colorectal cancer intrinsic subtypes are associated with prognosis, chemotherapy response, deficient...
TRANSCRIPT
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
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
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
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
Molecular classification based on nearest centroid single sample predictor (SSP) 3 gene expression profiles (A, B & C)
Development Set (stage I-IV) (n=188) Netherlands Cancer Institute, Leiden Medical Center, Slotervaart
Whole Genome Array
Dev
elo
pm
ent
Validation Set (stage II-III) (n=543)Technical University Munich,
Institut Catala d’Oncologia & Vall d’Hebron Hospital Barcelona, Medical University Vienna, University of Ferrara
Val
idat
ion
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
All
sets
Analysis of Epithelial and Mesenchymal genes – All samples
OS and Distant Metastasis-free survival (DMS) – All samplesEffect of adjuvant treatment – Stage III samples, validation cohort (n=123)
MSI analysis by IHC – All samplesMSI/dMMR gene expression pattern (64 gene signature1) – All samples
1Tian S et al. J Pathol. 2012
Development and Validation of the Molecular Subtype Signature
Development Cohort Validation Cohort
N 188 543
Hospital NKI, LUMC, Slotervaart Vall d’Hebron, ICO Barcelona, Munich
Stage IIIIIIIV
24 (13%)100 (53%)56 (30%)8 (4%)
-320 (59%)223 (41%)
-
Gender FM
104 (55%)84 (45%)
226 (42%)317 (58%)
Subtype ABC
65 (35%)98 (52%)25 (13%)
117 (22%)336 (62%)90 (16%)
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
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)
PROGNOSIS, MSI AND BENEFIT FOM ADJUVANT CHEMOTHERAPY
Clinical Characterization
Subtypes are significantly associated with prognosis
Risk of Distant Metastasis Risk of Death
C-TypeB-TypeA-TypeD
M R
isk
Dea
th
Subtypes are significantly correlated with benefit from adjuvant 5-FU-based treatment
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-TypeB-TypeA-Type
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)
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)
Types Mutated genes MSI/dMMR
A 36% 68%
B 17% 1%
C 34% 36%
Observed mutations in the cancer kinome
EPITHELIAL VS. MESENCHYMAL
Biological characteristics
Epithelial-Mesenchymal Transition
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)
CONCLUSIONMolecular Subtypes
Biological featuresClinical featuresSubtype Clinical utility
Chemotherapy
New targeted therapy?(companion Dx)
No adjuvantor 5FU
Colon molecular subtype model
AcknowledgementsAll collaborators and patients
• Vall d'Hebron Hospital• Agendia• Institut Català d'Oncologia• Technische Universität Munich• Netherland Cancer Institute• Slotervaart Hospital• Leiden Medical Center• Medical University of Vienna• University of Ferrara• COLTHERES, EU-FP7