Rapid Tumor Genotyping in Solid Tumors

AKT1
APC
BRAF
CTNNB1
EGFR
KIT
IDH1
MAP2K1
KRAS
NOTCH1
NRAS
PIK3CA
PTEN
Rapid Tumor Genotyping
in Solid Tumors
TP53
Tumor Genotyping
Personalized Medicine
Requires Personalized Diagnostics
Biological discoveries utilizing advanced sequencing
techniques are unraveling the key drivers of cancer.
These discoveries are now entering the clinic
by personalizing treatment based on molecular
profile. For example, conventional testing in lung
cancer relies on 1 or 2 mutational events (EGFR
and ALK) but research groups such as the Lung
Cancer Consortium1 are profiling patients across
several oncogenes implicated in oncogenesis. This
multidimensional view of cancer is taking hold in
various solid tumors.
1. The Lung Cancer Mutation Consortium (LCMC) is an NCI sponsored initiative made up of 14 leading cancer centers across
the country.
Major pathways have been identified in cancer proliferation including:
Mitogen Activated Protein Kinase (MAPK) signaling:
EGFR, BRAF, KRAS, NRAS, MAP2K1, KIT
mTOR:
PIK3CA, AKT, PTEN
Tumor Suppressor and DNA Repair:
TP53, PTEN, APC
Cell Signaling:
NOTCH1, CTNNB1
Mitogen Activated Protein Kinase (MAPK) Pathway
Growth
Factor
Receptor
tyrosine kinase
RAS
P
P
PI3K
RAF
AKT
MAP2K1
(MEK1)
mTOR
PTEN
ERK
Proliferation
Survival
The molecular profiling of cancer patients
is becoming the standard for disease
management in top medical centers.
w w w. g enpa thdiag n o st ics.co m / o n co lo g y/ O n ko Matc h
Same Histology but Different Genotypes = Different Targeted Therapies?
Example: 3 patients with stage IV adenocarcinoma
Tumor 1
Tumor 2
Tumor 3
Treatment naive
Refractory to cisplatin
regimens
Refractory to cisplatin
regimens
EGFR mutated
PIK3CA mutated
MEK mutated
Erlotinib
XL147 – PIK3CA inhibitor
MEK-162 inhibitor
FDA approved
Investigational Agent
Investigational Agent
Therapies Matched to the Patient’s Specific Molecular Profile
OnkoMatch
provides fast
results with a 7 day
turnaround.
The Paradigm Shift in Tumor Genotyping
Rapid Detection of 68 Mutations Across 14 Oncogenes from 1 Tumor Specimen
GenPath introduces OnkoMatch, a proprietary assay utilizing technology pioneered at Mass General
Hospital. OnkoMatch is a reliable and robust tumor genotyping platform for detecting 68 mutations across 14
oncogenes from one specimen.
Past
Conventional
Next Generation
Histology
Histology
Histology
Single Gene Test
(ex KRAS)
Tumor Genotyping
AKT1 - APC - BRAF - CTNNB1
EGFR - IDH1 - KIT - KRAS
MAP2K1 - NOTCH1 - NRAS
PIK3CA - PTEN - TP53
OnkoMatch Methodology: PCR amplification followed by single base extension
detection of hotspot mutations that have been identified as key driver mutations.
w w w. g enpa thdi a g n o st ics.co m / o n co lo g y/ O n ko Matc h
Tumor Genotyping
OnkoMatch represents the new paradigm in cancer diagnostics enabling clinicians to see a more
complete picture of cancer drivers and not mutations confined to one or more genes.
Tumor Genotyping
AKT1
EGFR
BRAF
NOTCH1
KIT
IDH1
PIK3CA
TP53
MAP2K1
CTNNB1
APC
KRAS
NRAS
PTEN
Single Gene Test
EGFR
KRAS
When is OnkoMatch
Genotyping Recommended?
Solid Tumor Cancer:
Lung, Breast, Colon, GI, Pancreas, Melanoma, Head and Neck, Ovarian, Thyroid
ADVANCED STAGE CANCER –
Patients who have become refractory (treatment resistant) to prior therapies and are searching
for investigational targeted therapies offered in clinical trials.
NON-METASTATIC CANCER –
Patients who do not have immediate requirement for investigational therapy
but would like to know their mutational profile for potential future clinical trials
or future approvals of targeted therapies.
