Transcript Template PPT - The Royal College of Pathologists

Personalised Medicine and the Future of Tissue Pathology
Manuel Salto-Tellez
Professor and Chair of Molecular Pathology
Queen’s University Belfast
BASIC SCIENCE
MACRO
HISTO/
CYTO
DIAGNOSTICS
IHC/
ICC
IN SITU HYBRIDIZATIONS
PCR
BASIC SCIENCE
DIAGNOSTICS
LACK OF KNOWLEDGE
LACK OF ROBUST
TECHNOLOGY
LACK OF ROBUST
RESEARCH DESIGN
(CLINICAL TRIALS)
BOTTLENECK
DIAGNOSTIC &
CLINICAL
APPLICATIONS
Molecular Tissue Pathology and Personalised Medicine
DEFINITIONS
TESTS – strengths and challenges
RELEVANCE TO TRADITIONAL TISSUE
DIAGNOSTICS
DIAGNOSTIC &
CLINICAL
APPLICATIONS
Molecular Tissue Pathology and Personalised Medicine
DEFINITIONS
TESTS – strengths and challenges
RELEVANCE TO TRADITIONAL TISSUE
DIAGNOSTICS
DIAGNOSTIC &
CLINICAL
APPLICATIONS
Association
Molecular
(AMP) of molecular
Molecularfor
diagnosis
is Pathology
the application
biology techniques and knowledge of the
molecular mechanisms of disease to diagnosis,
prognostication and treatment of diseases.
HAEMATOONCOLOGY
INFECTIOUS
DISEASES
Molecular
Diagnostics
SOLID
TUMORS
IDENTITY
TESTING
GENETIC
DISEASES
Diagnostic Molecular Oncology
Association
for Molecular
Pathology
(AMP)
Diagnostic
Molecular
Histopathology
&
Cytopathology is the application of molecular
diagnosis to those samples that are firstly
analysed by histopathologists and
cytopathologists:
FFPE Materials
FNAs, effusion and exfoliative cytology
Diagnostic Molecular
Histopathology / Cytopathology
Molecular Tissue Pathology and Personalised Medicine
DEFINITIONS
TESTS – strengths and challenges
RELEVANCE TO TRADITIONAL TISSUE
DIAGNOSTICS
DIAGNOSTIC &
CLINICAL
APPLICATIONS
Diagnostic Value
Translocations
in sarcomas
Translocations in sarcomas
Tumor
Ewing’s sarcoma
Peripheral PNET
Myxoid liposarcoma
Translocation
t(11;22)
t(21;22)
t(12;16)
t(12;22)
Alveolar Rhabdomyosarcoma
t(2;13)
t(1;13)
Clear cell sarcoma
t(12;22)
Desmoplastic small round
t(11;22)
cell tumor
Synovial sarcoma
t(X;18)
Myxoid chondrosarcoma
t(9;22)
Dermatofibrosarcoma
t(17;22)
protuberans
Infantile fibrosarcoma
t(12;15)
Fusion Product
EWS-FL11
EWS-ERG
TLS-CHOP
EWS-CHOP
PAX3-FKHR
PAX7-FKHR
EWS-ATF1
EWS-WT1
SYT-SSX1/ SYT-SSX2
EWS-CHN
COL1A1-PDGFB
STRONG DIAGNOSTIC VALUE
ETV6-NTRK3
Diagnostic t(11;22)(p13;q12) translocation
characteristic of DSRBCT
Pang B, Leong CC, Salto-Tellez M, Petersson F.
