![Page 1: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/1.jpg)
The Role of Pathology/Molecular
Diagnostics in Personalized Medicine
Ignacio I. Wistuba, M.D.
Jay and Lori Eissenberg Professor in Lung CancerDirector of the Thoracic Molecular Pathology Lab
Departments of Pathology andThoracic/Head & Neck Medical OncologyM. D. Anderson Cancer Center
![Page 2: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/2.jpg)
Conflict of Interest
• Honoraria: Sanofi Aventis, Johnson &Johnson, Genentech, Champions Inc.,Roche, AstraZeneca, and Bristol-MyersSquibbs
• Research Agreements: Genentech,Pfizer, AstraZeneca, Myriad, Eli-Lilly,and Merck.
![Page 3: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/3.jpg)
Traditional
NSCLC Landscape Change - 2011
Adenocarcinoma
Squamous
Large Cell
BRAFAKT
VEGFRHER2
EPHA/B
PDGFR
FGFR
INSR
PI3K
MAPK
KRAS
EGFR
ALK
Unknown
Adenocarcinoma
Unknown
FGFR1
Amp
EGFRvIII
PI3KCA
EGFR TK
DDR2
Squamous Cell Ca
![Page 4: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/4.jpg)
Lung Cancer Targeted TherapyLandscape Change - 2011
• Histology- Non-squamous 60% Bevacizumab
Pemetrexed
• Adenocarcinoma- EGFR mutation 10% Erlotonib/Gefitinib- ALK-EML4 fusion 3% Crizotinib- MET amplification 20%- PI3KCA mutation 5%- HER2 mutation 1%
• Squamous Cell Carcinoma- FGFR1 amplification 22% FGFR TKIs- EGFRvIII mutation 5% EGFR TKIs- PI3KCA mutation 4% PI3KCA inhibitors- DDR2 mutation 3% Dasatinib & Nilotinib
![Page 5: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/5.jpg)
EGFR Mutations in NSCLC
18
19
21
20
!C- helix
P- loop
A- loop
Deletions - 46%
L858R - 39%
Duplications/Insertions - 9%N-lobe
C-lobe
Extracellular domain
Regulatorydomain
ATP binding cleft TK
Domain
Treatment by subgroup interaction test, p<0.0001
EGFR mut ( + ) EGFR Mut ( - )
HR = 0.48P<0.0001
Gefitinib (n=132)Carboplatin/Paclitaxel (n=129)
HR = 2.85
P<0.0001
Pro
bab
ilit
y o
f p
rog
ressio
n-f
ree
su
rviv
al
0 4 8 12 16 20 240.0
0.2
0.4
0.6
0.8
1.0
Pro
bab
ilit
y o
f p
rog
ressio
n-f
ree
su
rviv
al
Gefitinib (n=91)Carboplatin/Paclitaxel (n=85)
0 4 8 12 16 20 240.0
0.2
0.4
0.6
0.8
1.0
Months Months
Mok TS et al. N Engl J Med 2009;361:947-957
IPASS Trial
![Page 6: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/6.jpg)
EML4-ALK in Lung Adenocarcinoma2p23 region
ALK
EML4
Protein (IHC)FISHHistology
60
40
20
0
–20
–40
–60
–80
–100
Progressive disease
Stable disease
Ma
xim
um
Ch
an
ge
in
Tu
mo
r S
ize
(%
)
–30%
Partial response
Complete response
Kwak EL et al. N Engl J Med 2010;363:1693-1703
• ORR: 57%• DCR at 8 weeks: 87%
Crizotinib in EML4-ALK (+)
![Page 7: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/7.jpg)
Lung Adenocarcinoma and NSCLCWhat is new in 2011?