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The Age of Targeted Therapy
Based on Molecular Profile
Medicine has moved past the age of broad based
toxic therapies whose efficacy in select populations
is unknown. Cancer genetics has revealed extensive
tumor heterogeneity within the same disease state.
This diversity requires tailored therapies based on the
patient’s tumor genotype.
Mutational Incidence Breakdown for Breast
CTNNB1: 2%
KRAS: 4%
APC: 3% HER2: 15%
NRAS: 2%
BRAF: 3%
AKT1: 4%
EGFR: 2%
MAP2K1: 2%
PTEN: 6%
TP53: 23%
PIK3CA: 25%
Mutational Incidence Breakdown for Lung
APC: 3%
CTNNB1: 3%
AKT1: 1%
PIK3CA: 3%
PTEN: 4%
HER2: 2%
ALK: 5%
EGFR: 15%
BRAF: 2%
TP53: 5%
KRAS: 25% MET: 5%
NRAS: 1%
Source: COSMIC database, Wellcome Trust Sanger Institute
FDA 2011 Approvals
Recent FDA approvals for ALK and BRAF inhibitors have
proven that MATCHING genetic profiling with a targeted
therapy is both efficacious and minimally toxic to the patient.
Response Rate
Crizotinib – ALK
61%
Vemurafenib – BRAF
48%
Source: FDA Package Insert
EGFR
Investigational therapies, currently in clinical trials,
are now targeting oncogenes such as AKT1, KRAS,
MEK and PIK3CA. Inhibitors of these pathways
could be the next success in cancer treatment.
BRAF
ALK
FDA
APROVED
AKT1
THE FUTURE
MEK
w w w. g enpa thdi a g n o st ics.co m / o n co lo g y/ O n ko Matc h
HER2
KRAS
PIK3
Tumor Genotyping
The time between biological marker discovery and drug development has significantly shortened. Gleevec was
developed 41 years after the discovery of the Philadelphia chromosome whereas Vemurafenib took only 9
years from BRAF identification in cell lines. The discovery of oncogenes that drive cancer progression has
spurred on a dramatic drug discovery race as shown in the more than 100 clinical trials (see Investigational
Agents sheet) currently underway.
Biomarker Discovery → Drug Development Has Accelerated
1960
1973
BCR-ABL inhibition
(Gleevec)
Discovery of
‘Philadelphia
chromosome’
1999
1993–1995
2001
41 Years
BCR-ABL inhibitors Hematological
(patent filed)
responses in CML
(53 of 54 patients)
Mechanism of action:
translocation of the
ABL oncogene
1985–1987
1996
ERBB2 inhibition
(Herceptin)
1998
13 Years
ERBB2 cloning &
ID amplification
ERBB2 expression is
predictive of response
2002
Years for FDA Approval
of Personalized Therapies
BRAF inhibition
(Vemurafenib)
2011
9 Years
ID of BRAF mutations
in cell lines and
malignant melanoma
Responses in
BRAF
mutant tumors
2007
ALK inhibition
(Crizotinib)
2011
4 Years
Drug repositioning
based on EML4-ALK
translocation in NSCLC
ALK fusions
predict
response
Source: Nature Medicine Vol 17 • Number 3 • March 2011 • Page 298
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Tumor Genotyping from MGH to your practice
Technology used routinely at Mass General Hospital is
now available nationally in community oncology practices.
OnkoMatch tumor genotyping technology has been licensed exclusively from Massachusetts General Hospital’s
(MGH) Division of Translational Medicine.1 Dr. John Iafrate, MD, PhD (Director of Molecular Diagnostics at MGH
and Associate Professor of Pathology, Harvard Medical School) and his team at MGH designed a multiplex
genotyping assay for solid tumors based on SNaPshot2 technology. GenPath leveraged MGH’s sophisticated
DNA extraction method and mutational analysis for detecting multiple mutations across several oncogenes in
one test.
original article
Annals of Oncology 22: 2616–2624, 2011
doi:10.1093/annonc/mdr489
Published online 9 November 2011
Tumor genotyping of solid tumors such as lung are part of MGH’s normal protocol for patient management. “Analysis
by SNaPshot Multiplex System is now part of the routine pathological assessment of lung cancers at Mass General
Implementing multiplexed genotyping of non-small-cell
Hospital”3, John Iafrate, MD, PhD.
