The Evolving Role of the Molecular
Pathologist:
Opportunities and Challenges
Personalized Medicine, Companion Diagnostics
CME & P.A.C.E.® Symposium at 2012 ASCO
Jeffrey S. Ross, M.D.
Department of Pathology and Laboratory Medicine
Albany Medical College
Albany, NY
rossj@mail.amc.edu
“A Perfect Storm” in the Healthcare Industry Driving Personalized
Oncology
New Customer Dynamics
Pharmaceutical
Industry Dynamics
 $ Out of pocket
 Informed
 Mergers
 Patent
expirations
New Communication
Mechanisms
 Wireless networking
 Broadband
Healthcare
Industry Dynamics
Advances in Medicine
Changing
Economics
 Generics cost shift
to consumer
 Pricing
Source: Craig Fitzgerald, Various industry sources






Genomics
Proteomics
Imaging technologies
Devices and biosensors
Molecular Medicine
Nanotechnologies
Personalized Oncology: Key Issues
• Which patients will benefit most?
• Improved efficacy?
• Reduced toxicity?
• Cost/benefit ratio?
• What time should the test(s) be performed?
• What sample to test?
• Tumor for Expression Profiling or Sequencing?
• Blood for Germline Sequencing?
• CTC?
• What technique to use?
•
•
•
•
Gene sequence (DNA)? Germline? Tumor Cells?
Gene dosage (DNA)?
Gene expression (mRNA)?
Protein expression (IHC) and Proteomics?
• Which algorithm or mathematic model should be used to make
predictions?
• Are the tests regulated by the FDA? EMA? CLIA?
• Will the test(s) be reimbursed or will the patient have to pay out of
pocket?
• Will the added test cost reduce overall expenditures by driving better
clinical outcomes?
Roles for Anatomic Pathologists in Molecular
Pathology and Personalized Medicine
• Providing slide-based biomarker services
– IHC
– FISH
– CISH
• Preparing biopsies and resections for
extraction-based biomarker services
– RT-PCR
– Genotyping by traditional sequencing techniques
– Next Generation Sequencing
Comparison of Molecular Pathology Test Platforms (1)
IHC
FISH CISH
mRNA by RTPCR or
Microarray
DNA
Sequencing
Traditional
DNA
Sequencing
NGS
Starting Material
FFPE
FFPE
FFPE
FFPE
PPFE
Slide
Based/Morphology
Driven
Requires Enrichment
Yes
Yes
No
No
No
No
No
On occasion
On occasion
On occasion
Impact of Sample
Storage/Processing
High
Low
High
Low
Low
Bio-informatics
Expertise
Requirement
Potential for False
Discovery
Low
Low
Moderate
Moderate
High
Low
Low
High
Low
Low
Comparison of Molecular Pathology Test Platforms (2)
IHC
FISH CISH
mRNA by RTPCR or
Microarray
DNA Sequencing
Traditional
DNA
Sequencing
NGS
Prediction of
Response to
Cytotoxic
Therapies
Not established
Not in current
routine clinical
practice
Not
In use in some
established
practices
Not in current
routine clinical
practice
In use in some
practices
Pending
Prediction of
Therapy Toxicity
Not established
Not in current
routine clinical
practice
Not
In use in some
established
practices
Not in current
routine clinical
practice
In use in some
practices
Pending
Cost
Low
Higher
Moderate for
each assay. High
for multiple
assays on same
sample.
High
High
Pathologist Roles in Preparing Clinical Samples
for mRNA Profiling and DNA Genotyping/NGS
• Selecting the best tissue block when multiple
blocks are available
– Highest percentage of malignant cells
– Selecting viable areas and avoiding necrosis and
wound healing/severe inflammation
• Recommending or performing sample
enrichment when necessary
Small Samples and FNAs
• A FFPE section with a 4 X 4 mm minimum surface area with
minimum of 40 micron thickness measurement is
recommended
• For FNAs
– Sample is pun into a cell pellet and then converted to an FFPE
tissue section
– Enrichment by macrodissection rarely possible
• Local IHC Procedures
– Local pathologists should be discouraged from performing
excessive numbers of immunostains that deplete the small
amounts of tissue needed for RNA/DNA analysis
• Critical importance for NSCLC biopsies
• Limit immunostains for the squamous vs non-squamous deision
Selected Common Examples of Slide Based Molecular
Pathology for Solid Tumors
• Breast Cancer
– ER and PR by IHC
– HER2 by IHC and FISH/CISH
• NSCLC
–
–
–
–
SCC vs Adenocarcinoma
ALK IHC Status
EGFR IHC in SCC for cetuximab
ERCC1 for platinin resistance
• CRC
– Mis-match Repair (MSI) IHC for hMLH1, hMSH2, hMSH6
Improving ER Testing
Open Issues
• Can IHC be standardized?