ApplImmunohistochem Mol Morphol. 2011 Jan;19(1):70-5
Haemato-oncology
Lymphomas
CLONALITY STUDIES
All lymphomas
IgH receptor and TCR gene rearrangement
TRANSLOCATIONS
c-ski (1q23); c-ets
(11q23-24); bcr-abl
Precursor B-ALL
t(1;19), t(4;11), del(6q), t(9;22)
B-CLL / SLL
del(13); trisomy 12
Mantle cell lymphoma
t(11;14)
Cyclin D1
Follicular lymphoma
t(14;18)
Bcl-2
Extranodal marginal zone B-cell lymphoma
t(11;18)
API2/ML1
Splenic Marginal zone B cell lymphoma
del(7), del(10)
Lymphoblastic lymphoma (immunocytoma)
t(9;14)
PAX-5
Diffuse large B-cell lymphoma
t(3;14) & t(14;18)
Bcl-6 & Bcl-2
Burkitt lymphoma
t(8;14), t(2;8), t(8;22)
c-myc
Plasmacytoma
t(4;14) & t (6;14)
FGFR3 & MUM1/IRF 4
T-cell prolymphocytic leukemia
Inv(14)
TCL-1
Angioimmunoblastic T cell lymphoma
+3, +5, +X
Anaplastic large cell lymphoma
t(2;5)
Hepatosplenic γδ
i(7)
(adapted from Ng, Lee and Salto-Tellez EOMD 2008)
NMP/ALK
Dec ‘02
Bladder biopsy – T-cell Lymphoma
Jan ‘03
First gastric biopsy – T-cell lymphoma
Jan ‘04
Lymphocytic gastritis-like biopsy
Thyroid Pathology
B-Raf
mutations
Malignant Melanoma
Therapeutics
GSK2118436
PLX4032
Diagnostics
Thyroid Cancer
Colon cancer
MSI and HNPCC
& KRAS = Prognostic and
?Therapeutics
Gliomas
Courtesy of
Brendan Pang
Diagnostic Value
Genetic Value
Diagnostic Value
Genetic Value
Therapeutic Value
Selected target therapeutics in the routine oncology practice
Targeted therapeutics
Target
Tumor
Trastuzumab
Her-2
Breast Ca
Rituximab
CD20
B-Cell Lymphoma
Cetuximab
EGFR/KRAS
CRC & HN Ca
Bevacizumab
VEGF
Breast Ca / CRC / NSCLC
Panitumumab
EGFR
CRC
Imatinib
c-kit / BCR-ABL
GIST and CML
Gefitinib
EGFR
Lung Ca
Erlotinib
EGFR
NSCLC & Pancreatic Ca
Lapatinib
Her-2 & EGFR
Breast Ca
Sorafenib
VEGFRs/PDGFR/RAF
HCC & RCC
Sunitinib
VEGFRs/PDGFR/RET
RCC & GIST
Tensirulimus / Everolimus
mTOR
RCC
Bortezomib
Proteasome
MM & MCL
VorinostatBortezomib
HDAC
Cutaneous TCL
Antibodies
Small Molecule Inhibitors
From: Quek, Yan, Yong and Salto-Tellez. Personalized Medicine (2009) 6(5),465-468
Selected target therapeutics in the routine oncology practice
Targeted therapeutics
Target
Tumor
Trastuzumab
Her-2
Breast Ca
Rituximab
CD20
B-Cell Lymphoma
Cetuximab
EGFR/KRAS
CRC & HN Ca
Bevacizumab
VEGF
Breast Ca / CRC / NSCLC
Antibodies
Drugs in theEGFR
pipeline inCRC
2010 = 850
Panitumumab
Small Molecule Inhibitors
Imatinib
c-kit / BCR-ABL
and CML
Source – AACR
2010 internalGIST
statistics
Gefitinib
EGFR
Lung Ca
Erlotinib
EGFR
NSCLC & Pancreatic Ca
Lapatinib
Her-2 & EGFR
Breast Ca
Sorafenib
VEGFRs/PDGFR/RAF
HCC & RCC
Sunitinib
VEGFRs/PDGFR/RET
RCC & GIST
Tensirulimus / Everolimus
mTOR
RCC
Bortezomib
Proteasome
MM & MCL
VorinostatBortezomib
HDAC
Cutaneous TCL
From: Quek, Yan, Yong and Salto-Tellez. Personalized Medicine (2009) 6(5),465-468
Molecular diagnostics and
personalised / predictive medicine
Gastrointestinal stromal tumour
Br J Cancer
2007;96:776–82
Cytopathology
2009;20:297–303
Mod Pathol 2003;16:79–85
Hum Pathol 2003;34:362–8
J Clin Pathol2010;63:839–42
J Clin Pathol 2011; July 14th
Arch Pathol Lab Med 2011; 135(6):693-5
C-kit mutations
Imatinib
HER2-neu FISH
Breast
cancer
Trastuzumab
Lapatinib
Gastric
cancer
Lung cancer
Clin Chem
2007;53:62–70
J Thorac Oncol
2011, on line
EGFR
mutations
EML4-ALK
Colon cancer
J Mol Diagn 2009;11:543–52
Pathology 2008;40:295–8
Cytopathology 2010; Oct 4th
Int J Colorectal Dis 2010; Dec 3th
Erlotinib
Gefitinib
ALK inhibitor
PF-02341066
Cetuximab
K-Ras mutations
Pathology 2008;40:295–8
Cytopathology 2010; Oct 4th
B-Raf
mutations
Malignant Melanoma
GSK2118436
PLX4032
Modern pathology must be a synergy of morphology, IHC and molecular Dx
Colon cancer
J Mol Diagn. 2009; 11:543-52
Pathology 2008;40:295–8
Cytopathology 2010, Oct 4, in press
Int J Colorectal Dis. 2010 Dec 3.