• All KRAS mutations are not the same
• Mutations data of a panel of genes(multiplex analysis) are available
• Gene signatures associated to EGFR TKIresponse in EGFR wild-type tumors
• Mechanisms of EGFR TKI resistance
![Page 8: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/8.jpg)
KRAS Mutations in Lung Adenocarcinoma
Codon 12 Codon 13Base change 1G2G3T 1G2G3C Amino Acid (replacing Gly)G"T (72%) 1Cys (45%) 1Cys (5%)
2Val (20%)G"A (14%) 2Asp (12%) 2Asp (1%)G"C (14%) 2Ala (9%)T"C (2%) 3Cys (2%)
Lodish et al
KRAS Mutation Sequencing
Codon 12 (G12C)Wild Type Codon 13 (G13A)
G G T G G C T G T G G C G G T G A C
![Page 9: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/9.jpg)
All treatments
Months since randomization0 6 12 18 24
Cys/Val n=24Other n=19Wild n=172
P = 0.046
Pro
gre
ssio
n-F
ree S
urv
ival
1.0
0.8
0.6
0.4
0.2
0
Sorafenib
Months since randomization0 6 12 18 24
Cys/Val n=11Other n=9Wild n=66
P = 0.026
Pro
gre
ssio
n-F
ree S
urv
ival
1.0
0.8
0.6
0.4
0.2
0
BATTLE Trial Novel Findings:Not All KRAS Mutations Are the Same
N. Ihle ,… G. Powis, et al, AACR 2011
mut-KRAS C or V other
Gene Expression Analysis
![Page 10: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/10.jpg)
BATTLE Trial Novel Findings:Not All KRAS Mutations Are the Same
Mut-KRAS C or V other
RPPA Analysis NSCLC Cell Lines
K-Ras
Akt Mek
p70S6K
mut-KRas-G12D
K-RAS
Akt Mek
p70S6K
RalGDS
mut-KRas-G12C
K-RAS
Akt MekRalGDS
p70S6K
wt-KRas
N. Ihle ,… G. Powis, et al, AACR 2011
![Page 11: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/11.jpg)
Mutations(8 genes/115 Assays)• AKT1
• BRAF
• EGFR
• HER2
• KRAS
• MEK1
• NRAS
• PIK3CA
FISH• C-MET amplification• EML4-LK fusion
GO Grant Panel1,000 Adenocarcinomas
Lung Cancer Mutation Consortium
51682
294
172
FISH
Pending
July, 20111,234 Consented
1,063 Studied
Mutation
B. Johnsons and the LCMC co-investigators, WCLC 2011
![Page 12: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/12.jpg)
Fine NeedleAspiration (FNA)
Core Needle Biopsy (CNB)
Advanced Tumor
Types of Histology and Cytology Specimens
Surgical Resection
Histology
Formalin-fixed and Paraffin-embedded (FFPE)
Endobronchial Ultrasound(EBUS) or Pleural Fluid
Alcohol-fixed
Alcohol-fixed – Cell Block
Alcohol-fixed
![Page 13: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/13.jpg)
Multiplexed Mutation AssaysMultiplex PCRTumor Tissue
Resected Specimen Core Biopsy
SNaPshot® (Applied Biosystem)
Dias-Santagata, EMBO Mol Med 2:146, 2010
10% Sensitivity and ~20ng DNA/multiplex reaction
Mass ARRAY SNP - Sequenom, Inc
![Page 14: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/14.jpg)
!"#$%&'&("!#
)*&*+&*)
*$,-.',/
01
!"#$%&'
()*+,#%&'
-./%#-(-.*0
1"#2
#*/0
/2'3
451
*672
#891
Lung Cancer Mutation ConsortiumIncidence of Mutations Detected
• Mutation found in 54% (280/516) of tumorscompletely tested
HER 2
B. Johnson. P. Bunn (PI) and the LCMC co-investigators, WCLC 2011
![Page 15: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/15.jpg)
Mutation Analysis by MassARRAY®
Sequenom® - NSCLC
BRAF (G464-G1391)
Wild-typeMutant
(Heterozygous)
Wild-typeMutant
(Homozygous)
BRAF (G469-G1406)
H. Erickson, E. Kim, and I. Wistuba, 2011
Well Spectrum
Data Analysis
![Page 16: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/16.jpg)
BATTLE-1 Clinical TrialPlatform for future research
• Clinical trial program (Phase II)
• Novel trial design
• Biopsy-mandated study in lung cancer
• Biomarker discovery
Accrual (3 yrs for accrual; Nov 2006 to Oct 2009)
• Biopsies obtained 324
• Patients randomized 255
• Patients evaluable 244
Kim et al, Cancer Discovery, April 2011
Molecular Profiling
• Frozen tumor: mRNA Affymetrix & proteomic (RPPA)
• Serum and PBMCs
![Page 17: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/17.jpg)
Erlotinib SorafenibVandetanib Erlotinib + Bexarotene
Randomization:Equal ! Adaptive
Primary end point: 8 week Disease Control (DC)
Patient Enrollment
Personalized Therapy in AdvancedNSCLC: BATTLE-1 Schema
EGFR KRAS/BRAFVEGF RXR/CyclinD1
Core Biopsy
BiomarkerProfile
E. Kim et al, Cancer Discovery 2011
![Page 18: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/18.jpg)
The BATTLE-1 Gene ExpressionSignatures Scorecard
Signature Derived Validation Predictive?
