M Salto-Tellez

Transcription

M Salto-Tellez

Manuel Salto-Tellez, MD (LMS), FRCPath, FRCPI
Professor and Chair of Molecular Pathology
Clinical Consultant Pathologist
Deputy Director, Centre for Cancer Research and Cell Biology
Why do we need to change the training of (Histo)pathology?
&
What is the Belfast Model?
&
Who is ultimately responsible?
&
&
Salto-Tellez M. Clinical Chemistry 2007 Jul;53(7):1188-90
•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
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
Diagnosis of
Breast Cancer
SURG PATH
Diagnosis of
Gastrointestinal
Stromal
Tumours
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
Diagnosis of
Breast Cancer
SURG PATH
Diagnosis of
Gastrointestinal
Stromal
Tumours
ANATOMICAL -CLINICAL -MOLECULAR DIMENSION
OF PATHOLOGY
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
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 D I M E N S I O N O F
PATHOLOGY
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
PATHOLOGY
Pharmacogenomics
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
HER2-neu
Status
Analysis
of
C-kit
Mutations
SURG PATH
Diagnosis of
Lung Cancer
SURG PATH
Diagnosis of
Breast Cancer
SURG PATH
Diagnosis of
Gastrointestinal
Stromal
Tumours
PATHOLOGY
Pharmacogenomics
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
HER2-neu
Status
Analysis
of
C-kit
Mutations
SURG PATH
Diagnosis of
Lung Cancer
SURG PATH
Diagnosis of
Breast Cancer
SURG PATH
Diagnosis of
Gastrointestinal
Stromal
Tumours
PATHOLOGY
Pharmacogenomics
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
HER2-neu
Status
Analysis
of
C-kit
Mutations
SURG PATH
Diagnosis of
Lung Cancer
SURG PATH
Diagnosis of
Breast Cancer
SURG PATH
Diagnosis of
Gastrointestinal
Stromal
Tumours
PATHOLOGY
Pharmacogenomics
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
HER2-neu
Status
Analysis
of
C-kit
Mutations
SURG PATH
Diagnosis of
Lung Cancer
SURG PATH
Diagnosis of
Breast Cancer
SURG PATH
Diagnosis of
Gastrointestinal
Stromal
Tumours
PATHOLOGY
Pharmacogenomics
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
HER2-neu
Status
Analysis
of
C-kit
Mutations
SURG PATH
Diagnosis of
Lung Cancer
SURG PATH
Diagnosis of
Breast Cancer
SURG PATH
Diagnosis of
Gastrointestinal
Stromal
Tumours
Siok-Bian N, Lee V, Das K, Salto-Tellez M.
Expert Opin Med Diagn. 2008 Dec;2(12):1401-14.
COURTESY OF DR. BRENDAN PANG
Selected target therapeutics in
clinical oncology practice
Salto-Tellez M. In: Tan & Lynch’s Principles of Molecular Diagnostics and Personalized
Cancer Therapy, Lippincott Williams & Wilkins, 2012.
Molecular biomarkers used in clinical standardof-care decision making in colorectal cancer
Biomarker
Purpose
Diagnostic
APC mutation detection
MMR protein expression (MSH2, MLH1, MSH6,
PMS2)
MSI (microsatellite instability) analysis
MMR mutation detection (MSH2, MLH1, MSH6,
PMS2)
BRAF mutation detection
MYH mutation detection
LKB1, SMAD4, BMPR1A, PTEN mutation detection
Diagnosis of FAP
Diagnosis of HNPCC
Diagnosis of MYH-associated polyposis
Diagnosis of harmartomatous polyp syndromes
Prognostic/Predictive
KRAS mutation analysis
BRAF mutation analysis
Thymidylate synthase protein expression
MSI
Gene expression signature
Molecular stratification for treatment with epidermal
growth factor receptor (EGFR) inhibitors
Identification of response to 5-FU
Identification of response to 5-FU
Prognostication
Van Schaeybroeck S, et al (Salto-Tellez M). Abeloff's Clinical Oncology. 5th edition; in press.
Molecular testing in breast cancer
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.
Boyle DP, et al. (Salto-Tellez M). Biochim Biophys Acta 2013;1835:230–42.
Molecular classification of
lung adenocarcinoma
Pao W & Hutchinson KE. Nat Med 2012;18:349–51.
Nat Med. 2013 May;19(5):619-25.
1.
2.
3.
4.
Tumours positive for Epstein–Barr virus
•
PIK3CA mutations
•
extreme DNA hypermethylation
•
amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (PD-L2)
microsatellite unstable tumours,
•
Elevated mutation rates, includingmutations of genes encoding targetable oncogenic
signalling proteins
genomically stable tumours,
•
diffuse histological variant
•
mutations of RHOA or fusions involving RHO-family GTPase-activating proteins
