javier puente, md, phd€¦ · 7 biomarcadores. 015 viejos paradigmas nuevos paradigmas un fármaco...
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01
Medicina de Precisión en OncologíaJavier Puente, MD, PhD
Hospital Universitario Clinico San CarlosMedical Oncology Department
Complutense UniversityAssociate Professor of Medicinejavier.puente@salud.madrid.org
02
Why we need apersonalizing medicine inoncology?
03
Classic chemotherapy agents: mechanism ofaction
04
Classic chemotherapy agents: toxicity profile
05
HumanGenomeProject
CeleraGenomics
2001
Manning G.-Science 2002
Hanahan & Weinberg, Cell 100, 2000“The Hallmark of Cancer”
Cell 20123 Hitos Oncológicos
06
Liquid
Nonsynonymous SomaticMutations by Tumor Type
Vogelstein B, et al. Science. 2013;339:1546-1558.
Non
syno
nym
ous
Mut
atio
nspe
r Tum
or (m
edia
n±
one
quar
tile)
15001000
250225500
200175150125100
755025
0
Col
orec
tal
(MSI
)Lu
ng(S
CLC
)Lu
ng(N
SCLC
)M
elan
oma
Esop
hage
al(E
SCC
)N
on-H
odgk
in’s
lym
phom
aC
olor
ecta
l (M
SS)
Hea
d an
d ne
ckEs
opha
geal
(EAC
)G
astri
cEn
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etria
l(e
ndom
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d)Pa
ncre
atic
aden
ocar
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Ova
rian
(hig
h-gr
ade
sero
us)
Pros
tate
Hep
atoc
ellu
lar
Glio
blas
tom
a
Brea
st
Endo
met
rial (
sero
us)
Lung
(nev
er s
mok
edN
SCLC
)C
hron
ic ly
mph
ocyt
icle
ukem
iaAc
ute
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loid
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Glio
blas
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Acut
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mph
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Med
ullo
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Rha
bdoi
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Mutagens Adult Solid Tumors Pediatric
07Clonal Evolution
Peter C. Nowell. The Clonal Evolution of Tumor Cell Populations. Science (1976).Douglas Hanahan & Robert A. Weinberg. Hallmarks of Cancer: The Next Generation. Cell (2011).Felipe De Sousa E Melo. Cancer heterogeneity - a multifaceted view. EMBO report (2013).
1. Genetic disease (of the
aged)
2. Evolving « system » (time
& space).
3. Heterogeneity !Clonal Evolution(stepwise acquisitionof mutations)
Epigenetics(DNA methylation,histone deacetylation )
Interaction(cell-cell, micro-enviroment)
08Clonal Evolution
Peter C. Nowell. The Clonal Evolution of Tumor Cell Populations. Science (1976).Douglas Hanahan & Robert A. Weinberg. Hallmarks of Cancer: The Next Generation. Cell (2011).Felipe De Sousa E Melo. Cancer heterogeneity - a multifaceted view. EMBO report (2013).
1. Genetic disease (of the
aged)
2. Evolving « system » (time
& space).
3. Heterogeneity !Clonal Evolution(stepwise acquisitionof mutations)
Epigenetics(DNA methylation,histone deacetylation )
Interaction(cell-cell, micro-enviroment)
4. Metabolism (almost) everywhere
09
Burrell, Mcgranahan, Bartek and Swanton Nature 2013
Intertumour Heterogeneity Intratumour HeterogeneityIntercellular Heterogeneity
Review principles of intratumour heterogeneity learned from Renal CancerApply methods to study cancer evolution in Non-Small Cell Lung Cancer
010
011
Medicina Personalizada enOncología:Un nuevo modelo en el tratamientodel cáncer, donde las decisionesterapéuticas son guiadas por losatributos moleculares de cada paciente.
Realmente: ¿son así las cosas?
eficacia (actividad).seguridad (toxicidad).eficiencia (costo).
