antonio llombart bosch prof emerito, univ valencia presidente...
TRANSCRIPT
![Page 1: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/1.jpg)
Antonio Llombart BoschProf Emerito, Univ Valencia
Presidente del Instituto Valenciano de Oncologia - IVOValencia, España
![Page 2: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/2.jpg)
-14,3 millones de nuevos casos de cáncer-8,9 millones de muertes -32,6 millones de personas viven con cáncer (supervivientes a los 5 años).
Incidencia estandarizada de cáncer por edades -25% mayor en los hombres que en las mujeres:
205 (hombres) y 165 (mujeres)
Estimated number of new cases in 2018, worldwide, all cancers, both sexes, all ages
Lung2 093 876 (11.6%)
Breast2 088 849 (11.6%)
Colorectum1 849 518 (10.2%)
Prostate1 276 106 (7.1%)
Stomach1 033 701 (5.7%)
Liver841 080 (4.7%)
Oesophagus572 034 (3.2%)
Other cancers8 323 793 (46%)
Total : 18 078 957
Data source: Globocan 2018
Graph product ion: Global Cancer
Observatory (ht tp:/ / gco.iarc.fr)
![Page 3: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/3.jpg)
![Page 4: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/4.jpg)
AUMENTO DE LA INCIDENCIA DE CANCER EN FUNCION DE LA EDAD
RANKING MUNDIAL :22/98 PAISES
![Page 5: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/5.jpg)
Basada en Síntomas
CohortesEstadística
PASADO PRESENTE
AlgoritmosIndividual
FUTURO?
Medicina intuitiva
Basada en la evidencia
Medicina de Precisión
![Page 6: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/6.jpg)
Análisis de sistemas complejos
Medicina de Precisión en Cáncer
Algoritmosinformáticos
Relación Médico - Paciente
Acceso al tumor en tiempo real
Análisis Moleculares Masivos
Big Data y machine learning
InvestigadoresEstructura de investigación adaptada a los nuevos retos
PatologiaPatologia
![Page 7: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/7.jpg)
1977-80sOncología
Clínica
2000-2020OncologíaMolecular
90s-2000OncologiaPatológica
CirugíaRadioterapia
Tratamiento Paliativo
Quimioterapia-Hodgkin-Testículo-Mama-Tto soporte
Tratamiento individualizado- Basado en alt. moleculares
PQTQT adyuvante
![Page 8: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/8.jpg)
Prevención primaria y secundaria
Desarrollo tecnológico
Conocimiento y comprensión de la biología del cancer
Genes implicados en inducción y desarrollo
Descubrimiento de múltiples nuevas dianas
Desarrollo de nuevos Fármacos.
![Page 9: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/9.jpg)
• LABORATORIO
– Inmunohistoquimia, FISH
– Biología molecular, genética,
microarray, NGS, etc.
IMAGEN
TAC, RM, PET
Radiología intervencionista
• CIRUGIA
• Cirugía robótica
• Cirugía laparoscópica
• Soporte
• RADIOTERAPIA
• IMRT, BT alta tasa
• Radiocirugia
• RT intraoperatoria
![Page 10: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/10.jpg)
SPEC - TC PET –TC DIGITAL
![Page 11: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/11.jpg)
![Page 12: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/12.jpg)
1967 a 2020
A.de GolgiRibosomas
cromatina
ADN
![Page 13: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/13.jpg)
©allbLA INVESTIGACION : FUNDAMENTO DEL DIAGNOSTICO
![Page 14: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/14.jpg)
Célula normal Célula tumoral
![Page 15: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/15.jpg)
La primera mutación en un cáncer humano fueidentificada en 1982 (oncogén H-RAS)
Desde 1982 a 2008, se identificaron, más de 400genes mutados en distintos tumores (Myc, Rb,p53, PTEN…)
Desde que se completó la secuencia delgenoma humano en 2001, se ha producido unavance espectacular en las tecnicas desecuenciación que estan permitiendosecuenciar genomas en poco mas de 48 horasy a un coste asequible.
Sin embargo ,los resultados de estos estudiosrevelan que los tumores son mucho máscomplejos de lo que habíamos imaginadoanteriormente.
![Page 16: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/16.jpg)
Mutación en los gametos
Mutaciones somáticas
Se producen en el tejido no germinal
No son heredables
Mutaciones somáticas(ej., mama)
Mutaciones germinales
Afectan a todas las células de la descencencia
Presentes en los gametos
Son heredables
Causan los síndromes de cáncer familiar
No heredables
![Page 17: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/17.jpg)
Esporádico70 - 80 %
Familiar
5 - 10 %
Hereditario 5-10 %Hereditario 5-10 %
???