KRAS mutations
B-Raf
mutations
K-Ras mutations
Cetuximab
Journal of Molecular Diagnostics 2009, Vol. 11, No. 6
DOI: 10.2353/jmoldx.2009.090057
A Multicenter Blinded Study to Evaluate KRAS Mutation
Testing Methodologies in the Clinical Setting
Vicki Whitehall* et al (Salto-Tellez M, Iacopetta B)
Pyrosequencing
DNA sequencing
Tib-MolBiol kit
DxS
SSCP
HRM
2009 – 2010
N = 1,555
12%
189
31%
483
18% 285
Molecular testing as
a revenue generator?
108
212
7%
14%
Clinical trials
NUH
Private Singapore
278
18%
Industry Sponsored
Re-structured Hospitals
Overseas
Lung cancer
Clin Chem
2007;53:62–70
JTO
2011, accepted
EGFR mutations
EGFR
mutations
EML4-ALK
Erlotinib
Gefitinib
ALK inhibitor
PF-02341066
Sharma et al.
Nat Rev Cancer 2007
IPASS
(Mok T, et al. 2009)
EGFR Testing
1.
2.
3.
4.
5.
6.
EGFR mutation testing model
EGFR mutation testing methodology
EGFR mutation testing materials
EGFR mutation testing turnaround time
EGFR mutation testing reporting
EGFR mutation testing – single biomarker
versus multiple biomarkers
7. Conclusions
The story of
1960’s - Isolation of a protein
that induced epithelial growth
1970’s - Discovered specific binding
receptors for EGF on target cells
1980’s - Modification of proteins by
phosphorylation on tyrosine residues
might be a critical step in tumorigenesis
BIOMARKER VALIDATION
PATHOLOGY DIAGNOSTICS
TECHNOLOGY TRANSFER
(MOLECULAR & IHC)
VALIDATION OF
CLINICAL MOLECULAR
DIAGNOSTIC TESTS
RESEARCH
(clinical trials)
TRANSLATIONAL
RESEARCH
BASIC RESEARCH
1987
1992
BASIC SCIENCE
2002
2004 2006-7
CLINICAL
COST
Phase I
Phase II
Phase III
Adapted from: Phasing out phase III trials? How much evidence do we need if the target is clearly hit? Jaap
AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics November 12-16, 201
Lung cancer
ClinChem
2007;53:62–70
J ThoracOncol
2011; accepted
EGFR
mutations
Gefitinib
Erlotinib
Colon cancer
6. LUNG CANCER
single biomarker versus multiple biomarkers
Breast Cancer (DNA microarrays of Q RT-PCR):
•70-gene profile MammaPrint
•21-gene recurrence score Oncotype DX
•76-gene outcome Rotterdam signature
Colon Cancer:
•12-gene expression signature: independent predictor of
recurrence in stage II disease
AML:
•133-gene signature in adult AML of normal karyotype:
prognostic information
Concerns:
1. Is this evidence supported by solid, randomized, prospective clinical trials?
2. Are single-lab results reproducible if the test is done in different centres?
Molecular classification of lung adenocarcinoma
Molecular classification of lung adenocarcinoma
LUNG
ADENOCA
EGFRmut
LUNG
ADENOCA
EGFR wt
Molecular classification of lung adenocarcinoma
LUNG
ADENOCA
EGFR mut
LUNG
ADENOCA
MET ampl
LUNG
ADENOCA
KRASmut
LUNG
ADENOCA
EML4-ALKpos
Pathology sequence – reflex testing (ver 2)
Diagnostic material (bronchoscopic, needle core or cytology)
SCLC
NSCLC
EGFR exons 18–21 mutation detection
EGFR mut
EGFR wt
KRAS Ex 2 & 3
KRAS mut?
KRAS wt?
EML4-ALK
EGFR-TKI
treatment
KRAS-related
treatment?
EML4-ALK AMP
EML4-ALK not AMP
ALK inhibitors?
Other treatments
Other treatments
Molecular Diagnostics and
the
Taxonomy of Cancer
DIRECTOR'S CHALLENGE: TOWARD A MOLECULAR
CLASSIFICATION OF TUMORS
Release Date: January 20, 1999 RFA: CA-98-027
P.T. National Cancer Institute
PURPOSE - The Director of the National Cancer Institute (NCI)
challenges the scientific community to harness the power of
comprehensive molecular analysis technologies to make the
classification of tumors vastly more informative. This challenge is
intended to lay the groundwork for changing the basis of tumor
classification from morphological to molecular characteristics.