lung cancers into routine clinical practice
1,2
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Patients at MGH with detected mutations
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Radiation Oncology, Massachusetts General Hospital, Boston; 10Yale University School of Medicine and Yale Cancer Center, New Haven; 11Department of Pathology,
Massachusetts General Hospital, Boston, USA
ME DIC INE
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Received
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Background:
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od and Dr
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prevent
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Bethesda,
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Methods:
Weeadeveloped
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mutations from
in several
ica
rch
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res
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instances,
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d Ha rv and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory
er reach
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sp ita l an
cer from ev
a response rate of 75%, PFS of 9–13 months and improved
typed after keyne
ra l Hogenes.
with lung can tumours will be geno ions are Ge
traditional chemotherapy [1–9]. This OMshifting
has
BL OG paradigm
Improvement Amendments-certified tests. Here, we present
of the first 589 patients referred for genotyping.
TH Eanalyses
FR
In the trial, mine whether mutat
quality of life compared with chemotherapy [8, 14–16].
an
Jap
deter
dramatically
impacted
lung
cancer
treatments.
recently,
Results:
Pathologic
prescreening
identified
552 (95%)
tumors withUntil
sufficient
tissue for SNaPshot; 51% had ‡1
surgery to
MO RE NE WS
funds
Similarly,
with EML4-ALK translocations have a 60%
re.
mutation
identified,
most commonly
in dKRAS
EGFR (13%),
PIK3CA
(4%)kuand
involving ALK patients
(5%).
a
go.natu (24%),
shimtranslocations
therapeutic
options
for
advanced
NSCLC
were
limited
to
lve
so
Fu
ry
ste
ll my
EX PL AIN ER
Unanticipated mutations
several associations
● Sickle-cewere observed at lower frequencies in IDH and b-catenin.
rate, 9-month PFS and a low degree of toxicity when
clean-upWe observed response
s
h
ite
x61
com/dx and clinical
jects
s to paras
between genotypes
characteristics,
including increased PIK3CApro
mutations
in squamous cell cancers.
aptation
The science
treated with crizotinib, an ALK TKI [6].
cient
*Correspondence
Drad
L. V.ne
Sequist,
Massachusetts General Hospital Cancer
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re.Center,
variation
go.natu
Genotyping distinguished
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Conclusions: Broad
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55 Fruit Street, Jackson 1028, Boston, MA 02114,
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+1-617-724-1261;
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determine the mutational status of many genes. Responding to
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Key
words: carcinoma,
non-small
cell,
genotype,
molecular targeted therapy
reserv
. All rights
original article
Implementing multiplexed genotyping of non-small-cell
lung cancers into routine clinical practice
TEPCO
original
article
COUNCIL
Downloaded from http://annonc.oxfordjournals.org/ at New York Medical College Health Sciences Library on November 29, 2011
introduction
Annals of Oncology 22: 2616–2624, 2011
doi:10.1093/annonc/mdr489
Published online 9 November 2011
MORE
AUSTRALIAN
CANCER
INE
1 MGH is a registered
of Massachusetts General Hospital
ONLtrademark
2 SNaPshot is a registered trademark of Applied Biosystems, Inc.
3 Shaw AT, Iafrate JA, et. al. Case 21-2011: A 31-Year-Old
Man
with ALK-Positive Adenocarcinoma of the Lung. NEJM 2011; 365:163.
ited
Lim
n Publishers
cmilla
© 2011 Ma
ª The Author 2011. Published by Oxford University Press on behalf
of the European
Society
for Medical
chemotherapies
that were
‘personalized’
onlyOncology.
by considering
introduction
All rights reserved. For permissions, please email: [email protected]
the side-effect profiles of a number of similar modestly effective
Certain genetically defined cancers are ‘oncogene addicted’ to
regimens. Response rates were typically 20%–30% and
activated kinases and are thereby highly sensitive to drugs that
survival (PFS) was 3–5 months [10–13]. But
selectively
the thdi
corresponding
Employing
w w w. ginhibit
enpa
a g n okinase.
st ics.co
m / o n co progression-free
lo g y/ O n ko
Matc h
now, we know that determining NSCLC genotype can inform
genotype-based therapy has been highly successful in chronic
the most effective personalized therapies. Patients with
myelogenous leukemia, gastrointestinal stromal tumors, nonmutations in the epidermal growth factor receptor (EGFR) gene
small-cell lung cancer (NSCLC) and melanoma, and in many
Tumor Genotyping
Clear Reporting of Results
®
Final Report
John Smith, M. D.
