molecular classification of colon cancer: new insights · molecular classification of colon cancer:...
TRANSCRIPT
![Page 1: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/1.jpg)
Molecular classification of colon cancer:new insights
Rodrigo DienstmannJul 2019
![Page 2: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/2.jpg)
Disclosures
Advisory role: RocheBoehringer-IngelheimNovartis
Speaker’s fee: RocheServierSymphogenMSDIPSENSanofiAmgen
Research support: MERCK
![Page 3: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/3.jpg)
BRAF V600EBRAF non-V600
MSITMB high
POLE mutHER2 ampl
MET ampl
Gene fusion
RAS mut +/-PIK3CA/PTEN mut
PIK3CA/PTEN mut
Wild-type
anti-EGFR therapies
BRAF inh + anti-EGFR +/- MEK inh
anti-PD1/L1
double anti-HER2
Kinase inh
45% 8%
26%
8%3%3%
1%
<1%
2%
1%
2%MET inh?
MEK inh + anti-EGFR?
To be defined
To be defined
Genomic markers
![Page 4: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/4.jpg)
Transcriptomic classification
CMS1
CMS2
CMS3
CMS4Mixed
13%
40%
25%
15%
7%
BULK-TUMOR subtypes (primary CRC)
![Page 5: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/5.jpg)
Consensus Molecular Subtype (CMS) groups
15%
¾ MSI
BRAF mut
BRAF mut-like
Immune infiltration
Immune-activated
Right-sided
40%
CIN
Epithelial
WNT/MYC
EGFR/ligands high
Immune-desert
Left-sided
13%
¾ CIN
Epithelial
RAS mut
BRAF mut-like
Metabolic
Immune-mixed
Right-sided
25%
CIN
Mesechymal
TGFß, angiogenesis
Stromal infiltration
Immunosuppression
Both sides
Guinney et al, Nat Med 2015
Molecular Enrichments
![Page 6: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/6.jpg)
Right vs. left
Loree, Clin Cancer Res 2018
![Page 7: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/7.jpg)
Context matters
Fontana et al, Annals Oncol 2018Chang et al, Annals Oncol 2018
![Page 8: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/8.jpg)
RF
12.7%
23.8%
7.4%
18.3%
4.4%10.2%
1.3%
21.9%
<<<<<<c
<
CMS attribution is uncertain* for most samples (63%)
…and most samples (57%) show intra-tumor heterogeneity*
* i.e. RF classifier probability < 70%
Internal circle : CMS RF classificationExternal circle : Dark : CMS RF probability > 70%; Bright : CMS RF probability < 70%
* i.e. more than 1 CMS with a (WISP-derived) weight above 20%
Internal circle : WISP subtype with heighest weightExternal circle : WISP subtype with second heighest weight (if above 20%)
<<<<<<c
Intra-tumor heterogeneity in early-stage CRC
Marisa et al, ESMO 2018
![Page 9: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/9.jpg)
Adjusted multivariablee analysis:CMS1 / CMS4 HR: 2.17 [1.36-3.5] CMS4 / CMS1 HR: 1.79 [1.14-2.8]
Intra-tumor heterogeneity in early-stage CRC
Marisa et al, ESMO 2018
![Page 10: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/10.jpg)
Dunne et al, Nature Commun 2017
Intra-tumor heterogeneity
Spatial stability
Tumor center Invasive front
Piskol et al, Clin Cancer Res 2019
Primary-metastasis
![Page 11: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/11.jpg)
Stage II and III
Becht et al, Clin Cancer Res 2016
CMS1 CMS2 CMS3
CMS4
CMS1 CMS2 CMS3 CMS4
T cell chemokine
T cell inhibition
Myeloid cell
Angiogenesis
Immunosuppression
Complement
Microenvironment of CRC
CMS4
![Page 12: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/12.jpg)
Karpinski et al, Oncotarget 2017
Microenvironment of CRC
![Page 13: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/13.jpg)
Take-home messages
• CMS groups = not driven by content (clustering of other classifiers)