Dr Harold Varmus, 1999
Every year there are more samples coming into
Pathology Departments
New molecular diagnostic approaches and
classifications are based on very solid morphological
interpretations –
Phenotype and Genotype are not
mutually exclusive, but are complementary
WHO classification of lung adenocarcinoma
1.3.3. Adenocarcinoma
1.3.3.1. Acinar
1.3.3.2. Papillary
1.3.3.3. Bronchioloalveolar carcinoma
1.3.3.3.1. Non-mucinous (Clara / pneumocyte type II)
1.3.3.3.2. Mucinous
1.3.3.3.3. Mixed mucinous and non-mucinous
or intermediate cell type
1.3.3.4. Solid adenocarcinoma with mucin
1.3.3.5. Adenocarcinoma with mixed subtypes
1.3.3.6. Variants
1.3.3.6.1. Well-differentiated fetaladenocarcinoma
1.3.3.6.2. Mucinous ("colloid") adenocarcinoma
1.3.3.6.3. Mucinouscystadenocarcinoma
1.3.3.6.4. Signet-ring adenocarcinoma
1.3.3.6.5. Clear cell adernocarcinoma
Travis et al. J ThoracOncol 2011
1.3.3. Adenocarcinoma
1.3.3.1. Acinar
1.3.3.2. Papillary
1.3.3.3. Bronchioloalveolar carcinoma
1.3.3.3.1. Non-mucinous (Clara / pneumocyte type II)
1.3.3.3.2. Mucinous
1.3.3.3.3. Mixed mucinous and non-mucinous
or intermediate cell type
1.3.3.4. Solid adenocarcinoma with mucin
1.3.3.5. Adenocarcinoma with mixed subtypes
1.3.3.6. Variants
1.3.3.6.1. Well-differentiated fetal adenocarcinoma
1.3.3.6.2. Mucinous ("colloid") adenocarcinoma
1.3.3.6.3. Mucinous cystadenocarcinoma
1.3.3.6.4. Signet-ring adenocarcinoma
1.3.3.6.5. Clear cell adernocarcinoma
Objectivity
Reproducibility
Clinical
Relevance
Affordability
Mod Pathol 2003;16:79–85
Hum Pathol 2003;34:362–8
JCP2010;63(9):839-42
JCP 2011, accepted
Archives Path Lab Med 2001, in press
HER2-neu FISH
Breast
cancer
Gastric
cancer
Her-2/neu amplification
Trastuzumab
Lapatinib
54 | 1.1 Topic goes here | Project number | 14.12.08
Copyright © 2008 National University Health System
American Society of Clinical Oncology/College of American Pathologists Guideline
Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast
Cancer - Antonio C. Wolff AC et al.
JCO Jan 1 2007: 118-145.
HER2-neu FISH
C-erbB2 IHC
OR
SCORE 0, 1+ 0R 3+
SCORE 2+
HER2-neu FISH
Final Report
 4 signals or
 1.8 ratio
1.8 to 2.2 ratio
> 6 signals or
>2.2 ratio
C-erbB2 IHC
Final Report
Guidelines for Human Epidermal Growth Factor Receptor 2 Testing: Biologic and
Methodologic Considerations
Guido Sauter, James Lee, John M.S. Bartlett, Dennis J. Slamon, Michael F. Press
JCO Mar 10 2009: 1323-1333.
Table 3. FISH in Central Laboratory and
IHC With DAKO Herceptest in Local/Community Hospital Laboratories
FISH in Central
Laboratory
IHC With DAKO Herceptest in Local/Community
Hospital Labs (No. of samples)
0
1+
2+
3+
Total
Positive
11 (a)
8 (b)
21 (c)
204
(d)
244
(e)
Negative
296
(f)
142
(g)
103
(h)
57 (i)
598 (j)
Sauter, G. et al. J Clin Oncol; 27:1323-1333 2009
Copyright © American Society of Clinical Oncology
Table 3. FISH in Central Laboratory and
IHC With DAKO Herceptest in Local/Community Hospital Laboratories
FISH in Central
Laboratory
Positive
IHC With DAKO Herceptest in Local/Community
Hospital Labs (No. of samples)
0
1+
2+
3+
Total
11 (a)
8 (b)
21 (c)
204
(d)
244
(e)
103
(h)
57 (i)
598 (j)
7.8%
Negative
296
(f)
Sauter, G. et al. J Clin Oncol; 27:1323-1333 2009
Copyright © American Society of Clinical Oncology
142
(g)
Table 3. FISH in Central Laboratory and
IHC With DAKO Herceptest in Local/Community Hospital Laboratories
FISH in Central
Laboratory
Positive
IHC With DAKO Herceptest in Local/Community
Hospital Labs (No. of samples)
0
1+
2+
3+
Total
11 (a)
8 (b)
21 (c)
204
(d)
244
(e)
103
(h)
57 (i)
598 (j)
7.8%
Negative
296
(f)
Sauter, G. et al. J Clin Oncol; 27:1323-1333 2009
Copyright © American Society of Clinical Oncology
142
(g)
9.6%
From:
Jared N. Schwartz, MD, PhD, FCAP
Director, Pathology & Lab Medicine
Presbyterian Healthcare Charlotte,
Past President, College of American Pathologists
Correlation between HER2 IHC and ISH (CISH and SISH) show a
significant number of false positive and false negative results,
confirming the decision for mandatory ISH testing to determine
HER2 status in Australia.