Pathway Signatures
EGFR 3 Clinical sets3 Clinical sets
1 Cell line set
Yes: EGFR mutations
Yes: outcome in resected NSCLC with wt
EGFR (prognostic)
No: erlotinib response in wt EGFR patients
KRAS 2 Clinical sets1 Clinical set
1 Cell line set
Yes: KRAS mutations in BATTLE
No: erlotinib response in wt EGFR patients
EMT Cell lines 2 Clinical sets Yes: erlotinib DC in wt EGFR
Clinical signatures
5 geneWEE
BATTLE Cell lines Yes: erlotinib DC in wt EGFR patients
Heymach, Saintigny, Byers, Kim, et al, AACR 2011
![Page 19: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/19.jpg)
TRIM72
NPR3
C5orf23
LCN2
OGG1
8wDC: Yes
8wDC: No
8wDCYes
8wDCNo
P<0.001
Sig
natu
revalu
e
8w
DC
(%
)Signature +P<0.001
Signature -
P=ns
Sorafenibarm
Erlotinibarms
Test forinteractionP=0.023
Log-rank <0.001
HR=0.1295 CI 0.03-0.46
P=0.001Pro
bab
ilit
y o
fsu
rviv
al
PFS time (months)
Median PFS: 12.5 weeks vs.
7.2 weeks
Signature -
Signature +
Saintigny et al, AACR 2011
5-Gene Signature Predicts 8-wk DC inEGFR Wild-type Tumors
BATTLE-1 mRNA Profiling (n=139)
![Page 20: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/20.jpg)
Fig. 1 The frequency of observed drug resistance mechanisms.
Sequist L V et al. Sci Transl Med 2011;3:75ra26-75ra26
Mechanisms of Resistance to EGFR TKI
Novel Mechanisms
• T790M Mutation – 49%
• MET amplification – 5%
• PI3KCA Mutation - 5%
• EMT Changes – 5%
• SCLC Features – 14%
• Unknown – 30%
![Page 21: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/21.jpg)
Mechanisms of Resistance to EGFR TKI
Sequist L V et al. Sci Transl Med 2011;3:75ra26-75ra26
Adenocarcinoma SCLC
H&E Synaptophysin H&E Synaptophysin
![Page 22: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/22.jpg)
Traditional
Squamous Cell Lung CarcinomaLandscape Change - 2011
Adenocarcinoma
Squamous
Large Cell
Unknown
FGFR1
Amp
EGFRvIII
PI3KCA
EGFR TK
DDR2
2011
![Page 23: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/23.jpg)
New Target Therapy in SquamousCell Carcinoma of the Lung
Gen Frequency Drug
FGFR1 amplification 22% FGFR TKIs
EGFRvIII mutation 5% EGFR TKIs
PI3KCA mutation 3.6% PI3KCA inhib.
EGFR TK mutation 3.4% EGFR TKIs
DDR2 mutation 3.2% DasatanibNilotinib
Okashi and Pao, Cancer Discovery, April 2011
![Page 24: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/24.jpg)
FGFR1 Amplification in Squamous CellCarcinoma (9%)
Weiss J et al. Sci Transl Med 2010;2:62ra93-62ra93
![Page 25: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/25.jpg)
FGFR1 Copy Number Gain (CNG) Analysisby FISH in NSCLC (n=326)
Tang et al, 2011
0
5
10
15
20
25
!4 !10 Amplification
FGFR1 CNG
Fre
qu
en
cy (
%)
Adenocarcinoma (n=217)
Squamous Cell (n=89)
7%
13%
1%
11%
17%
20%
![Page 26: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/26.jpg)
FGFR1 Copy Number Analysisby FISH in NSCLC
Tang et al, 2011
!10 Copies (ADCA) !10 Copies (ADCA)
!10 Copies (SCC) Amplification (SCC)
![Page 27: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/27.jpg)
DDR2 Gene Mutations in Squamous CellCarcinoma of the Lung (3.2%)
Hammerman et al, Cancer Discovery April, 2011
![Page 28: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/28.jpg)
DDR2 Mutant Tumor Sensitive to Dasatinib
Hammerman et al, Cancer Discovery April, 2011
![Page 29: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/29.jpg)
BRAF Inactivating Mutation AssociateSensitive to Dasatinib
B. Sen,…and F. Johnson et al, unpublished, 2011
Tumor BRAF
Y472C Mutation
![Page 30: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/30.jpg)
What’s the problem?I gave you at least 10 cells!