Impacto
012
Quimioterapia (siglo XX)1960-2000 (1ª era): Tto del tumor
Un nuevo actor> Año 2.000: Dianas molecularesTto dirigido por estratos (2ª era)
EVOLUCIÓN DEL TRATAMIENTO MÉDICO DEL CÁNCER
1. Gen “driver”2. Tto con AM o ITK
Citotóxicos
Anti-Hormonas
IntegraciónCirugía+QT+RXT+AP
Sinbiomarcador
Conbiomarcador
Foco en el tipode Cáncer
Foco en el tipode Cáncer + Alt.Molecular
013
>200 enfermedadesDe 2 a 8 mutaciones “driver” por tumorDada su heterogeneidad involucra 140genes (driver genes)Afecta a 12 vías de señalización
Vogelstein B.- Cancer Genome Landscape. Science 29 March 2013
LANDSCAPESmall number of “mountains”:(genes altered in a high % of tumors)Larger number of “hills”(genes altered infrequentely)
El papel de las mutaciones:Los genes “driver” y los “pasajeros”
014Medicina Personalizada Oncología = molecular
Identificación de un gen driver
Desarrollo de un fármaco
Caracterización de biomarcador
Medicina Predictiva
Medicina de Precisión(alt.moleculares similares en varios tumores)
24 dianas
20 fármacos
7 biomarcadores
015
Viejos ParadigmasViejos Paradigmas Nuevos ParadigmasNuevos Paradigmas
Un fármaco para cadatumor
Un fármaco para cadatumor
Un fármaco para cadavía molecular alteradaUn fármaco para cadavía molecular alterada
016
Terapia basada en dianas enOncologia
017
Personalizing medicine…
Myth or reality
018
DeMatteo RP, et al. Lancet. 2009;373:1097-1104
Inhibition of KIT activated signaltransduction, causing reduced GISTproliferation or induction of apoptosis
ADPP
PP
IMAT IMAT
ADPP
PP
Y Substrate
Imatinib Mesylate
NN
N
HN
HN
NN
O CH3So3H
019Is Chemotherapy beneficial in NSCLC?
• “ The survival benefit of combinationchemotherapy to patients withadvanced NSCLC is controversial”(Rapp, JCO 1988; 6: 633-41)
• “ Previous controlled studiescomparing chemotherapy andsupportive care for treatment of thistype of cancer (NSCLC) have not givenconsistent results” (Cartei, JNCI 1993;85: 794-800)
• “Chemotherapy for NSCLC remainscontroversial” (Cullen, JCO 1999; 17:3188-94)
020
Historical context: chemotherapy reached atherapeutic plateau in early 2000s
Schiller, et al. NEJM 2002
021
Understanding of NSCLC subtyping has evolved in parallelwith treatment strategies
*Bronchioloalveolar carcinoma 6%, adenosquamous 2%; †Of all histologies.
1. Carney DN. N Engl J Med. 2002;346:126–28; 2. American Cancer Society. Lung Cancer (Small Cell). Available from http://www.cancer.org/cancer/lungcancer-smallcell/detailedguide/small-cell-lung-cancer-what-is-small-cell-lung-cancer. Accessed September 2014;3. Chansky K, et al. J Thorac Oncol. 2009;4:792-801; 4. Pao W, et al. Lancet Oncol. 2011;12:175–180;5. Molecular profiling of lung cancer. Available at http://www.mycancergenome.org/content/disease/lung-cancer. Accessed September 2014;6. American Cancer Society. Lung Cancer (Non-Small Cell); What is non-small cell lung cancer? Available at http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed September 2014; 7. Kim HS, et al. Lung Cancer. 2013;80:249–255; 8. The CancerGenome Atlas Research Network. Nature. 2012;489:519–525.