![Page 18: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/18.jpg)
SI EL CÁNCER ES……….
UNA ENFERMEDAD DEL GENOMA
![Page 19: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/19.jpg)
• Mutación conductora (driver): Confiere a una célula una ventaja fundamental para su transformación neoplásica
• Mutación accionable: Aquella que además tiene un abordaje de tratamiento (mutaciones diana)
• Mutación pasajera: No confiere ninguna ventaja añadida sea la célula normal o maligna. Característicamente en las células tumorales estas mutaciones están muy presentes
![Page 20: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/20.jpg)
Nature 505 1914
49 “cancer driver genes” solapados entre germinales y somaticos
![Page 21: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/21.jpg)
CROSSTALKS BETWEEN EPIGENETICS AND METABOLISM IN CANCER DEVELOPMENT.
CC Wong, Y Qian, J Yu Oncogene (2017) 36, 3359–3374
EPIGENETICA Y METABOLOMICA
Juegan papel critico en la tumorogenesissosteniendo de modo coordinado la
proliferacion, metastasis y la pluripotencialidad de la celula cancerosa.
![Page 22: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/22.jpg)
©allb
![Page 23: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/23.jpg)
Cada cancer se comporta de modo individual
Existen numerosos genes y vias de señalizacion distintas alteradas en cada cancer
Se precisa de tecnicas computacionales para compreder la complejidad individual
L.Phen , APO-DECIDE EU PROYECT 2014
![Page 24: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/24.jpg)
![Page 25: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/25.jpg)
• La morfología provee la información mas
adecuada para el mejor manejo del
paciente oncológico
• La morfología no va a ser sustituida por
técnicas moleculares, por el contrario es su
vía de entrada.
![Page 26: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/26.jpg)
Paul Cézanne 1839-1906
![Page 27: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/27.jpg)
©allb
![Page 28: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/28.jpg)
![Page 29: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/29.jpg)
![Page 30: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/30.jpg)
![Page 31: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/31.jpg)
![Page 32: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/32.jpg)
![Page 33: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/33.jpg)
![Page 34: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/34.jpg)
Arch Pathol Lab Med. 2018;142:1383–1387A.Evans et al.,
Philips IntelliSite Pathology Solution
-WSI is similar to conventional light microscopy. -WSI systems is made up of 2 subsystems:
- image acquisition component (i.e. thescanner)
- workstation ( image viewing software, computer and display).
WSI: WHOLE SLIDE IMAGE
![Page 35: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/35.jpg)
1988 – 2001 Proyecto Genoma HumanoCoste: 3.000.000.000 $ (4 Genomas)
PLATFORMS : ILLUMINA / ION TORRENT
![Page 36: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/36.jpg)
Genomics at single cell resolution: allows the detection of rare mutationsand subclonal populations, enablingreconstruction of the evolutionaryhistory of a tumor, while also providinginsights into its true diversity
![Page 37: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/37.jpg)
DESCIFRANDO EL GENOMA DE LOS TUMORES
MEDIANTE NGS
La secuenciación masiva de los genomas de los tumores
humanos ha puesto de manifiesto que los tumores sólidos
avanzados (metastásicos) contienen cientos de mutaciones
que afectan a múltiples funciones celulares
![Page 38: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/38.jpg)
Cancers 2015, 7, 2023–2036
![Page 39: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/39.jpg)
AÑO 2000
![Page 40: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/40.jpg)
AÑO 2011
![Page 41: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/41.jpg)
SCIENCE 649 2255, 2015,
LA CARGA MUTACIONAL FACTOR DECISIVO EN LA EVOLUCION NEOPLASICA
![Page 42: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/42.jpg)
![Page 43: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/43.jpg)
![Page 44: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/44.jpg)
![Page 45: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/45.jpg)
Science 2013