highly reproducible in cohorts of primary CRC
has biology enrichments (not unique features from
pathway and tumor microenvironment perspectives)
• CMS classifiers = technical and heterogeneity issues
![Page 14: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/14.jpg)
CRC Consensus Molecular Subtypes: prognostic value considerations
![Page 15: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/15.jpg)
Prognosis of CMS groups in early-stage CRC
Guinney et al, Nat Med 2015 Song et al, JAMA Oncol 2016
RFS in 1,785 stage II/III CRC RFS in 1,151 stage III CRC(NSABP C-07 trial)
![Page 16: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/16.jpg)
Prognostic value of CMS groups in metastatic CRC
Guinney et al, Nat Med 2015 Lenz et al, J Clin Oncol 2019
Survival after relapse (n=405) Overall survival metastatic CRC (n=581)
![Page 17: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/17.jpg)
Prognostic value of CMS groups in multivariable models
Dienstmann et al, under review
![Page 18: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/18.jpg)
Disease free survival Cox models (all patients) (n=2,636, 769 events)
Univariate analysis Multivariable analysis
HR 95% CI P value HR 95% CI P value
Age 1.01 1 – 1.02 <0.001 1.01 1 – 1.02 <0.001
pT2/pT1 versus pT3 1.07 0.65 – 1.75 0.8 0.86 0.52 – 1.43 0.56
pT4 versus pT3 1.37 1.11 – 1.69 0.003 1.46 1.18 – 1.81 <0.001
pN1 versus pN0 1.99 1.61 – 2.46 <0.001 2.05 1.65 – 2.55 <0.001
pN2 versus pN0 3.08 2.41 – 3.93 <0.001 3.15 2.45 – 4.05 <0.001
Rectum versus left 1.03 0.76 – 1.40 0.83 0.94 0.69 – 1.29 0.72
Right versus left 0.84 0.72 – 0.97 0.02 0.86 0.73 – 1.00 0.06
MSI versus MSS 0.76 0.61 –0.93 0.008 0.88 0.7 – 1.11 0.29
KRAS mut versus wild-type 1.04 0.9 – 1.21 0.55 - - -
BRAF mut versus wild-type 0.9 0.72 - 1.13 0.35 - - -
CMS4 score 1.37 1.07 – 1.76 0.01 0.93 0.64 – 1.32 0.67
CAF infiltration score 1.6 0.93 – 2.74 0.09 2.54 1.08 – 6.02 0.03
CytoLym infiltration score 0.45 0.25 – 0.78 0.005 0.26 0.12 – 0.55 <0.001
Prognostic value of CMS groups in multivariable models
Dienstmann et al, under review
![Page 19: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/19.jpg)
Prognostic value of CMS groups in multivariable models
Overall population (N=2,636)
Dienstmann et al, under review
![Page 20: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/20.jpg)
Prognostic value of CMS groups in multivariable models
Dienstmann et al, under review
![Page 21: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/21.jpg)
Prognostic value of Immunoscore in multivariable models
Pages et al, Lancet 2018
![Page 22: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/22.jpg)
CRC Consensus Molecular Subtypes: predictive value considerations
![Page 23: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/23.jpg)
Predictive value of CMS groups in early-stage disease
Pogue-Geile et al, ASCO 2019
![Page 24: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/24.jpg)
Predictive value of CMS groups in early-stage disease
Pogue-Geile et al, ASCO 2019
in MOSAIC
![Page 25: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/25.jpg)
CALGB80405 1st line KRAS wild-type RCT (n=581)
FOLFOX-cetuximab vs.
FOLFOX bevacizumab
(75%)
CMS1 > OS with
FOLFOX-bevacizumab,
CMS2 > OS with
FOLFOX-cetuximab
Custom
Nanostring
FFPE
FIRE-3 1st line RAS wild-type RCT (n=438)FOLFIRI-cetuximab vs.
FOLFIRI bevacizumab
CMS4 > OS with
FOLFIRI-cetuximab
Almac Xcell
FFPE
CAIRO2 1st line all-comers RCT (n=311)
CAPOX-bevacizumab vs.