NSCLC>85%
SCLC<15%
Chemotherapy only (1990s)
Lung cancer as 2 main diseases1–2 Current NSCLC landscape4–8
Tumour histology and genotype influence treatment selection (From 2011)
Non-squamousNSCLC –
adenocarcinoma1,2
(~40%) †,3
†Squamous NSCLC4,5
(~2530%) †,3Squamous
49%
ADC36%
Large cell7%
Other*8%
Chemotherapy and targeted therapies (Early 2000s)
NSCLC: histology-based subtyping3
KRAS,25%
EGFR,15%
ALK, 7%BRAF, 3%PI3K,
3%MET,
3%HER2,2%
RET, 1%ROS1, 1%MEK1, 1%AKT1, 1%
VEGFR, 1%PDGFR, 1%NRAS, 1%
Unknown,35%
PIK3CA,16%
PTEN,15%
FGFR1,15%EGFR,
9%PDGFRA,
9%
DDR2,4%
BRAF,4%
HER2,4%
FGFR2,3%
HLA-A,3% Unknown,
18%
022
EGFR TKIs as first line therapy for EGFR mutated NSCLC: <br />afatinib (LUX-Lung 3) vs chemotherapy
Presented By Daniel Costa at 2014 ASCO Annual Meeting
EGFR TKIs as first line therapy for EGFRmutated NSCLC: afatinib (LUX-LUNG 3) vschemotherapy
023Combined OS analysis: mutation categories
James Chih-Hsin Yang, et al. ASCO 2014
1.0
0.8
0.6
0.4
0.2
0
Estim
ated
OS
prob
abilit
y
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51Time (months)
1.0
0.8
0.6
0.4
0.2
0
Estim
ated
OS
prob
abilit
y
Time (months)0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
236 230 223 217 202 192 173 160 145 131 117 90 50 38 22 6 1 0119 113 103 95 87 72 63 55 51 43 38 27 14 9 1 1 0 0
AfatinibChemo
No of patients183 181 167 154 141 128 111 91 80 70 64 51 27 20 11 3 0 093 86 82 78 75 69 61 55 50 40 32 25 20 14 9 4 1 0
AfatinibChemo
No of patients
Del19Afatinibn=236
Chemon=119
Median,months 31.7 20.7
HR (95%CI),p-value 0.59 (0.45–0.77),
p=0.0001
L858RAfatinibn=183
Chemon=93
Median,months 22.1 26.9
HR (95%CI),p-value 1.25 (0.92–1.71),
p=0.1600
024
Transforming activity of EML4-ALK: apotent oncogenic fusion
025
Development of crizotinib
026
PROFILE 1014 Phase III trial: RR
027
PROFILE 1014 Phase III trial: PFS (ITT population)
028
Immuno-Oncology: blocking CTLA-4 and PD-1 pathwayswith monoclonal antibodies
Tumour cell
- - -
CTLA-4 pathway blockade PD-1 pathway blockade
Anti-CTLA-4Anti-PD-1/PD-L1
+ ++
Anti-PD-1- - -
- --
Periphery Tumour microenvironment
T cell activation(cytokines, lysis, proliferation,
migration to tumour)
Dendriticcell ++ +
CTLA-4 = cytotoxic T-lymphocyte antigen-4; PD-1 = programmed cell death 1; PD-L1/2 = PD ligand 1/2; TCR = T cell receptor.
Adapted from Wolchock J, et al. Oral presentation at ASCO 2013 (Abstract 9012).
T cellT cell
+++CD28B7
B7
MHC TCRTCR
MHC
PD-L1PD-1
PD-L2PD-1
CTLA-4
029
030
FISH +IHC HER2 3+
Dennis Slamon 2001
Trastuzumab
Her-2 the paradigm of individualizingmedicine in breast cancer
031
Supervivencia librede enfermedad
87% 85%
67%75%
%
HR=0.48,2P=3x10-12
ACTH
ACT
Años tras la Randomización
Análisis combinadoNSABP-B31/NCCTG-N9831
18%
2005
032
Baselga J
Pertuzumab and TrastuzumabComplementary Mechanisms of action
033Final OS Analysis
Median follow-up 50 months (range 0–70 months)
33ITT population. Stratified by geographic region and neo/adjuvant chemotherapy.CI, confidence interval; Pla, placebo; Ptz, pertuzumab. 33
OS
(%)
0102030405060708090
100
0 10 20 30 40 50 7060Time (months)
HR 0.6895% CI = 0.56, 0.84
p = 0.0002
Ptz + T + DPla + T + D
12810422626831837102391179230289350
n at riskPtz + T + DPla + T + D
402406
40.8months
56.5months
Δ 15.7months
ESMO 2014
034
Nuevas dianas disponibles en Oncología:T.Sólidos (2015)
FÁRMACO (13) DIANAS (12) TUMOR (10) BIOMARCADOR (7)
Imatinib KIT, BCR-ABL, PDGFR GIST C-Kit, PDGFR
