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Josep Tabernero, Vall d’Hebron Hospital

Colorectal cancer intrinsic subtypes are associated with prognosis, chemotherapy response, deficient mismatch repair and epithelial to mesenchymal transition (EMT). Josep Tabernero, Vall d’Hebron Hospital

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Josep Tabernero, Vall d’Hebron Hospital

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  1. Colorectal cancer intrinsic subtypes are associated with prognosis, chemotherapy response, deficient mismatch repair and epithelial to mesenchymal transition (EMT) Josep Tabernero, Valld’Hebron Hospital and Iris Simon, Paul Roepman, Andreas Schlicker, Ian Majewski, Victor Moreno, Christine Chresta, Robert Rosenberg, Ulrich Nitsche, Teresa Macarulla, Gabriel Capella, Ramon Salazar, George Orphanides, Lodewyk Wessels, Rene Bernards

  2. Disclosure InformationRelationships relevant to this session Tabernero, Josep VHIO has received research funding from Agendia Please note, all disclosures are reported as submitted to ASCO, and are always available at gicasym.org

  3. Colorectal cancer different subtypes • Colorectal cancer is the second leading cause of cancer death • Although several treatments exist we do not have an optimal way to select treatments for individual patients • Only KRAS status has been established as a predictor of anti-EGFR treatment activity • New technology platforms allow genetic definition of different types of cancer based on gene expression and characterization • Unbiased genome-wide analyses of gene expression patterns have been successful for molecular classification of BC & GBM

  4. Whole Genome Array Development Set (stage I-IV) (n=188) Netherlands Cancer Institute, Leiden Medical Center, Slotervaart Development Molecular classification based on nearest centroid single sample predictor (SSP) 3 gene expression profiles (A, B & C) Validation Set (stage II-III) (n=543) Technical University Munich, InstitutCatalad’Oncologia& Valld’Hebron Hospital Barcelona, Medical University Vienna, University of Ferrara Validation Analysis of mutations in BRAF(V600), KRAS (codons 12, 13 & 61) and PIK3CA (exons 9 & 20) – All samples Analysis of 615 (incl. kinome) by NGS – 73 samples MSI analysis by IHC – All samples MSI/dMMR gene expression pattern (64 gene signature1) – All samples All sets Analysis of Epithelial and Mesenchymal genes – All samples OS and Distant Metastasis-free survival (DMS) – All samples Effect of adjuvant treatment – Stage III samples, validation cohort (n=123) 1Tian S et al. J Pathol. 2012

  5. Development and Validation of the Molecular Subtype Signature

  6. Unsupervised hierarchical clustering of whole genome reveals 3 distinct patient groups Gene profiles were developed to identify these subgroups A-Type B-Type C-Type

  7. Unsupervised hierarchical clustering of whole genome reveals 3 distinct patient groups Gene profiles were developed to identify these subgroups A-Type (32 genes) B-Type (53 genes) C-Type (102 genes)

  8. Clinical Characterization Prognosis, MSI and BENEFIT FOM ADJUVANT CHEMOTHERAPY

  9. Subtypes are significantly associated with prognosis C-Type DM Risk Death B-Type A-Type Risk of Distant Metastasis Risk of Death

  10. Subtypes are significantly correlated with benefit from adjuvant 5-FU-based treatment

  11. Difference in proliferation between subtypes might explain difference in treatment benefit • significantly reduced expression of Ki67 and AURKA in C-type compared to A- and B-type • Ki67 p=6.06e-5, AURKA p=4.53e-6 C-Type B-Type A-Type

  12. Subtypes differ significantly in mutation and MSI frequency (Mismatch Repair deficiency) • Cancer kinome sequencing (~600 kinases and other cancer related genes) • high mutation frequency in A and C-type (dMMR) • B type represent proficient mismatch repair (pMMR)

  13. Subtypes differ significantly in mutation and MSI frequency (Mismatch Repair deficiency) • Cancer kinome sequencing (~600 kinases and other cancer related genes) • high mutation frequency in A and C-type (dMMR) • B type represent proficient mismatch repair (pMMR) Observed mutations in the cancer kinome

  14. Biological characteristics Epithelial vs. mesenchymal

  15. Epithelial-MesenchymalTransition

  16. EMT markers are differently expressed in subtypes • Mesenchymal markers (higher in C-type) • VIM, CDH2, FN1, FGFR1, FLT1, TWIST1, AXL, TGFB1 • Epithelial markers • CDH1, CDH3, CLDN9, EGFR, MET • Mesenchymal Character of C-type was confirmed by EMT signature developed at MDACC (Loboda et al. 2011)

  17. Molecular Subtypes Conclusion

  18. Colon molecular subtype model Subtype Clinical features Biological features Clinical utility No adjuvant or 5FU Chemotherapy New targeted therapy? (companion Dx)

  19. Acknowledgements All collaborators and patients • Valld'Hebron Hospital • Agendia • InstitutCatalàd'Oncologia • TechnischeUniversität Munich • Netherland Cancer Institute • Slotervaart Hospital • Leiden Medical Center • Medical University of Vienna • University of Ferrara • COLTHERES, EU-FP7

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