• Do we want simple positive or negative
results only?
• Can mRNA testing select the best hormonal
therapy options?
• How do we predict tamoxifen resistance in ER
IHC+ tumors?
• Can we “personalize” hormonal therapy
The ASCO-CAP 2010 Guidelines for Hormone
Receptor IHC Testing
• Did not require IHC staining intensity in slide scoring
• Focused on pre-analytic issues
• Pre-analytic guidelines differ from HER2 guidelines (72
vs 48 hrs max fixation)
• CAP Certification + Proficiency testing required
• Did not establish a cut-off staining percentage for ER or
PR positive status
ER mRNA Testing*: Concordance Between IHC Status
and mRNA Levels
Relative ER mRNA
Expression
25
20
15
10
5
0
+ + ++ + ++ ++ + ++ ++ + ++ ++ + ++ ++ + - - - - - - - - - - - - - - - - - - - + - + - IHC > 20% ER +
IHC ER -
ER Status by IHC on Core Needle Biopsies
* Measured by either RT-PCR (eg Oncotype Dx)
or by Microarray (eg TargetPrint)
HER-2 Testing
Is CISH the “Kish of Death” for FISH and IHC?
•
Is IHC still the international method of choice for screening with 2+ cases
triaged to FISH?
•
Will primary FISH testing ever become the standard?
•
Will mRNA detection gain in popularity?
•
Will the recently approved CISH (SISH) assay become the preferred method?
•
Has the ToGA Trial and Gastic/GEJ trastuzumab approvals changed how HER2
testing is done?
•
Will trastuzumab-DM1 and pertuzimab require HER2+ testing prior to use?
The ASCO-CAP Guidelines for HER2 Testing*
Key Issues
- 20% of testing in the field incorrect
- Required higher thresholds for HER2 positive status
- 10% to 30% IHC 3+ required
- FISH ratio increased from 2.0 to 2.2
- Serious concerns for patients who are HER2 positive
by trastuzumab package insert guidelines but not
positive by ASCO-CAP criteria not receiving anti-HER2
therapy
- Criteria for HER2 positive differ from the gastric/GEJ
approvals
- Some laboratories no longer use the ASCO-CAP
guidelines and have reverted to the package insert
guidelines
* Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of
American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor
2 Testing in Breast ancer. J Clin Oncol. 2006 Dec 11;
IHC: Positive Control on Same Slide with
Sample from Each New Patient
It has been estimated that 3-4% of all US HER2 testing is falsely negative.
HER2 Gene Copy Number Alteration Validation
Increased HER2 gene copies detected by NGS
HER2 FISH Positive Breast Invasive Duct Carcinoma
Demonstrating High HER2 Copy Number
ERBB2 RARA
HER2 Protein 3+ Expression by IHC
Chromogenic In Situ Hybridization
Overall FISH/CISH
Concordance = 98%
NOT AMPLIFIED:
2 SIGNALS PER
NUCLEUS
HIGHLY
AMPLIFIED DETAIL
CISH
• Chromogenic ISH
• Light microscope ready
• All the advantages of the
DNA target in paraffin
sections, but does not require
fluorescent detection
• FDA approval 7/2/08
Emerging HER2 Tests
mRNA Oncotype
Dx™
Genomic Health
Redwood City, CA
2005
Not
Approved
On the
market
RT-PCR
(FFPE)
RNA
mRNA
TargetPrint
Agendia
Amsterdam, NE
2008
Not
Approved
On the
market
Agilent Array
(Fresh tissue)
RNA
HER2 Gene
Mutation
Testing
Foundation Medicine
Cambridge, MA
2010
Not
Approved
Homebrews
Hybrid Capture
Sequencing
(FFPE)
DNA
Centralized in
commercial and
academic labs
Centralized at
company
headquarters
Same
Others
Next-Gen
Sequencing
Di-merization
HERmark™
Monogram
Biosciences/USLabs/LCA
South San Francisco, CA
2008
Not
Approved
On the
market
VeraTag™
Capillary
electrophoresis
(FFPE)
Protein
dimers
Decentralized in
clinical and
commercial labs
ELISA Serum
HER2 Advia
Centaur™
Siemens Healthcare
Diagnostics
Deerfield, IL
2002
Approved
(PMA)
On the
market
Sandwich
Immunoassay
(serum)
Protein
(serum)
Decentralized in
clinical and
commercial labs
CTC Based
Assays
Veridex
OncoVista
Others
2004
Not
Approved
On the
market
DNA
RNA
Centralized and
decentralized
FISH
RT-PCR
(whole blood)
Squamous vs Non-Squamous
(Adenocarcinoma) in NSCLC
• At least 75% of cases can be resolved on H & E
• IHC to decide Squamous vs Non-Squamous consumes vital tissue
reserves for clinical trial biomarkers
• Over-use of IHC markers must be discouraged