![Page 46: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/46.jpg)
Nature 5 4 5 , 446 , 2 0 1 7Abbosh et al.,
![Page 47: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/47.jpg)
Errores de la segregacion cromosomica producenmicronucleos cuya fragmentacion en el citoplasma permite la diseminacion de DNA
genomico tumoral en la sangre circulante
2 5 ja n u a ry 2 0 1 8 | VO L 5 5 3 | NA T UR E | 4 6 7
![Page 48: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/48.jpg)
Genetic alterations that characterize paediatric cancers reveal keydifferences from adult cancers, and point to ways of optimizing therapeuticapproaches to combating cancer in children
P Bandopadhayay , M Meyerson - N at u r e 5 5 5, 3 1 6, 2 0 1 8
![Page 49: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/49.jpg)
ultramutators
hypermutators
pediatric high
Germline variants:-Small mutation plusstructural/copy-number variant
Structural variants:-Hyperdiploidy and Chromothripsis-Linked to TP53 mutation andmutational signatures children adults
Nature 555. 321. 2018
![Page 50: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/50.jpg)
![Page 51: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/51.jpg)
Nature 2017
![Page 52: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/52.jpg)
Nature, 555, 469 ,2018
![Page 53: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/53.jpg)
NATURE, 556 51 2018
![Page 54: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/54.jpg)
LA “ONCOLOGIA DE PRECISION” DEFIENDE QUE LOS MARCADORES MOLECULARESPRESENTES EN UN TUMOR Y DETECTADOS MEDIANTE NGS PUEDEN PREDECIR LARESPUESTA A TERAPIAS DIRIGIDAS INDEPENDIENTE DEL TIPO HISTOLOGICO DENEOPLASIA
SIN EMBARGO SE DEBE TENER EN CONSIDERACION:
-LA COMPLEJIDAD BIOLOGICA DE CADA PACIENTE-LA UBIQUA VARIABILIDAD DF LA PROPIA TECNOLOGIA-LA HETEROGENEIDAD INTRATUMORAL E INTERTUMORAL-NUEVAS MUTACIONES EN EL TRANSCURSO DE LA EVOLUCION TUMORAL
¿ DEBE BASARSE LA DECISION CLINICA DE UNA TERAPIA ONCOLOGICA EN UNA SEQUENCIA DE DATOS GENICOS?
¿NO ES OBSTACULO PARA UN DISEÑO RACIONAL DE UN ENSAYO CLINICO ?
![Page 55: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/55.jpg)
METODOS PARA CARACTERIZAR PACIENTES Y TUMORES DE MODO INDIVIDUALIZADO
Recursos computacionales y herramientas capaces de almacenar,procesar y analizar “NGS data” mediante potentes métodoscapaces de caracterizar pacientes y tumores individualmentepudiéndolos tratar y comparar en grupos o de modoindividualizado
![Page 56: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/56.jpg)
Los ensayos clinicos deben ser diseñados en base a toda lainformacion individualizada del paciente con criteriosmoleculares e histologicos incluyendo una estratificacionimplementada con algoritmos computacionales.
COMPREHENSIVE COLLABORATIVE EFFORTS
• -ICGCmed (http://icgcmed.org/) CancerLinQ. (I-SPY 2, BATTLE-2) • -NCI-MATCH, IMPACT 2 :targeted NGS gene panels in advanced solid tumours
-ALCHEMIST and Lung-MAP: alterations in a specific tumour type • -CREATE 37: specific molecular alteration across tumour types• -National Cancer Institute ‘Exceptional Responders’ study, NCT02243592• -ASCO/TAPUR: advanced cancer WITH potentially actionable genomic variants
![Page 57: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/57.jpg)
GENIE 6.1-public 2019-07-13
![Page 58: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/58.jpg)
THE AACR PROJECT GENOMICS, EVIDENCE, NEOPLASIA, INFORMATION, EXCHANGE (GENIE) : A MULTI- PHASE, MULTI-YEAR, INTERNATIONAL DATA-SHARING PROJECT THAT AIMS TO
CATALYZE PRECISION CANCER MEDICINE.
Contributing Centers: Each Center will provide a particular Genomic Profile
![Page 59: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/59.jpg)
![Page 60: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/60.jpg)
![Page 61: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/61.jpg)
MOLECULAR TUMOUR BOARD
Medical Oncologists
Histopathologists
Radiologists
Radiotherapeutics
Molecular biologist
Residents from Oncology
![Page 62: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/62.jpg)
Precision Pathology as Part of Precision Medicine: Are We Optimizing Patients’ Interests
in Prioritizing Use of Limited Tissue Samples?
Shannon J. McCall, MD and Sarah M. Dry, MD
American Society of Clinical Oncology: ascopubs.org ,august2019
WHERE ARE WE AS PATHOLOGISTS ????
