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Discusión: Ramon Salazar Institut Català d´Oncologia
Tertulias Oncológicas Clasificación molecular del colangiocarcinoma extrahepático Discusión: Ramon Salazar Institut Català d´Oncologia
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Scientific Advisory Boards & IDMC (last 5 years): Bio-Techs: VCN-BCN, Agendia, Guardant Health, Roche Diagnostics, Ferrer Pharma: Pfizer, Novartis, Ipsen, Amgen, Merck, Roche Farma, Tayhoo, Lylli, MSD Speaker (last 5 years): Pharma: Pfizer, Novartis, Ipsen, Amgen, Merck, Roche Farma, Lylli, MSD,AZD, Celgene. Owner of Scientific Blog:
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KEY POINTS ABOUT CCAs The most frecuent presentation is mass forming type (>90%). No specific serum, urine, biliary or histological biomarkers. Usually advanced at Dx and challenge to biopsy 5-y OS rate = 10% Heterogeneus group Risk factors, genomic landscape Anatomical subtype influence phenotype i/p/d CCA (different cells of origin) hardly accounted for in EBM studies until know CCA = unmet medical need
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Checkpoint blockade Adoptive T cell therapy
Systemic Therapy Cytotoxic Chemotherapy Targeted Therapy Immunotherapy FGFR2 IDH1 HER2 PI3K BRAF MAPK and more Gemcitabine Cisplatin 5-FU/Capecitabine Oxaliplatin Irinotecan Checkpoint blockade Adoptive T cell therapy CAR T cells
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Valle, J, et al. NEJM 2010
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Molecular spectra of BTC. Location matters
ROS Blue symbols indicate targetable genes Blue symbols indicate targetable genes No approved targeted therapies (yet). Nakamura et al. Nat Genetics 2015
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Molecular Heterogeneity in BTC
CGP Findings IHCCA EHCCA GBCA Total GA/patient 3.6 4.4 4.0 CRGA/patient 2.0 2.1 ERBB2 Amplification 4% 11% 16% BRAF Substitutions 5% 3% 1% KRAS Substitutions 22% 42% PI3KCA Substitution 7% 14% FGFR1-3 Fusions and Amplifications CDKN2A/B Loss 27% 17% 19% IDH1/2 Substitutions 20% ARID1A Alterations 18% 12% 13% MET Amplification 2% ROS Fusions 16%* The more frequently occurring GA are described here. Frequency is similar across the three diseases. However, the nature of GA is very different. ERBB2 EHCCA has KRAS, P53 and p16, A pattern resembling pancreas cancer. IHCCA has IDH1, FGFR, BRAF Javle etal, Cancer. 2016;122(24): * Peraldo et al Gene Chrom Ca 2014; 53:
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Implications for Therapeutic Development
TARGET AGENT NCT NUMBER FGFR Derazantinib NCT TAS 120 NCT Debio 1347 NCT INCB054828 NCT Ponatinib NCT IDH1 Ivodesinib NCT BAY NCT IDH1, IDH2 Olaparib NCT HER2 Trastuzumab NCT BRAF, MEK Dabrafenib, trametinib NCT ALK/ROS1 Ceritinib NCT Crizotinib NCT ROS1,ALK TRKA,TRKB, TRKC Entrectinib NCT EGFR, HER2,HER4 Varlitinib NCT Current targeted therapy clinical trials in cholangiocarcinoma Current targeted therapy clinical trials in cholangiocarcinoma
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Implications for Therapeutic Development
TARGET AGENT NCT NUMBER FGFR Derazantinib NCT TAS 120 NCT Debio 1347 NCT INCB054828 NCT Ponatinib NCT IDH1 Ivodesinib NCT BAY NCT IDH1, IDH2 Olaparib NCT HER2 Trastuzumab NCT BRAF, MEK Dabrafenib, trametinib NCT ALK/ROS1 Ceritinib NCT Crizotinib NCT ROS1,ALK TRKA,TRKB, TRKC Entrectinib NCT EGFR, HER2,HER4 Varlitinib NCT CDK inhibidors in CDKN2A/B loss? Current targeted therapy clinical trials in cholangiocarcinoma Current targeted therapy clinical trials in cholangiocarcinoma
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Inmune therapy in CCC? TARGET AGENT NCT NUMBER FGFR Derazantinib NCT TAS 120 NCT Debio 1347 NCT INCB054828 NCT Ponatinib NCT IDH1 Ivodesinib NCT BAY NCT IDH1, IDH2 Olaparib NCT HER2 Trastuzumab NCT BRAF, MEK Dabrafenib, trametinib NCT ALK/ROS1 Ceritinib NCT Crizotinib NCT ROS1,ALK TRKA,TRKB, TRKC Entrectinib NCT EGFR, HER2,HER4 Varlitinib NCT Current targeted therapy clinical trials in cholangiocarcinoma Current targeted therapy clinical trials in cholangiocarcinoma
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T cell adoptive therapy: 1 CR
Inmune therapy in CCC TARGET AGENT NCT NUMBER FGFR Derazantinib NCT TAS 120 NCT Debio 1347 NCT INCB054828 NCT Ponatinib NCT IDH1 Ivodesinib NCT BAY NCT IDH1, IDH2 Olaparib NCT HER2 Trastuzumab NCT BRAF, MEK Dabrafenib, trametinib NCT ALK/ROS1 Ceritinib NCT Crizotinib NCT ROS1,ALK TRKA,TRKB, TRKC Entrectinib NCT EGFR, HER2,HER4 Varlitinib NCT Keynote-016 (MMR): 1/4 CR Keynote-028 (PDL1 +): 4/24 PR Keynote-158 ongoing T cell adoptive therapy: 1 CR Current targeted therapy clinical trials in cholangiocarcinoma Current targeted therapy clinical trials in cholangiocarcinoma
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pathological characteristics Whole genome expression
Methods Flow chart of the study Patients recruited (N=208) Collaborating center Mount Sinai (New York) [N=59] Clínic (Barcelona) [N=39] CHUV (Lausanne) [N=36] Mayo Clinic (Rochester) [N=28] Lenox Hill (New York) [N=19] Johns Hokpkins (Baltimore) [N=15] Vall Hebron (Barcelona) [N=12] Surgically resected eCCA Patients excluded (N=19) (14 iCCA, 4 non-resected eCCA, 1 non-viable eCCA) Patients included (N=189) Tumor macrodissection RNA DNA Unstained slides Clinical- pathological characteristics Whole genome expression (N=182) Targeted exome sequencing (N=163) Immunohistochemistry (ERBB2, PD1, PD-L1) (N=182) Unsupervised clustering Integrative characterization