There were insufficient data to correlate CISH or SISH with FISH
but laboratories should validate CISH and SISH testing as specified
by the HER2 Advisory Board.
Copyright © American Society of Clinical Oncology
Her2 and Gastric Cancer
Lancet. 2010 Aug 28;376(9742):687-97. Epub 2010 Aug 19.
Trastuzumab in combination with chemotherapy versus chemotherapy
alone for treatment of HER2-positive advanced gastric or gastrooesophageal junction cancer (ToGA):
a phase 3, open-label, randomised controlled trial.
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A,
Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E,
Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators.
Her2 and Gastric Cancer
J Clin Pathol. 2011 Jul 14. [Epub ahead of print]
Her2 and Gastric Cancer
Her2 and Gastric Cancer
Molecular Tissue Pathology and Personalised Medicine
DEFINITIONS
TESTS – strengths and challenges
RELEVANCE TO TRADITIONAL TISSUE
DIAGNOSTICS
DIAGNOSTIC &
CLINICAL
APPLICATIONS
ANATOMICAL DIMENSION OF PATHOLOGY
ANATOMICAL / CLINICAL DIMENSION OF PATHOLOGY (HISTOLOGY AND CYTOLOGY)
“… transforming pathology of the dead into pathology of the living.”
Lauren V. Ackerman
Gordon Signy
K Shanmugaratnam
ANATOMICAL -CLINICAL DIMENSION OF
PATHOLOGY
TREATMENT AND/OR PROGNOSIS
Paediatric
Sarcomas
Colorectal
Cancer
Lympho –
proliferative
Disorders
Lung Cancer
Breast Cancer
Gastrointestinal
Stromal
Tumours
Salto-Tellez M. Clinical Chemistry 2007 Jul;53(7):1188-90
ANATOMICAL -CLINICAL DIMENSION OF
PATHOLOGY
TREATMENT AND/OR PROGNOSIS
SURG PATH
Diagnosis of
Paediatric
Sarcomas
SURG PATH
Diagnosis of
Colorectal
Cancer
SURG PATH
Diagnosis of
Lympho –
proliferative
Disorders
SURG PATH
Diagnosis of
Lung Cancer
SURG PATH
SURG PATH
Diagnosis of
Diagnosis of Gastrointestinal
Breast Cancer
Stromal
Tumours
Salto-Tellez M. Clinical Chemistry 2007 Jul;53(7):1188-90
ANATOMICAL / CLINICAL DIMENSION OF PATHOLOGY
Salto-Tellez M. Clinical Chemistry 2007 Jul;53(7):1188-90
ANATOMICAL / CLINICAL / MOLECULAR DIMENSION OF PATHOLOGY
Salto-Tellez M. Clinical Chemistry 2007 Jul;53(7):1188-90
MACRO
HISTO/
CYTO
IHC/
ICC
MACRO
HISTO/
CYTO
IHC/
ICC
IN SITU HYBRIDIZATIONS
PCR
ANATOMICAL -CLINICAL DIMENSION OF
PATHOLOGY
TREATMENT AND/OR PROGNOSIS
SURG PATH
Diagnosis of
Paediatric
Sarcomas
SURG PATH
Diagnosis of
Colorectal
Cancer
SURG PATH
Diagnosis of
Lympho –
proliferative
Disorders
SURG PATH
Diagnosis of
Lung Cancer
SURG PATH
SURG PATH
Diagnosis of
Diagnosis of Gastrointestinal
Breast Cancer
Stromal
Tumours
Salto-Tellez M. Clinical Chemistry 2007 Jul;53(7):1188-90
ANATOMICAL -CLINICAL DIMENSION OF
PATHOLOGY
TREATMENT AND/OR PROGNOSIS
Molecular
Detection
of
Translocations
SURG PATH
Diagnosis of
Paediatric
Sarcomas
KRAS/BRAF
Mutation Analysis
Specific
translocations
Microsatellite
Instability
Analysis
B & T cell
rearrangements
SURG PATH
Diagnosis of
Colorectal
Cancer
SURG PATH
Diagnosis of
Lympho –
proliferative
Disorders
Analysis
of
EGFR
Mutations
SURG PATH
Diagnosis of
Lung Cancer
HER2-neu
Status
Analysis
of
C-kit
Mutations
SURG PATH
SURG PATH
Diagnosis of