Fine NeedleAspiration (FNA)
Core Needle Biopsy (CNB)
Advanced Tumor
Tissue is the Emperor -For diagnosis, the pathologist needs some!
![Page 31: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/31.jpg)
Pathology Algorithm of Small Tissue Specimens forManagement of Lung Cancer Patients - 2011
Small Biopsy
SCLC NSCLC – NOS?
Adenocarcinoma Squamous Cell Ca Others
IHC: TTF-1CK 5/7
P63
NSCLCNOS
EML4-ALK
EGFR
Panel:MET ampl
PI3KCA
BRFA
HER2
K-, N-, H-
RAS
MEK
AKT…
FGFR1 Amp
DDR2 Mut
Panel:PI3KCA
BRAF
HER2
K-, N-, H-RAS
MEK
AKT…
EML4-ALK
EGFR
FGFR1 Amp
DDR2 Mut
Panel:MET ampl
PI3KCA
BRAF
HER2
K-, N-, H-RAS
MEK
AKT…
![Page 32: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/32.jpg)
Evolution of Genome SequencingTechnology
1986: Sequencing one genome:
Cost = $3 billion
Time = 1 decade
2010: Sequencing one genome:
Costs = $10 thousand
Time = 3 weeks
2012: Sequencing one genome:
Cost = $1 thousand
Time = 1 week
![Page 33: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/33.jpg)
1mm
Frozen CNB: NSCLC
WT
Seq
T/N
lo
g2
Microarray T/N log2
r=0.48P=10-8
Correlation of WT Seq and mRNA Array Profiling of 11 NSCLCs
Percentage of WT Reads Mapped:10 CNB vs. 10 Resected NSCLCs
% R
ead
s M
ap
ped
CNB Resected
Next Generation of SequencingNSCLC Core Needle Biopsies (CNB)
• Exome Seq (DNA)
• Whole Transcriptome (WT-mRNA)
• Small RNA Seq (miRNA)
Wistuba et al, unpublished, 2011
![Page 34: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/34.jpg)
Molecular Pathology of Lung Cancer: 2011
• New actionable genetic abnormalities continued to bediscovered in NSCLC
• In lung adenocarcinoma and NSCLC:
! All KRAS mutations are not the same
! ~50% of tumors have actionable gene mutations
! Gene expression signatures predict response toEGFR TKI in EGFR wild-type tumors
! Novel mechanisms and changes associated to EGFRTKI resistance
• Squamous cell carcinoma shows distinct geneticabnormalities: FGFR1 amp and DDR2 mutations
• Next generation sequencing shows a promise forapplication to clinical settings
![Page 35: The Role of Pathology/Molecular Diagnostics in ...e-syllabus.gotoper.com/_media/_pdf/ILC11_08_Wistuba...Wistuba et al, unpublished, 2011 Molecular Pathology of Lung Cancer: 2011 ¥New](https://reader035.vdocuments.us/reader035/viewer/2022071411/6107970f508b7a1f44369976/html5/thumbnails/35.jpg)
Acknowledgements
• MD Anderson Cancer Center
Thoracic Molecular Pathology Lab
Heidi Erickson
Hector Galindo
Nana Hanson
Christina McDowell
Annette Basey
Chi-Wan Chow
Zuoming Chu
Junya Fujimoto
Lakshmi Kakarala
• MD Anderson Cancer Center
Edward Kim (Medical Oncology)
Waun Ki Hong (Medical Oncology)
Roy Herbst (Medical Oncology)
John Heymach (Medical Oncology)
Scott Lippman (Medical Oncology)
Gordon Mills (System Biology)
Katherine Stemke-Hale (System Biology)
Cesar Moran (Pathology)
Neda Kalhor (Pathology)
Jack Lee (Biostatistics)
Support
• US Department of Defense BATTLE andPROSPECT, Stading Family, Cohen-Reinauch BATTLE-2 Fund and VFoundation