![Page 63: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/63.jpg)
• Pathologists are the caretakers of all tissueremoved during clinical care
• By law, we are the custodians of diagnostictissues, and as such we must comply withlegal regulations covering the preservation
and use of the tissue
American Society of Clinical Oncology: ascopubs.org ,august2019
![Page 64: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/64.jpg)
.
More biologic information can be extracted from tissue, butthere is less tissue available for testing: the majority of tissue-based assays are performed on formalin-fixed, paraffin-embedded (FFPE) tissues:-DNA sequencing-RNA and fusion protein by in situ hybridization-immunohistochemistry to detect protein expression.
There is less diagnostic tissue available because:-smaller biopsies-less invasive sampling:core biopsies, fine-needle aspiration-earlier identification of small tumors-successful neoadjuvant treatments
American Society of Clinical Oncology: ascopubs.org ,august2019
![Page 65: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/65.jpg)
• Many cases have only limited amounts of tissue available afterstandard-of-care testing.
• Submitting material for clinical trials will exhaust the remainingbiopsy sample.
• Fulfilling the request: will violate regulations to retain theblocks for 2 to 10 years (USA:CAP, CLIA recommendations )
• Refusing the request: the patient will not qualify for the study,which will deny therapy with the potential to extend theirsurvival and/or improve their quality of life.
American Society of Clinical Oncology: ascopubs.org ,august2019
![Page 66: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/66.jpg)
• Pathology departments should review andupdate their protocols for processing smallbiopsy and cytology samples to maximize theirpotential downstream utility.
BUT HOW TO DO THAT???
American Society of Clinical Oncology: ascopubs.org ,august2019
![Page 67: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/67.jpg)
• Separation of multiple biopsy cores intoindividual paraffin blocks.
• Saving tissue (frozen biobanking) for researchand retention of representative diagnosticmaterial.
• Prevents wasting tissue in microtome processing
• Follow established protocols, particular for eachtumor type: breast, lung, colon, melanoma…
American Society of Clinical Oncology: ascopubs.org ,august2019
![Page 68: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/68.jpg)
Cancer biology as revealed by the research autopsy C. A. Iacobuzio- Donahue et al.Nature Reviews Cancer 9, sept.2019
Autopsy is an underusedapproach to investigate thefundamental questions in cancerbiology and holds tremendouspotential for precision medicine strategies
![Page 69: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/69.jpg)
C-KIT DOG1HE
![Page 70: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/70.jpg)
Extracellular domain
Cell membrane
Juxtamembrane domain
Tyrosine kinase domain
TK1 domain
TK2 domain
Kinase insert
Regulation of dimerization
Ligand-binding domain
KIT ex 9 / PDGFRa ex 10
KIT ex 11 / PDGFRa ex 12
KIT ex 13 / PDGFRa ex 14
KIT ex 17 / PDGFRa ex 18
![Page 71: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/71.jpg)
• 2-phenylamin-pirimidine phosphate
inhibitor of tyrosine kinase in ABL, BCR-
Abl, PDGF and c-KIT.
• With a structure similar to the ATP
binding site.
•Oral administration.
• 400 mg per day.
• 1 year in the case of response or
stabilization of the disease.
C29H31N7O•CH4SO3
• CH3SO3H
C29H31N7O•CH4SO3
• CH3SO3H
Membrane
CytoplasmPP
PP
PP
PP
PP PP
PP
PP
PPPP
PPPP
PP
PP
PPPP
PPPP
PPPPPPPP PPPPPPPP
Apoptosis
Proliferation, Inhibition of
apoptosis
ATP
STI571
Apoptosis
![Page 72: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/72.jpg)
Before Imatinib 4 weeks after starting with Imatinib
Sep 7, 2000 Sep 21, 2000
![Page 73: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/73.jpg)
Primary KIT, PDGFRA or NF1: initiating an oncogenic driver followed by accumulation of chromosomal aberrations, withputative tumor suppressor genes, and cell cycle dysregulating events. Metastatic GISTs develop treatment resistancethrough evolving TKI-resistant subclones, additional secondary KIT or PDGFRA mutations.