Diagnosis of Gastrointestinal
Breast Cancer
Stromal
Tumours
Salto-Tellez M. Clinical Chemistry 2007 Jul;53(7):1188-90
A N A T O M I C A L - C L I N I C A L – MO L E C U L A R
DIMENSION OF PATHOLOGY
TREATMENT AND/OR PROGNOSIS
Multiple Biomarker Analysis
Molecular
Detection
of
Translocations
SURG PATH
Diagnosis of
Paediatric
Sarcomas
KRAS/BRAF
Mutation Analysis
Specific
translocations
Microsatellite
Instability
Analysis
B & T cell
rearrangements
SURG PATH
Diagnosis of
Colorectal
Cancer
SURG PATH
Diagnosis of
Lympho –
proliferative
Disorders
Analysis
of
EGFR
Mutations
SURG PATH
Diagnosis of
Lung Cancer
HER2-neu
Status
Analysis
of
C-kit
Mutations
SURG PATH
SURG PATH
Diagnosis of
Diagnosis of Gastrointestinal
Breast Cancer
Stromal
Tumours
Salto-Tellez M. Clinical Chemistry 2007 Jul;53(7):1188-90
A N A T O M I C A L - C L I N I C A L – MO L E C U L A R
DIMENSION OF PATHOLOGY
TREATMENT AND/OR PROGNOSIS
Pharmacogenomics
Multiple Biomarker Analysis
Molecular
Detection
of
Translocations
SURG PATH
Diagnosis of
Paediatric
Sarcomas
KRAS/BRAF
Mutation Analysis
Specific
translocations
Microsatellite
Instability
Analysis
B & T cell
rearrangements
SURG PATH
Diagnosis of
Colorectal
Cancer
SURG PATH
Diagnosis of
Lympho –
proliferative
Disorders
Analysis
of
EGFR
Mutations
SURG PATH
Diagnosis of
Lung Cancer
HER2-neu
Status
Analysis
of
C-kit
Mutations
SURG PATH
Diagnosis of
Breast Cancer
SURG PATH
Diagnosis of
Gastrointestinal
Stromal
Tumours
Salto-Tellez M. Clinical Chemistry 2007 Jul;53(7):1188-90
Selected targeted therapeutics in routine oncology practice
Targeted therapeutics
Target
Tumour
Trastuzumab
Her-2
Breast Ca
Rituximab
CD20
B-Cell Lymphoma
Cetuximab
EGFR/KRAS
CRC & HN Ca
Bevacizumab
VEGF
Breast Ca / CRC / NSCLC
Panitumumab
EGFR
CRC
Imatinib
c-kit / BCR-ABL
GIST and CML
Gefitinib
EGFR
NSCLC
Erlotinib
EGFR
NSCLC & Pancreatic Ca
Lapatinib
Her-2 & EGFR
Breast Ca
Sorafenib
VEGFRs/PDGFR/RAF
HCC & RCC
Sunitinib
VEGFRs/PDGFR/RET
RCC & GIST
Temsirolimus/ Everolimus
mTOR
RCC
Bortezomib
Proteasome
MM & MCL
Vorinostat
HDAC
Cutaneous TCL
Antibodies
Small molecule inhibitors
Adapted from: Quek et al. (Salto-Tellez M). Personalized Medicine 2009
A N A T O M I C A L - C L I N I C A L – MO L E C U L A R
DIMENSION OF PATHOLOGY
TREATMENT AND/OR PROGNOSIS
Pharmacogenomics
Multiple Biomarker Analysis
Molecular
Detection
of
Translocations
SURG PATH
Diagnosis of
Paediatric
Sarcomas
KRAS/BRAF
Mutation Analysis
Specific
translocations
Microsatellite
Instability
Analysis
B & T cell
rearrangements
SURG PATH
Diagnosis of
Colorectal
Cancer
SURG PATH
Diagnosis of
Lympho –
proliferative
Disorders
Analysis
of
EGFR
Mutations
SURG PATH
Diagnosis of
Lung Cancer
HER2-neu
Status
Analysis
of
C-kit
Mutations
SURG PATH
Diagnosis of
Breast Cancer
SURG PATH
Diagnosis of
Gastrointestinal
Stromal
Tumours
Salto-Tellez M. Clinical Chemistry 2007 Jul;53(7):1188-90
A N A T O M I C A L - C L I N I C A L – MO L E C U L A R
DIMENSION OF PATHOLOGY
TREATMENT AND/OR PROGNOSIS
Pharmacogenomics
Multiple Biomarker Analysis
Molecular
Detection
of
Translocations
SURG PATH
Diagnosis of