D
O
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T
O
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ONCOLOGY CENTER
123 MAIN ST
Elmwood Park, NJ
12345
X1111
M1
P
A
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I
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Name: Barbara Jones
Addr: 123 Smith Street
DOB: 1/12/1952
Age: 60
SEX: F
ID No:
S
A
M
P
L
E
Date of Report:
1/22/2012
Date Collected:
1/15/2012
Date Received:
1/15/2012
Specimen ID:
30000000
Source:
Skin
Clinical Info:
Metastatic melanoma
OnkoMatch
Primary Tumor Type
®
Results
Protein
P
D ONCOLOGY CENTER
A
None Detected
OAKT1
T
123 MAIN ST
CAPC
None Detected
I
12345
T Elmwood Park, NJ
E
BRAF
c.1798_1799GT>AA
p.V600K
O X1111
M1
N
RCTNNB1
None Detected
T
None Detected
IDH1
None Detected
KIT
None Detected
PIK3CA
None Detected
TP53
None Detected
Final Report
HER1
(EGFR)
Oncogenes Tested
John Smith, M. D.
Gene
DNA Variant
EGFR
MELANOMA
Name: Barbara Jones
Variant
Addr: 123 Smith Street
DOB: 1/12/1952
SEX: F
ID No:
Date Collected:
Cell
1/22/2012
Membrane
1/15/2012
Date Received:
1/15/2012
Date of Report:
Age: 60
CT
S
A
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PP
L
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Specimen
ID:
30000000
Tyrosine Kinase
Domains
Source:
Skin
P
Clinical Info:
PIK3CA
Interpretative Information (continued)
Metastatic melanoma
RAS
PTEN
RAF
melanoma
with
the BRAF V600E or V600K mutations, when compared to chemotherapy (dacarbazine)
KRAS
None Detected
(Chapman, 2011). Preliminary results from early phase clinical studies using other targeted agents are
AKT1
MAP2K1
None Detected
MAP2K1
encouraging
and
include the BRAF inhibitor GSK2118436, and the RAF kinase inhibitor XL281
(Shepherd,
NOTCH1
None
Detected
2011). Multiple MEK inhibitors are currently being evaluated for the treatment of advanced
melanoma
and
MAPK
other
and include AZD6244, PD0325901 and GSK1120212 (Flaherty, CurrOpinOnc
2010).
NRASsolid tumors,
None Detected
Cytoplasm
Nucleus
Comments None Detected
PTEN
CT See report section on open clinical trials
Additional Markers
EGFR exon 19 deletion
Cell Proliferation, Cell Survival,
Invasion & Metastasis
Tumor-Induced Neoangiogenesis
Not Detected
Failed Probes
Reporting of open clinical trials
• Results consolidated in 1 simple table
• Mutation identified in pathway
EGFR,
c.2156G>C (p.G719A)
Interpretative
Information
related
to mutation
detected
BRAF c.1798_1799GT>AA,p.V600K
Clinical Trials
Description:
1.Variant
A Study
of RO5212054 (PLX3603) in Patients With BRAF V600-mutated Advanced Solid Tumours
The BRAF V600K mutation arises from a complex nucleotide change (c.1798_1799GT>AA) and results in
an amino acid substitution
of the valine (V) at position
600 byRoche
a lysine (K).
Sponsor:
Hoffmann-La
ClinicalTrials.gov Identifier:
NCT01143753
ClinicalTrials.gov Identifier:
NCT01221077
Prognostic Relevance:
In one study of a consecutive series of patients with metastatic melanoma, the presence of a BRAF muta2. A Phase I Study of Oral LGX818 in Adult Patients With Advanced or Metastatic BRAF Mutant Melanoma
tion was associated with a more aggressive clinical course and shorter survival for patients that were not
Sponsor:
Novartis Pharmaceuticals)
treated with a BRAF inhibitor.
(Long, Menzies, 2011).
Therapeutic Relevance:
A phase III clinical trial showed that vemurafenib (PLX4032), a potent and orally-available BRAF kinase inhibitor,
improved the rates of overall and progression-free survival in patients with previously untreated metastatic
Tumor Genotyping
Genpath is a business unit of BioReference Laboratories Inc.
481Drive
Edward H Ross Drive · Elmwood Park, NJ 07407 ·1 800 627 1479 tel · 1 201 791 8760 fax · www.genpathdiagnostics.com
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James
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AM
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07407 is a business unit of BioReference
GenPath
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rights 1/23/12
reserved.
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TP2011-202778295
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