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STATEMENT OF SIGNIFICANCE eCCA MOLECULAR CLASSIFICATION
Sound, unsupervised clustering State of the art methodology wet lab Bioinformatics, data analysis & interpretation Transcriptomic based and exome sequencing identified four molecular classes
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eCCA molecular classes
Summary eCCA molecular classes Metabolic (18.7%) Proliferation (22.5%) Mesenchymal (47.3%) Immune (11.5%) Activated signaling pathways Bile acid receptors RTK/mTOR Hedgehog PD1-PDL1 Myc CTNNB1 Cell cycle TNF-alpha IL6-JAK-STAT3 DNA repair Tumor micro-environment Immune excluded Active Stroma (CAFs) Immune exhausted (CD8 TILs) Clinical-pathological characteristics Papillary histology Metastasis Precursor lesions (IPNB) Poor outcome Potential targeted therapies Nuclear receptor modulators ERBB2 mab Hedgehog inh. Immune checkpoint inh. mTOR inh. BCL-2 inh (CAFs) Wnt antagonists CDK4/6 inh. IL6-JAK-STAT3 Inh. HA degradation PARP inh.
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STATEMENT OF SIGNIFICANCE eCCA MOLECULAR CLASSIFICATION
Advanced understanding of the relationship between genotype, clinical and histological features, and gene ontology Room for Consensus? ICGC (Cancer discov 2017; 7(10) ) N: 489 (only 40 eCCA) Also 4 cluster/subtypes.... Elucidation of the role of anatomic location/prognosis
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Therapeutic Implications?
N = 189 included, all resected. ICGC (Cancer discov 2017; 7(10) ) N: 489 (only 40 eCCA) Also 4 cluster/subtypes....Room for Consensus? Elucidation of the role of anatomic location Advance understanding of the relationship between genotype, clinical and histological features, and gene ontology IVD in progress?
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NEXT STEP: PRECISION MEDICINE FOR BTC?
“include only patients with specific subtypes of these cancers and stratify patients according to their genetic drivers” Razumilaba et al . Nat Genetics 2015
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NEXT STEP: PRECISION MEDICINE FOR BTC?
Or VICEVERSA?
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NEXT STEP: PRECISION MEDICINE FOR BTC?
“include only patients with genetic drivers of these cancers and stratify patients according to their specific subtypes ”
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ESC ESMO ESCAT
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Structural genomic aberrations in eCCA
Ongoing Structural genomic aberrations in eCCA Identification of somatic mutations, copy number alterations and fusion events through next-generation sequencing custom panel containing the 75 more frequently altered genes in biliary tract cancer1-4. 1Farshidfar et al. Cell reports (2017). 2Jusakul et al. Cancer Discovery (2017). 3Nakamura et al. Nat Genetics (2015). 4Lee et al. J Clin Pathol (2016).
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Structural genomic aberrations in eCCA
Ongoing Structural genomic aberrations in eCCA Identification of somatic mutations, copy number alterations and fusion events through next-generation sequencing custom panel containing the 75 more frequently altered genes in biliary tract cancer1-4. ROS 1 fusions 1Farshidfar et al. Cell reports (2017). 2Jusakul et al. Cancer Discovery (2017). 3Nakamura et al. Nat Genetics (2015). 4Lee et al. J Clin Pathol (2016).
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NEXT STEP: PRECISION MEDICINE FOR BTC?
ICI for Inmune class?
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Cholangiocarcinoma (Bile Duct Cancer) 2018 2008
Multiple reasons for increased interest in cholangio. 1) positive randomized phase III trial published in NEJM, 2) discovery of targets such as IDH and FGFR < 50 trials trials
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GRACIAS ramonsalazar@iconcologia.com www.tertuliasoncologicas.com
Acknowledgement (slides) Tertulias Oncológicas Robert Montalt & Josep M Llovet Hospital Clinic Provincial. IDIBAPS Lipika Goyal, MD, MPhil Massachusetts General Hospital Cancer Center Berta Laquente, MD Catalan Institute of Oncology. IDIBELL GRACIAS
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www.tertuliasoncologicas.com Tertulias Oncológicas
La plataforma de divulgación científica especializada en oncología Tertulias Oncológicas con el objetivo de divulgar información sobre oncología, objetiva, accesible y contrastada científicamente. Se distingue de los demás medios de comunicación por incorporar en su oferta informativa un formato innovador: las tertulias. Además, la plataforma publica diariamente en formato artículo las últimas novedades en oncología. Satisfacer las necesidades informativas de los profesionales y los afectados por la patología, ya sean pacientes o familiares, es la meta prioritaria del medio.
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