
Right-sided, MSI-H, Hypermethylated, BRAF mut, Chromosomal stability Left-sided, Rectal, MSS, KRAS mut, CIN +ve Cancer Genome Atlas Network, Nature 2012
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Training cohort: 188 Validation cohort: 543 Deficient Epithelial
Proliferative Epithelial Mesenchymal A BC Training cohort: 188 Validation cohort: 543 Roepman et al. Int J Cancer 2013
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A-type B-type C-type 22% 62% 17% BRAFmt 39% BRAFmt 2% BRAFmt 13%
MSI 49% MSS 87% MSI 13% dMMR 68% dMMR 1% dMMR 36% Adj Rx + Adj Rx - Roepman et al. Int J Cancer 2013 Loboda et al. BMC Medical Genomics 2011
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Unsupervised molecular subtyping of CRC - Microarray
Multiple signatures 3-6 subtypes Mainly stages II-III Discordant (nightmare?)
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Colorectal cancer subtyping consortium (CRCSC) identifies consensus molecular subtypes
Dienstmann R. J Clin Oncol 2014
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Population 4,562 Data set Source Platform Tissue Samples
GEO (14 data sets) public Affymetrix HG133plus2 Fresh-frozen 1,542 PETACC-3 proprietary Almac's Affymetrix ADXCRC FFPE 688 TCGA RNA sequencing 603 French (GSE39582) public* 566 KFSYSCC 320 MDACC Agilent 37K discoverprint_32627 219 Agendia ICO208 Agilent 37K discoverprint_19742 208 Agendia (GSE42284) 188 AMC-AJCCII (GSE 33113) 90 Agendia VH70 76 NKI-AZ (GSE35896) 62 4,562 Total *with private clinical annotation Dienstmann R. J Clin Oncol 2014
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Population Features Samples Statistics Age 3,063 Median (range)
66 years (21-98) Gender 3,394 Male 54% Female 46% Site 3,164 Right colon 39% Left colon Rectum 15% Stage at diagnosis 3,499 I 11% II III 43% IV 7% Microsatellite status 2,597 MSS 84% MSI 16% Relapse-free survival 2,252 Median follow-up 72 months Overall survival 2,796 68 months Dienstmann R. J Clin Oncol 2014
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Results - network of subtypes
Canonical Mesenchymal MSI - Immune Metabolic Dienstmann R. J Clin Oncol 2014
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Results – distribution & clinical correlates
Stage Age diagnosis Gender (median) (female) CMS1 13% y % CMS2 35% y % CMS3 11% y % CMS4 20% y % Uncl. 21% 21% y % IV III II I CMS1 CMS2 CMS3 CMS4 Unclassified Dienstmann R. J Clin Oncol 2014
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Results – clinical and molecular correlates
Site MSI status Right Rectum Left MSS MSI CMS1 CMS2 CMS3 CMS4 Unclassified CMS1 CMS2 CMS3 CMS4 Unclassified Dienstmann R. J Clin Oncol 2014
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Results – molecular correlates
Mutations exome-level (n=282) Copy number alterations genome-level (n=550) CMS1 CMS2 CMS3 CMS4 Unclassified CMS1 CMS2 CMS3 CMS4 Unclassified Dienstmann R. J Clin Oncol 2014
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Results – mutation profile (n=2,386)
BRAF mut KRAS mut CMS1 CMS1 CMS2 CMS3 CMS4 CMS2 CMS3 CMS4 Unclassified Unclassified Dienstmann R. J Clin Oncol 2014
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Results – reverse phase protein arrays (n=439)
IGFBP2 expression CMS1 DNA repair, cell cycle, apoptosis, inflammation CMS2 Beta-catenin, receptors, kinases CMS3 Beta-catenin, receptors, kinases, IGFBP2 CMS4 NOTCH3, VEGFR2, fibronectin, caveolin Unclassified - CMS1 CMS2 CMS3 CMS4 Unclassified Dienstmann R. J Clin Oncol 2014
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Results – pathway analysis (n=3,891)
Epithelial signature WNT activation MYC activation Mesenchymal signature Epithelial-mesenchymal transition TGFβ activation Stromal infiltration Immune activation Immune infiltration VEGFR ligands Epithelial signature WNT activation MYC activation Mesenchymal signature Epithelial-mesenchymal transition TGFβ activation Stromal infiltration Immune activation Immune infiltration VEGFR ligands p > 0.05* p = 0.05 – * p < * CMS1 CMS2 CMS3 CMS4 Unclassified Fisher’s combined probability test of p values (across all datasets) for enrichment in Gene Set Analysis (GSA) Dienstmann R. J Clin Oncol 2014
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Summary – clinical and molecular correlates
CMS1 Females, older age, right colon MSI, hypermutation, BRAF mut, immune activation CMS2 Left colon Epithelial, MSS, high CIN, TP53 mut, WNT/MYC pathway activation CMS3 Epithelial, heterogeneous CIN/MSI, KRAS mut, IGFBP2 overexpression CMS4 Younger age, stage III/IV Mesenchymal, CIN/MSI, TGFβ/VEGF activation, NOTCH3 overexpression Unclassified Immune and stromal infiltration, variable epithelial-mesenchymal activation Dienstmann R. J Clin Oncol 2014
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Summary – clinical and molecular correlates