IM Schaefer et al., Adv Anat Pathol 24,259,2017
-MAX -Myc ass.factor X-DMD -gene of dystrophin-Loss of p16,p53,Rb1genes
RIPRETINIB TURNS OFF RESISTANCE TO GIST MUTANTS (Cancer Cell 35,738,2019)
![Page 74: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/74.jpg)
Journal of Molecular Diagnostics, Vol. 21, No. 4, July 2019
![Page 75: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/75.jpg)
TRK receptor tyrosine kinases,activating neurotrophins and themajor signal transduction pathways:
(A) the genomic structures of NTRK1,NTRK2, and NTRK3, with the size ofeach gene
(B) the ETV6 and NTRK3 gene fusionand the resultant constitutively activefusion protein
![Page 76: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/76.jpg)
Secretory carcinoma of the breast:ETV6-NTRK3 gene fusion and activation of neurotrophin 3 inducing malignant tranformation
Bayer 2019 https://global.trkcancer.com/global/imprint/
![Page 77: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/77.jpg)
![Page 78: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/78.jpg)
Hong DS, et al. Abstract CT008. Presented at: American Association for Cancer ResearchAnnual Meeting; April 16-20, 2016; New Orleans.
Detection of Tumor NTRK Gene Fusions to Identify Patients Who May
Benefit from Tyrosine Kinase (TRK) Inhibitor TherapySusan J. Hsiao,* Ahmet Zehir,y Anthony N. Sireci,z and Dara L. Aisnerx TH
Journal of Molecular Diagnostics, Vol. 21, No. 4, July 2019
![Page 79: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/79.jpg)
![Page 80: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/80.jpg)
RE + : Dos subtipos
Luminal A
Luminal B - C
RE - : Dos subtipos
Her2 +
Basal-like – Normal-like
Diferente biología y
comportamiento
Perou C et al: 2000
ASCO 2015
![Page 81: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/81.jpg)
Oncotype Dx1,2 Mammaprint5PAM504Endopredict3
16+5 genes 70 genes50 genes8 genes
Utiles en Ca Mama Luminal (RE[+], HER2[-]) estadios I - II
Valor Pronostico: Riesgo de recaida Valor Predictivo: Beneficio de la Quimioterapia
Bajo Riesgo Molecular: 99% SLED a 5 años
Alto Riesgo Clínico pero Bajo Molecular: No hay
beneficio de la QT
![Page 82: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/82.jpg)
QT
QT
TERAPIAHORMONAL
TERAPIA ANTI-HER2
QUIMIOTERAPIA
ENFERMEDAD LUMINAL
ENFERMEDAD HER2
CM TRIPLE NEGATIVO
T ANTI-HER2ENFERMEDAD LUM / HER2
TH QT
ESTADIO I
ESTADIO II
ESTADIO IV
ESTADIO III
CURATIVO
PALIATIVO
CURATIVO
PALIATIVO
PRONÓSTICO - TNM PREDICCIÓN - Fenotipos
![Page 83: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/83.jpg)
-Defects in DNA damage repair-TP53 mutations-Activation of PI3K pathway-EGFR amplification/mutations-Activation of RAF-MEK signaling- Rb loss
![Page 84: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/84.jpg)
Tasas Mortalidad por Cáncer de mama ajustada por 100,000 habitantesFuente: Instituto Salud Carlos III
![Page 85: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/85.jpg)
![Page 86: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/86.jpg)
![Page 87: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/87.jpg)
![Page 88: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/88.jpg)
Skoulidis F1, Heymach JV Nat Rev Cancer. 2019 Sep;19(9):495-509
TUMOR PRIMARIO METASTASIS
![Page 89: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/89.jpg)
N AT U R E | VO L 5 5 3 | 2 5 January 2 0 18
Alterations in targetable oncogenicpathways in LUAD and LUSC
![Page 90: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/90.jpg)
![Page 91: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/91.jpg)
0
2000
4000
6000
8000
10000
12000
1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006
Total
Hombres
Mujeres
PRIMERA CAUSA DE MUERTE POR CANCER EN ESPAÑA
![Page 92: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/92.jpg)
©allb
![Page 93: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/93.jpg)
Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer Rodrigo Dienstmann et al.NATURE REVIEWS CANCER 17 2017 79
MSI: INESTABILIDAD DE MICROSATELITES CIN: INESTABILIDAD CROMOSOMICA
![Page 94: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/94.jpg)
NATURE REVIEWS CANCER 17,2017,87
![Page 95: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/95.jpg)
1900
1949
1977
1985
2000
2010
2017
<5%
25%
40%
43%
45%
53%
59%
Cada año se curan mas pacientes
Dos de cada tres pacientes con
cáncer viven más de cinco años tras
el diagnóstico de un cáncer
– Prevalencia: 1.500.000
2019 63%