• Adenocarcinoma
– TTF-1 (Best), Napsin, PE-10
• Squamous Carcinoma
– P63 (Best), CK5/6, 34βe12
– Desmocolin-3 (Need More Testing)
• Cocktails – Nuclear/Cytoplasmic Antibodies
– Adenocarcinoma – TTF-1/Napsin
– Squamous – P63/CK5/6
EML4-ALK Rearrangement in NSCLC
• Crizotinib
– Oral ALK4 receptor kinase inhibitor
– Phase I Trial on NSCLC patients with
EML4-ALK rearrangement
• “echinoderm microtubule-associated
protein-like 4” – “anaplastic lymphoma
kinase”
– 10/19 (53%) had a partial response
• Seen in 5-13% of adenocarcinomas
• More common in non-smokers
• All ELM4-ALK Positive NSCLC are
Negative for EGFR and KRAS mutations
• ELM4-ALK translocation can be
detected by FISH or NGS
• ALK IHC (Cell Signaling Ab) being
developed as a CDx for crizotinib
Shaw et al. J Clin Oncol. 27;2009:4247-4253.
EGFR IHC Testing in Squamous Cell NSCLC
• May be developed as a CDx for selection of
NSCLC SCC for treatment with cetuximab
• ECCO/ESMO data indicated that “H Score” IHC
scoring must be used and tumors must have a
score > 200
• EGFR IHC not currently required for HNSCC
case selection for cetuximab use
ERCC1 Testing in NSCLC
• ERCC1 as a predictive marker in cisplatin-based adjuvant chemotherapy in
resected NSCLC has been suggested in large, retrospective analyses
• Confirmation needed in large prospective studies
• Data mainly for cis-platinin, data for carbo-platinin lacking
• Hypothesis that low/negative ERCC1 IHC expression is predictive of platinumbased chemotherapy-sensitivity has not yet been fully validated
• ERCC1 by RT-PCR efficacy varies due to the quality of material
• IHC may vary on inter-observer variability and the target lesion chosen for
examination
• Blood-based SNPs methods determining ERCC1 polymorphisms holds
promise
• The role of ERCC1 in NSCLC patient-tailored chemotherapy although far from
being firmly established may possibly prove to play an important role in
tailored chemotherapy for NSCLC
Detecting MSI in CRC with IHC
• Routine use in many CRC treatment
institutions
• Mis-match Repair Defective CRC defined as
Loss of expression of 2 or more mis-match
repair enzymes (MLH1, MSH2, MSH6, others)
• Associated with improved prognosis and
potential for reduced treatment intensity
stage for stage
• IHC results also may indicate HNPCC
Selected Common Examples of mRNA
Profiling for Solid Tumors
• Cancer of Unknown Primary Origin
• Non-Hodgkin’s Lymphoma
• Breast Cancer
– Molecular Portraits
– Tumor Grading
– Predicting prognosis and guiding management
• Pharmacogenomics
Technology Platforms For High Throughput
Analysis Of mRNA Expression
cDNA arrays
Oligonucleotide
arrays
Multiplex RT-PCR
Probe length
Hundreds to
thousands of base
long cDNA
20-75 base
oligonucleotides
15-30 base
PCR primers
Probes per array
100 –5,000
>20,000
Few hundred
Probes per
transcript
1-2
1- >10
1
Examples of sources
Clontech, Agilent,
Incyte,
core laboratories
Affymetrix,
Amersham, Mergen,
Agilent,
core laboratories
Qiagen, Applied
Biosystems,
Roche Molecular
Systems, Genomic
Health
Detection system
Chemiluminescence
Chemiluminescence
Chemiluminescence
Radioisotope
Gel electrophoresis
Challenges that Face Genomic Microarrays
• Over-fitting The Data
• Discovery Research without a hypothesis
• Initial excitement followed by failure to reproduce the
results
• Test results may vary with the extent of the disease
• Lack of Currently Approved Rules of Evidence
• No standardized approach to data validation
• Multivariate Analysis finds independent significance but
association with disease outcome was actually due to
chance
• “Too many genes, not enough patients”
Microarray Classification of Non-Hodgkin’s Lymphoma
Staudt. Cancer Cell Vol. 2, No. 5, 11/02: 363 - 366
Site of Origin for Metastatic Adenocarcinoma
Dennis et al Cancer Res 2002;62:5999-6005
Expression Profiles of
61 Genes by SAGE
Established Tumor Markers by RTPCR in Common Adenocarcinomas
Molecular Portrait of Breast Cancers
Basal–like
HER-2
“Normal
Luminal B
Luminal A
Sørlie et al. Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-10874.