WNT and MYC inhibitors? Metabolic inhibitors? MSI - Immune Canonical Metabolic Mesenchymal TGFb inhibitors New antiangiogenics Matrix inhibitors Immune checkpoint inhibitors Immune regulators BRAF strategies Dienstmann R. J Clin Oncol 2014
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Survival curves Dienstmann R. J Clin Oncol 2014
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Outline Molecular determinants of primary and secondary resistance to EGFR inhibitors in mCRC Unsupervised genotyping of CRC Genotype-driven targeted treatment combinations in mCRC: BRAF and RAS mutant populations
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BRAF (V600E) mutated CRC Small population: 8-10% early stage
4-5% late stage BRAF V600E mutations as a biomarker? very poor prognosis in late stage (mCRC) no clear prognostic effect in early stage predictive: negative predictive effect for anti-EGFR MoAbs in some studies: Cetuximab: refractory (European cons.)1,2 & first-line setting (CRYSTAL study)3 Panitumumab: 2nd line setting (PICCOLO study)4 No change in the label by any regulatory authority predicted 1 Di Nicolantonio F, J Clin Oncol 2018; 2 De Roock et al, Lancet Oncol 2010; 3Van Cutsem et al, J Clin Oncol 2011; 4Seymour MT et al, Lancet Oncol 2013
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New studies in the BRAFV600E mutant CRC population
As examples of clinical trials evaluating the combination of BRAFV600E inhibitors plus anti-EGFR inhibitors in the BRAF mutant population in CRC: NCT : Vemurafenib + Cetuximab (BASKET) – Roche: Phase Ib NCT : BRAF/MEK Inhibitors (dabrafenib + trametinib) + Panitumumab – GSK: Phase Ib RP2 NCT : LGX818 and Cetuximab or LGX818, BYL719, and Cetuximab – Novartis: Phase IbRP2 NCT (MDACC): Vemurafenib + Cetuximab + Irinotecan Dienstmann R & Tabernero J. ASCO Educ Book 2014
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Early efficacy comparison of BRAFi/EGFRi combos
Regimen N PR/CR (%) SD (%) DCR (%) Dabrafenib + Trabetinib 43 12 51 63 Dabrafenib + Panitumumab 15 13 73 87 Vemurafenib + Cetuximab* 11 - 36 Encorafenib + Cetuximab 24 29 50 79 Dabrafenib + Trabetinib + Panitumumab 40 80 Vemurafenib + Cetuximab + Irinotecan 8 100 Encorafenib + Cetuximab + BYL719 20 30 60 90 *No confirmation response assessment Dienstmann R &Tabernero J. ASCO Educ Book 2014
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RAS mutant CRC Big population: 49-52% KRAS mutations
5-11% NRAS mutations RAS mutations as a biomarker? no clear prognostic effect in early/late stage predictive: negative predictive effect for anti-EGFR MoAbs: KRAS for Cetuximab & Panitumumab: 1st, 2nd and late stage NRAS for Cetuximab & Panitumumab: 1st, 2nd and late stage 1 Di Nicolantonio F, J Clin Oncol 2018; 2 De Roock et al. Lancet Oncol 2010; 3Van Cutsem et al, J Clin Oncol 2011; 4Seymour MT et al, Lancet Oncol 2013
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MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors
Turke A et al. Cancer Res 2012
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Studies in RAS mutant mCRC
Genomic profile Strategy Trial KRAS mut anti-EGFR mAbs + MEK inhibitors Phase 1/2 Panitumumab + MEK162 NCT novel anti-EGFR/HER3 mAbs + MEK inhibitors MEHD7945A + Cobimetinib NCT anti-IGF1R mAbs + MEK inhibitors AMG MEK162 NCT KRAS G13D anti-EGFR mAbs Phase 2 Cetuximab ICECREAM KRAS mut FcγRIIa genotype (CD32) NCT NRAS mut MEK inhibitors +/- PI3K path inh. MEK162 + BKM120 NCT Dienstmann R & Tabernero J. ASCO Educ Book 2014
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Summary Target discovery has resulted in numerous novel drugs in clinical development but with very limited survival gain in mCRC Within the largest collection of CRC samples CRCSC has identified recurrent signals of 4 biologically distinct subtypes that are enriched for key clinical, molecular, pathway traits and have prognostic implications Need for strong science-sound rationale for the combinations, these addressing mechanistic interactions: BRAF mutant Need to sequentially evaluate tumor cells (tumor tissue, CTCs, circulating DNA, …) to have evolutive/dynamic information
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Acknowledgements All the patients and their families
Vall d’Hebron University Hospital Oncology Dep. Pathology Dep. S. Landolfi P. Nuciforo J. Jiménez R. Dienstmann E. Elez T. Macarulla G. Argiles J. Rodon Genomic Lab. A. Vivancos A. Prat Translational Lab. V. Serra H. García-Palmer F. Ciardiello E. Martinelli . S. Siena A. Sartore-Bianchi . A. Cervantes . J. Schellens R. Dienstmann J. Guinney S. Friend R. Salazar G. Capella V. Moreno I. Simon L. Dekker R. Bernards S. Kopetz E. Vilar E. Van Cutsem S. Tejpar A. Bardelli F. Di Nicolantonio
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