tumours with chromosomal instability
•
marked aneuploidy and
•
focal amplification of receptor tyrosine kinases
J Natl Cancer Inst. 2014 Jan;106(1):djt335. doi: 10.1093/jnci/djt335.
Speicher MR, Pantel K.Nat Biotechnol. 2014 May;32(5):441-3.
As comprehensive
(high-throughput) as
possible
• Plasma-free DNA (PB)
Phase 1 Disease
Diagnosis &
Treatment
Phase 3 Disease
Diagnosis &
Treatment
Phase 4 Disease
Diagnosis &
Treatment
DISEASE BURDEN
Phase 2 Disease
Diagnosis &
Treatment
(…)
Disease
Monitoring
Disease
Monitoring
Disease
Monitoring
As sensitive as possible, blood-based
TIME
1. Technological Advancement
Salto-Tellez M, Gonzalez de Castro D.J Pathol. 2014 Sep;234(1):5-10
KRAS
NRAS
BRAF
PI3KCA
p53
= £200 per sample
Dr David González de Castro
SOLID TUMOURS - LEVELS OF TESTING
HUMAN CANCER
COMPREHENSIVE
160
Tumour
COMPREHENSIVE
38
CLINICALLY
RELEVANT
32
ACTIONABLE
MUTATIONS
8 (3-4)
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 Surg Pathol. 2010 Jan;34(1):115-7
Lauwers, Black-Schaffer & Salto-Tellez. Am J Surg Pathol. 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 Jan;34(1):115-7
INTEGRATION LEADING TO FULL DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC OPINION
CLINICO-PATHOLOGICAL INTEGRATION
MORPHO-MOLECULAR INTEGRATION
Lauwers, Black-Schaffer, Salto-Tellez
Am J Surg Pathol 2010;34:115-117
TRADITIONAL INTEGRATION
Pulmonary pathology
Urological
Pathology
CNS Pathology
Lymphoreticular
Pathology
Gynaecological
Pathology
Gastrointestinal
Pathology
Soft Tissue Pathology
Breast
Pathology
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
M
I
C
R
O
S
C
O
P
Y
Various
Chromosomal
Abnormalities (BC)
1p 19q LOH (Gliomas)
B- and T-cell receptor
gene rearrangements
Clinical History
and
Clinical
Presentation
Multiple translocations
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
&
&
&
1. Training during training - FRCPath
2. Training outside training – Fellowship / MSc
Flynn C, (Salto-Tellez M) .J Clin Pathol. 2014 Jul;67(7):632-6.
&
1. Training during training - FRCPath
2. Training outside training – Fellowship / MSc
CRUK Accelerator
CRUK DIGITAL MOLECULAR PATHOLOGY & TRAINING NETWORK
SOUTHAMPTON
BELFAST
Manchester
UCL Neuro
Newcastle
£3.7M
Leicester
MARSDEN
Target 1
HETEROGENEITY AND CANCER IMMUNOLOGY
Target 2
DIGITAL PATHOLOGY & GENOMICS
Hamilton P (Salto-Tellez M). Oncotarget 2015 (accepted)
Target 3
DIGITAL NEUROPATHOLOGY
BACKGROUND 1
AN INTEGRATED MOL PATH MODEL
THE CLINICAL FELLOWSHIP PROGRAMME
MSc in Molecular Pathology
Taught Components – Weeks 1-14
Wk1: Induction
Wk2: Molecular Diagnostics
Wk3: Digital Pathology
Wk4: Low-throughput Technologies
Wk5: High-throughput Technologies
Wk6: Bioinformatics
Wk7: First Assessment
Wk8: Test Validation
Wk9: Accreditation procedures
Wk10: Laboratory QA & QC
Wk11: Biobanking
Wk12: Industrial Collaborations
Wk13: Clinical Trials
Wk14: Second Assessment
Sub-specialty Projects Weeks 15-40
UCL: Molecular Neuropathology
Southampton: Cancer Immunology
Manchester: Liquid Biopsy Pathology
Belfast: Biomarker Discovery & Validation
Newcastle: Clinical Trials
Belfast: Translational Bioinformatics
Leicester: Molecular Pathology of Lung Cancer
ICR/Belfast: Digital Molecular Pathology
Belfast: High-throughput Technologies
THE CLINICAL FELLOWSHIP PROGRAMME
MSc in Molecular Pathology
CRUK DIGITAL MOLECULAR PATHOLOGY & TRAINING NETWORK
Leicester
Lung Ca
Training
BELFAST
Manpower, IT,
Instrumentation
EPITHELIAL
INTERROGATION
Training
UCL Neuro
Manpower
Training
SOUTHAMPTON
Manpower, IT
Instrumentation
CANCER IMMUNE
INTERROGATION
Training
MARSDEN
Newcastle
Clin Trials
Training
Manchester
Liq Bx
Training
Manpower
WGS QA/QC
Training
&
&
WE ARE NOT TEACHING THE HISTOPATHOLOGISTS OF THE FUTURE
THERE IS NO CONFIDENCE THAT HISTOPATHOLOGISTS
WILL LEAD THE FUTURE OF DIAGNOSTICS, OR THE
FUTURE OF CLINICAL/APPLIED RESEARCH
?
The College needs to lead an urgent
review of the histopathology curriculum
JANUARY 2020
From:
Jared N Schwartz, MD, PhD, FCAP
Director, Pathology & Lab Medicine
Presbyterian Healthcare Charlotte,
Past President, College of American Pathologists
Tom Simms Memorial Fund

M Salto-Tellez

Transcription

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