Paediatric
Sarcomas
KRAS/BRAF
Mutation Analysis
Specific
translocations
Microsatellite
Instability
Analysis
B & T cell
rearrangements
SURG PATH
Diagnosis of
Colorectal
Cancer
SURG PATH
Diagnosis of
Lympho –
proliferative
Disorders
Analysis
of
EGFR
Mutations
SURG PATH
Diagnosis of
Lung Cancer
HER2-neu
Status
Analysis
of
C-kit
Mutations
SURG PATH
Diagnosis of
Breast Cancer
SURG PATH
Diagnosis of
Gastrointestinal
Stromal
Tumours
Salto-Tellez M. Clinical Chemistry 2007 Jul;53(7):1188-90
A N A T O M I C A L - C L I N I C A L – MO L E C U L A R
DIMENSION OF PATHOLOGY
TREATMENT AND/OR PROGNOSIS
Pharmacogenomics
Multiple Biomarker Analysis
Molecular
Detection
of
Translocations
SURG PATH
Diagnosis of
Paediatric
Sarcomas
KRAS/BRAF
Mutation Analysis
Specific
translocations
Microsatellite
Instability
Analysis
B & T cell
rearrangements
SURG PATH
Diagnosis of
Colorectal
Cancer
SURG PATH
Diagnosis of
Lympho –
proliferative
Disorders
Analysis
of
EGFR
Mutations
SURG PATH
Diagnosis of
Lung Cancer
HER2-neu
Status
Analysis
of
C-kit
Mutations
SURG PATH
Diagnosis of
Breast Cancer
SURG PATH
Diagnosis of
Gastrointestinal
Stromal
Tumours
Salto-Tellez M. Clinical Chemistry 2007 Jul;53(7):1188-90
A N A T O M I C A L - C L I N I C A L – MO L E C U L A R
DIMENSION OF PATHOLOGY
TREATMENT AND/OR PROGNOSIS
Pharmacogenomics
Multiple Biomarker Analysis
Molecular
Detection
of
Translocations
SURG PATH
Diagnosis of
Paediatric
Sarcomas
KRAS/BRAF
Mutation Analysis
Specific
translocations
Microsatellite
Instability
Analysis
B & T cell
rearrangements
SURG PATH
Diagnosis of
Colorectal
Cancer
SURG PATH
Diagnosis of
Lympho –
proliferative
Disorders
Analysis
of
EGFR
Mutations
SURG PATH
Diagnosis of
Lung Cancer
HER2-neu
Status
Analysis
of
C-kit
Mutations
SURG PATH
Diagnosis of
Breast Cancer
SURG PATH
Diagnosis of
Gastrointestinal
Stromal
Tumours
Salto-Tellez M. Clinical Chemistry 2007 Jul;53(7):1188-90
Molecular Pathology in Contemporary Diagnostic Pathology
Laboratory
An Opinion for the Active Role of Surgical Pathologists
Gregory Y Lauwers, Stephen Black-Schaffer,
and Manuel Salto-Tellez
Am J SurgPathol. 2010 Jan;34(1):115-7
To maintain its central role in the evaluation of patients, surgical pathology will
need completely to incorporate the molecular diagnostic for the understanding
and characterization of diseases.
If surgical pathologists attempt, even passively, to resist this change, it could
have 3 hugely significant consequences:
1) inviting others to perform molecular testing of surgical pathology samples,
moving the central role of tissue-based diagnosis out of the field of pathology
2) compromising the strategic position of our discipline at the crossroads
between the clinical practice of medicine and the scientific understanding of
diseases
3) Loosing on revenue: molecular diagnostics is the fastest growing area of
medicine, moving a budget of many billions of dollars, and a share of it should
justifiably find it way to divisions of anatomic pathology, where it has the
potential best to be understood and most appropriately integrated.