Molecular Grading of Breast Cancer
• Gene expression profiling data indicates that there
are 2 molecular grades of breast cancer
• Histologic Grade 2 cases redistribute into Molecular
Grades 1 and 2
• Molecular grading has outperformed histologic
grading in multivariate analysis of traditional
prognostic factors including ER/PR and HER2 status
• The Genomic Grade IndexTM has been
commercialized by Ipsogen, Inc.
Patterns of expression of grade-related genes and their association
with histologic grade (HG) and relapse-free survival. GGI score of
each tumor is plotted below the corresponding column. Relapse-free
survival times in years are indicated below the GGI scores.
Sotiriou C, et al.. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J
Natl Cancer Inst. 2006 Feb 15;98(4):262-72.
Multigene Classifiers and Predictors of Breast Cancer Clinical Outcome*
Classification
Test
Sorlie-Perou
Classifier
Grading
ARUP
Bioclassifier
Prognosis
Sotiriou Molecular
Grading
Mammostrat®
Prognosis and Response to Therapy
eXagenBC
Rotterdam
Signature
Oncotype Dx®
Two-Gene Ratio
MammaPrint®
Roche
AmpliChip® P450
Manufacturer
Not
In Development Ipsogen, Inc
Commercialized
Applied
Genomics
Exagen
Diagnostics
Veridex
Genomic Health
AviaraDx/Quest
Agendia BV
Cytochrome P450
CYP2D6
Roche
Diagnostics/Merck
Medco/Lab Corp
Method
Microarray
RT-PCR
Microarray
IHC
FISH
Microarray
RT-PCR
RT-PCR
Microarray
Microarray
Platform
Stanford
University
Agilent array
Light Cycler
Affymetrix U-133
Immunoperoxidas 3 probe multiAffymetrix U-133 Taqman
e
color FISH assay
Manual scoring
(Applied
Biosystems
Taqman
Rosetta
Roche
Inpharmatics/Agile AmpliChip®
nt Custom Array (Affymetrix
Platform)
Custom cDNA
Sample Conditions Fresh/Frozen
(Roche
Diagnostic
Systems)
(Applied
Biosystems)
FFPE
Fresh/Frozen
FFPE
FFPE
Fresh/Frozen
FFPE
FFPE
Fresh/Frozen
Fresh/Frozen
Preserved mRNA
Unknown
Resections
Resections
Core Biopsies
Resections
Core Biopsies
Resections
Resections
Core Biopsies
Resections
Resections
Resections
Number of Genes 427
55
97
5
3
76
21
6
70
1
Indication
ER Positive
All cases on invasive ER Positive
breast cancer
LN Negative
ER Positive
ER Positive
ER Positive
ER Negative
ER Negative
LN Negative
LN Positive
Staring Material
Requirement
Resections
All cases on
invasive breast
cancer
ER Negative
LN Negative ER ER Positive and ER Positive
positive or
Negative
negative
LN Positive and LN Negative
Negative
LN Negative
LN Negative
Stand Alone
Prognostic Role
Established
Partially
Yes
Yes
No
No
Yes
Yes
No
Yes
No
Guide to Specific No
Therapy
No
No
Yes
Tamoxifen
No
Possible
(Tamoxifen)
Yes
Tamoxifen
Yes
Tamoxifen
No
Yes
Tamoxifen
CypChip
Commercial Status In development
In Development In Development
In development
FDA Status
Unknown
Submitted for
Not submitted
510(k) Clearance
On the market
On the market
Centralized
Testing
Approved (510k) Approved
Cost
Unknown
Unknown
-
On the market
In Development In Development
Centralized
Testing
Exepmt
Submitted for
Not submitted
510k clearance
(Home brew
(4/07)
assay)
Billed as 5 88342 Billed as a
Unknown
Global CPT codes multiplex FISH
(approximately test. ($700-1,000
$600)
expected
reimbursement)
Adjuvant CMF
On the market
Centralized
Testing
Exempt
>$4,000
Not submitted
>$1,500 >$4,000
Approximately
$350
*Ross, JS, Hatzis C, Symmans WF, Pusztai L, Hortobagyi GN. Commericalized multi-gene predictors of clinical outcome in
breast cancer. Oncologist. 2008;13:477-493.