CAPOX-bevacizumab-
cetuximab
CMS2/CMS3 > OS with
cetuximab
(RAS /BRAF wt)
IHC FFPE
MAX 1st line all-comers RCT (n=237)
Capecitabine +/-
mitomycin +/-
bevacizumab
CMS2/CMS3 > PFS with
bevacizumab
Almac Xcell
FFPE
Japan 1st line all-comers Retrospective (n=193)Oxaliplatin vs.
Irinotecan
CMS4 > PFS and OS
with IrinotecanAgilent FF
Predictive value of CMS groups in metastatic disease
Lenz et al, J Clin Oncol 2019; Stintzing et al, ASCO 2017; Trinh et al, Clinical Cancer Res 2017; Mooi et al, Annals Oncol 2018; Okita et al, Oncotarget 2018
100%
87%
![Page 26: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/26.jpg)
CALGB 80405
Lenz et al, ASCO 2017
PFS OS
CMS1
CMS2
CMS3
CMS4
All (CMS Population)
Favors Bevacizumab Favors Bevacizumab
0.1 1 10 0.1 1 10
Favors Cetuximab
Predictive value of CMS groups in metastatic disease
![Page 27: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/27.jpg)
CALGB 80405
Lenz et al, J Clin Oncol 2019
Predictive value of CMS groups in metastatic disease
Bevacizumab- treated Cetuximab-treated
CMS1 interaction P value < 0.001
![Page 28: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/28.jpg)
Becht et al, Advances Immunol 2016
Microenviroment targeting in metastatic CRC
![Page 29: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/29.jpg)
Karpinski et al, Oncotarget 2017
Microenvironment of CRC
Primary-metastasis heterogeneity?
![Page 30: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/30.jpg)
Take-home messages
• CMS prognostic value = largely explained by tumor microenvironment
• CMS predictive value = has driver pathway enrichments (maybe not
the one that matters to a targeted/immunotherapy matched drug)
![Page 31: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/31.jpg)
Future: combine CMS with pathway signatures
Pogue-Geile et al, ASCO 2019
RPS: recombinant proficiency score – DNA damage repair
![Page 32: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/32.jpg)
CIN
MSI
KRA
S/N
RA
Sm
uta
tio
ns
Left
(T
um
or
Loca
tio
n)
Rig
ht
BR
AF
mu
tati
on
s
Dienstmann et al, Nat Rev Cancer 2017
Mu
tati
on
co
unt
Co
py
nu
mb
er
CMS2
Immune activationJAK-STAT activationCaspasesDNA damage repairGlutaminolysisLipodogenesisCell cycleWNT/MYC targets HER (ligands) expressionVEGF/VEGFR activationIntegrins activationTGFβ activationMesenchymal transitionComplement activationImmunosuppression
CMS3
CMS4
CMS1
Met
hyla
tio
n
Poorly immuno-
genic
Can
cer-
asso
ciat
ed fi
bro
bla
sts Highly
immuno-genic
Inflamed immuno-
suppressive
Future: Integrative CRC classification
![Page 33: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/33.jpg)
RAS targeting in CRC
COLOSSUS project – functional subtypes of MSS RAS mutant CRC for Precision OncologyFunding: H2020 grantProject Coordinator: Annette Byrne
Scientific Leader: Rodrigo Dienstmann
![Page 34: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/34.jpg)
CMS classifiers in the clinics
IHC FFPE
NanoString FFPE
![Page 35: Molecular classification of colon cancer: new insights · Molecular classification of colon cancer: new insights Rodrigo Dienstmann Jul 2019. Disclosures Advisory role: Roche Boehringer-Ingelheim](https://reader036.vdocuments.us/reader036/viewer/2022071603/613edee8c500cf75ab362a6c/html5/thumbnails/35.jpg)
Thanks to
Gastrointestinal Tumors GroupMolecular Prescreening Program
ODysSey Group
Ragnhild LotheJustin GuinneyJosep Tabernero