Trastuzumab HER-2 Mama HER 2
Pertuzumab HER-2 Mama HER-2
Lapatinib TKI HER2 Mama HER-2
Gefitinib EGFR TKI NSCLC EGFR
Erlotinib EGFR TKI NSCLC, Páncreas EGFR
Cetuximab EGFR MA CRC, Cabeza y Cuello K-Ras
Panitumumab EGFR MA CRC K-Ras, N-Ras
Temsirolimus mTOR RCC No
Everolimus mTOR RCC, Mama, NETs Pancreáticos No
Vandetanib EGFR,VEGF,RET Medular Tiróides No
Vemurafenib BRAF Melanoma B-Raf
Crizotinib EML4-ALK NSCLC ALK
035
Antiangiogénicos: T.Sólidos (2015)FÁRMACO (7) DIANAS (12) TUMOR (10) BIOMARCADORBevacizumab VGF-A CRC, Mama, NSCLC, Ovario,
GlioblastomaNO
Aflibercept VGF-A, VGF-B, PIGF CRC NOSorafenib VEGFR, PDGFR, KIT, RAF RCC, Hepatocarcinoma NO
Sunitinib VEGFR, PDGFR RCC, GIST, NETs Pancreático NO
Pazopanib VEGF, KIT, PDGFR RCC, Sarcomas NORegorafenib VEGFR, TIE2, PDGFR, RET,
KIT, RAFRCC NO
Cabozantinib VEGF, RET, MET, TRKB, TIE2 Medular de tiróides NO
Ramucirumab VEGFR2 Colon, Gástrico NO
036
Programa de biomarcadoresorientados a la terapéutica
• MSI (CRC)• RAS (CRC)• Her2 (Mama, Gástrico)• C-kit (GIST)• PDGFR (GIST)• EGFR (Pulmón)• ALK (Pulmón)• ROS (Pulmón)• BRAF (Melanoma)• BCRA1, BCRA2 (Mama, Ovario)
bioanalizador
secuenciación Sanger
Cobas
Pirosecuenciación
NSG (paneles)
037
Personalizing medicine…
Next steps:- redefining clinical trials- new techniques
038
Levi A.Garraway.- J Clin Oncol 2013
Aunque muchas alteraciones tienen especificidad tumoral, las mismaspueden encontrarse en baja frecuencia en otros muchos tumores
039
Biomarker-enrichment design
Presented By Martine Piccart-Gebhart at 2015 ASCO Annual Meeting
040
Slide 17
Presented By Martine Piccart-Gebhart at 2015 ASCO Annual Meeting
041
Slide 3
Presented By Martine Piccart-Gebhart at 2015 ASCO Annual Meeting
042
Slide 34
Presented By Martine Piccart-Gebhart at 2015 ASCO Annual Meeting
043
Heterogeneidad tumoral(modelo “darwiniano” evolutivo)
Gerlinger M et al. NEJM 2012
B Vogelstein et al. Science 2013;339:1546-1558
“La biopsia de un solo lugar es insuficiente”
044
Diaz L and Bardelli A.- JCO 2014
Los tumores son dinámicos
“La biopsia en un solo momento de laevolución del paciente es insuficiente”
“Concepto de la evolución clonal”
045
Slide 47
Presented By Martine Piccart-Gebhart at 2015 ASCO Annual Meeting
046The liquid biopsy
CTCs
Cell free DNA
MATRIX
SerumPlasma (EDTA)
Proteins
Metabolites
047
Daniel Haber; Victor Velculescu Cancer Discovery June 2014
New techniques under development
048
Giulia Siravegna and Alberto Bardelli.- Genome Biology 2015
Clinical applications of cell-free DNA analysis
049
Dancey JE, et al. Cell 2012;148:409-20
050
I-O
The future in oncology: the combinationsof multiple strategies
Drake C. Ann Oncol. 2012;23(suppl 8):viii41–viii46; Hannani D, et al. Cancer J 2011;17:351–358;Ménard C, et al. Cancer Immunol Immunother. 2008;57:1579–1587; Ribas A, et al. Curr Opin Immunol. 2013:25:291–296.
Liquid biopsy
051
Quimioterapia (siglo XX)1960-2000 (1ª era)
Dianas molecularesTto dirigido (> año 2000) (2ª era)
EVOLUCIÓN DEL TRATAMIENTO MÉDICO DEL CÁNCER
Tratamiento personalizado (3ª era)
Era genómica:-transcriptómica-proteinómica-epigenómica-farmacogenómica-otras ómicas
Genoma:1) tumoral2) huesped (GWAS)
052
Ben Solomon, Sidney 2013
053
THANK YOUJavier Puente, MD, PhD
Hospital Universitario Clinico San CarlosMedical Oncology Department
Complutense UniversityAssociate Professor of Medicine
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