Comparison of Oncotype DxTM and MammaprintTM
Oncotype Dx
MammaPrint
Provider/Cost
Genomic Health, Inc.
$3,647
Agendia, BRV
$4,166
Starting Material
FFPE
Fresh mRNA and FFPE
Number of Genes
21
70
Rank of Importance of Pathways
Assessed
1 Proliferation
1 Proliferation
2 ER
3 HER2
2 ER
3 HER2
Current Indication
Node-Negative
ER-Positive
Node Negative
ER-Positive/Negative
Eligible Patient Age
Older patients
Young and Old Patients
Prognostic vs Predictive
Prognostic and Predictive
Prognostic and Predictive
Outcome Prediction
Continuous
Dichotomous
ASCO Biomarkers Guidelines Status
Recommended for use
Under Investigation
Cost Effectiveness Validation
Cost-effective in one published
study
Not reported
FDA Status
Not submitted
Cleared at 510k level
Tissue Requirements for DNA Sequencing
• DNA yield from FNAs may not always be satisfactory
– Needle core biopsies preferred whenever possible
– DNA is typically extracted from FFPE cellblocks from fluids and FNAs
• Genotyping DNA in routine practice
– EGFR for gefitinib/erlotinib in NSCLC
– KRAS for cetuximab in CRC
– BRAF for metastatic melanoma
• NGS can be performed on FFPE samples
– Currently requires 50 ng of DNA (approximately 10,000 cells)
– Likely will require less (? 20 ng) as technology improves
– Enrichment rarely needed for samples with <20% tumoral DNA
present on clinical sample
Traditional DNA Sequencing Methods
Ross J, Cronin M. Am J Clin Pathol, 2010.
Next Generation Sequencing
• The Human Genome sequence using original Sanger sequencing
techniques was completed in 12 years at a cost of $ 3 Billion
• The rate-limiting step in Sanger sequencing is the need to separate
randomly terminated DNA polymers by gel electrophoresis
• NGS bypasses this by physically arraying DNA molecules on solid surfaces
and determining the DNA sequence in situ enabled by the development of
reversible (chemically or enzymatically) DNA chain terminators
• The DNA sequence is determined by measuring which bases are added into
an elongating DNA chain, physically anchored to a glass slide or array of
beads
• In the next few years, the cost of NGS will continue to decrease rapidly and
a clinically relevant gene sequence for a tumor may approach $1,000 cost
range with turn-around time of only several days
Comparison of Traditional (Sanger)
Sequencing and NGS
Ross J, Cronin M. Am J Clin Pathol, 2010.
Next Generation DNA Sequencing
Platforms
Ross J, Cronin M. Am J Clin Pathol, 2010.
EGFR Mutation Testing in NSCLC
•
•
•
•
•
Primary used to predict response to anti-EGFR tyrosine kinase small molecule drugs (erlotinib/gefitinib)
No standardized test with multiple methods of gene sequencing in clinical use
Currently, standard of care for EGFR-mutated lung cancer patients should be first-line TKI, using either
gefitinib or erlotinib
EGFR mutation correlates with gene amplification
Does not predict the response to anti-EGFR antibodies (cetuximab, panitumumab)
EGFR Activating Mutation – NSCLC
•
•
•
•
Mutation: EGFR_c.2573T>G_p.L858R
Freq=32%, depth=53
79 year old white female
FNA of lung mass: NSCLC
FNA sample cytocentrifuged and
converted to an FFPE tissue block.
Very small numbers of viable tumor
cells. Extensively necrotic.