Lauwers, Black-Schaffer, Salto-Tellez
Am J Surg Pathol 2010;34:115-117
(Humble) recommendations:
1) now is the time for surgical pathology eagerly to embrace
molecular pathology
2) actively to petition for its integration, when indicated, into daily
clinical practice at sign out
3) vigorously to revisit and ensure its teaching in our residency
programs
all of this building on the role of board-certified molecular
pathologists as invaluable bridges between pathologists’ roles
as responsible diagnosticians and as clinical scientists
Lauwers, Black-Schaffer, Salto-Tellez
Am J Surg Pathol 2010;34:115-117
INTEGRATION LEADING TO FULL DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC OPINION
CLINICO-PATHOLOGICAL INTEGRATION
MORPHO-MOLECULAR INTEGRATION
TRADITIONAL INTEGRATION
Pulmonary pathology
Urological
Pathology
CNS Pathology
Lymphoreticular
Pathology
Gynaecological
Pathology
Gastrointestinal
Pathology
Soft Tissue Pathology
Breast
Pathology
Lauwers, Black-Schaffer, Salto-Tellez
Am J Surg Pathol 2010;34:115-117
EGFR Mutations
I
M
M
U
N
O
H
I
S
T
O
C
H
E
M
I
S
T
R
Y
E
L
E
C
T
R
O
N
Various
Chromosomal
Abnormalities (BC)
1p 19q LOH (Gliomas)
B- and T-cell receptor
gene rearrangements
Clinical History
and
Clinical
Presentation
Multiple translocations
M
I
C
R
O
S
C
O
P
Y
HPV Subtype Identification
Other
Laboratory
Investigations
KRAS/BRAF mutations (CRC)
MSI analysis
c-kit mutation (GIST)
Her-2/neu amplification (GC)
Diagnostic
Imaging
Multiple translocations
Her-2/neu amplification
TOP 2A amplification
Multiple gene amplification
FINAL
PATHOLOGICAL
DIAGNOSTIC
OPINION
The increasingly important role of
pathologists in personalised medicine
Selected targeted therapeutics in routine oncology practice
Targeted therapeutics
Target
Tumour
Trastuzumab
Her-2
Breast Ca
Rituximab
CD20
B-Cell Lymphoma
Cetuximab
EGFR/KRAS
CRC & HN Ca
Bevacizumab
VEGF
Breast Ca / CRC / NSCLC
Panitumumab
EGFR
CRC
Imatinib
c-kit / BCR-ABL
GIST and CML
Gefitinib
EGFR
NSCLC
Erlotinib
EGFR
NSCLC & Pancreatic Ca
Lapatinib
Her-2 & EGFR
Breast Ca
Sorafenib
VEGFRs/PDGFR/RAF
HCC & RCC
Sunitinib
VEGFRs/PDGFR/RET
RCC & GIST
Temsirolimus/ Everolimus
mTOR
RCC
Bortezomib
Proteasome
MM & MCL
Vorinostat
HDAC
Cutaneous TCL
Antibodies
Small molecule inhibitors
Adapted from: Quek et al. (Salto-Tellez M). Personalized Medicine 2009
Molecular diagnostics and personalised / predictive
medicine
Gastrointestinal stromaltumour
Br J Cancer
2007;96:776–82
Cytopathology
2009;20:297–303
C-kit mutations
Imatinib
Mod Pathol 2003;16:79–85
Hum Pathol 2003;34:362–8
J ClinPathol2010;63:839–42
J ClinPathol 2011; July 14th
Breast
Arch Pathol Lab Med 2011; 135(6):693-5 cancer
HER2-neu FISH
Trastuzumab
Lapatinib
Gastric
cancer
Lung cancer
ClinChem
2007;53:62–70
J ThoracOncol
2011, on line
EGFR
mutations
EML4-ALK
Colon cancer
J Mol Diagn 2009;11:543–52
Pathology 2008;40:295–8
Cytopathology 2010; Oct 4th
Int J Colorectal Dis2010; Dec 3th
Erlotinib
Gefitinib
ALK inhibitor
PF-02341066
Cetuximab
K-Ras mutations
Pathology 2008;40:295–8
Cytopathology 2010; Oct 4th
B-Raf
mutations
Malignant Melanoma
GSK2118436
PLX4032
Modern pathology must be a synergy of morphology, IHC and molecular Dx
From:
Jared N. Schwartz, MD, PhD, FCAP
Director, Pathology & Lab Medicine
Presbyterian Healthcare Charlotte,
Past President, College of American
Pathologists