KRAS Mutation Testing in CRC
Issues
• KRAS mutated in 27-53% of CRC
• Mutated KRAS identifies 50% of
cetuximab/panitumumab resistant CRC
• RT-PCR method more sensitive than
direct sequencing
• ASCO Opinion
- All patients with metastatic colorectal carcinoma
who are candidates for anti-EGFR antibody therapy
should have their tumor tested for KRAS mutations in
a CLIA-accredited laboratory
- If KRAS mutation in codon 12 or 13 is detected, then
patients with metastatic colorectal carcinoma should
not receive anti-EGFR antibody therapy as part of
their treatment
Pivotal KRAS Data from Randomized Clinical Trials
Ross J. Arch Pathol Lab Med, 2011
Established Techniques for KRAS Genotyping
Ross J. Arch Pathol Lab Med, 2011
Biomarkers Linked to Cetuximab/Panitumumab
Resistance in CRC
Ross J. Biomarkers in Med., 2011
KRAS Mutation – CRC
•
•
•
•
•
Mutation: KRAS_c.35G>T_p.G12V
Freq=30%, depth=283
52 year old white male
KRASG12V mutation by “hot-spot” genotyping at
Commercial Laboratory
pT3 pN2 pMx CRC
Classic CRC
with origin
from
mucosal
surface at
lower right
Novel ALK Fusion in CRC Detected by NGS
A 5,194,955-bp tandem duplication generates
an in-frame C2orf44-ALK gene fusion
The RNA sequence of the C2orf44-ALK gene
fusion shows aberrant splicing
pT4pN1pM1 Mucinous Adenocarcinoma
associated with a serrated sessile polyp
RNA sequencing shows an 89.8-fold increase
in expression of ALK beginning at exon 20
relative to exons 1–19.
Lipson et al. Nature Med, Feb, 2012
Vemurafenib in BRAF Mutated Melanoma
•
Vemurafenib inhibits V600E mutated BRAF tyrosine kinase
• BRAF mutation occurs in 50-60% of melanomas
• Vemurafenib specifically blocks the activity of the mutated
but not wild-type BRAF mutation and causes apoptosis
• Phase I escalating dose study of 16 BRAF V600E mutated
metastatic melanoma patients presented at ASCO 2009
• Of the 16 treated melanoma patients, 9 had partial
responses , 6 had stable disease and one had progressive
disease as their best responses.
• None of 5 non-mutated melanoma patients also treated
with vemurafenib had any responses.
• ASCO ‘10: 1/29 BRAF-mutated CRC cases showed a partial
response to vemurafenib
BRAF V600K Mutation – Metastatic MM
•
•
•
•
•
Mutation: BRAF_c.1798_1799GT>AA_p.V600K
Freq=10%, depth=416
77 year old white male
Thick melanoma of back
Multiple posterior cervical lymph nodes positive for metastatic
melanoma
Metastatic Melanoma to a
cervical lymph node
Molecular Pathology for Clinical Management for Major Solid Tumors
Breast
Cancer
NSCLC
CRC
Prostate
Cancer
Metastatic
Melanoma
IHC
ER and PR
HER2
Ki-67
IHC4 and
Mammastrat
Squamous vs
Adenoca
Alk inhibitors
pending
(crizotinib)
ERCC1
controversial
EGFR for erbitux in
SCC pending
EGFR for erbitux
and panitumumab
MSI and HNPCC
PIN4 (racemase)
for diagnosis
None
FISH/CISH
HER2
Alk inhibitors
(crizotinib)
None
TMPRSS:ERG
fusions
Melanoma
diagnosis
mRNA
Profiling
Oncotype
MammaPrint
None
Oncotype Colon
ColoPrint
None
None
Traditional
Genotyping
None
EGFR inhibitors
(erlotinib)
KRAS for
erbitux/panitumum
ab
None
BRAF for
vemurafenib
NGS
HER2
Hormonal Rx
Targeted Rx for
TNBC pending
EGFR TKI
EML4:ALK
Other targets
(RET-kif5B)
Other targets
TMPRSS:ERG
fusions
Other targets
BRAF for
vemurafenib
Other targets
Targeted Therapies for Cancer
Molecular profiling is driving many new targeted cancer therapeutics
• ~500 compounds hitting ~140
targets in development
• Growing number of newly
identified potential targets
Subset of analyzed targets
listed; data from BioCentury
Online Intelligence
Database