![Page 96: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/96.jpg)
CA: A Cancer Journal for Clinicianspages n/a-n/a, 17 JAN 2013 DOI: 10.3322/caac.21166http://onlinelibrary.wiley.com/doi/10.3322/caac.21166/full#fig6
![Page 97: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/97.jpg)
• 2014
– 8 nuevos fármacos aprobados
– 4 indicaciones nuevas de fármacos aprobados
• 2015
– 8 nuevos fármacos aprobados
– 12 indicaciones nuevas de fármacos aprobados
• 2016
– 20 nuevos fármacos aprobados en 12 tumores
–13 nuevas indicaciones
![Page 98: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/98.jpg)
• La clasificación molecular está
convirtiendo a muchos tipos de
cánceres en enfermedades raras
- Subtipos moleculares (1%-5%)
Beneficiar mucho…….. a pocos pacientes
![Page 99: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/99.jpg)
Hanahan 2011
![Page 100: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/100.jpg)
• Elevado numero de respuestas
– 20% de resistencias primarias y 20-40 % largos supervivientes
• Mas eficaces con:
– mayor sobreexpresión de PDL-1
– mayor carga mutacional
• La combinación de fármacos mas activa pero mas toxica
– con QT ó RT
– Con IT: anti PDL1 + anti CTLA4
![Page 101: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/101.jpg)
PD-1 inhibitorsPD-L1 inhibitorsCAR-T-cells
Meng X, et al. Cancer Treat Rev. 2015;41:868-76. Guan J, et al. Arch Pathol Lab Med. 2017;141:851-861.Gong J, et al. J Immunother Cancer. 2018;6:8-18
James P Allison Tasuku Honjo
PREMIOS NOBEL MEDICINA 2018
![Page 102: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/102.jpg)
Inflamed tumors(TIL+, PD-L1+)
Tolerant tumors(TIL+, PD-L1-)
PD1/PDL1monotherapy
PD-1/PD-L1 combination therapy
Anti-VEGFCytokines IDO inhibitors inhibitors
Noninflamed tumors(TIL-, PD-L1-)
PD-1/PD-L1 combination therapy
VaccinesEngineered T cells
![Page 103: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/103.jpg)
Atezolizumab
![Page 104: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/104.jpg)
J G. Reiter et al., An analysis of genetic heterogeneity in untreated cancersNature Reviews Cancer volume 19, pages639–650 (2019)
81% NEOPLASIAS SON TUMORES SOLIDOS 57% SON RESECABLES MEDIANTE CIRUGIA
![Page 105: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/105.jpg)
CIRUGIA ROBOTICA DE PRECISION: EQUIPO DA VINCI Xi
![Page 106: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/106.jpg)
High-precision radiotherapy for local tumour control withmolecular targeted drugs and immunotherapies forsystemic control provides a powerful opportunity toimprove cancer outcomes
www.thelancet.com/oncology Vol 19 May 2018
![Page 107: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/107.jpg)
-2014: the average cost of a new orally administered cancermedicine exceeded $135,000 a year — up to six times the cost ofsimilar drugs approved in the early 2000.
-2017 : a one-time cost of $475,000 per patient for a personalizedcell-based therapy for childhood leukaemia.
8 M A R C H 2 0 1 8 | VO L 5 5 5 | N AT U R E | S 2 9
![Page 108: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/108.jpg)
-In recent years a growing body of data have been produced regarding the
molecular biology landscape of tumors
-However, this large amount of new data has only been translated into alimited number of practical innovations with clinical value for precisiononcology
-The next step must be based on an integrative approach of molecularprofiles, being read in the light of their histological features
-Within this new scenario, pathology will continue to play a major role incancer diagnosis, prognosis and treatment.
OECI MEETING BARI 2019
![Page 109: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/109.jpg)
-Our clinical colleagues want increasingly detailed, reliable
and relevant information from pathology specimen analyses
that can be translated into optimal treatments
-As pathologists we must re-educate and re-invent ourselves if
we are to maintain the central role we now play as the
ultimate arbiters of disease treatment
![Page 110: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/110.jpg)
“Every anatomical change is a material one as well, but is
every material change, therefore, also anatomical? Can it not
be molecular? Can a deep reaching molecular alteration of
the inner composition of matter not take place with the
preservation of its inner form and outer appearance... One
can have the greatest respect for morphological and
histological studies… but must one proclaim them, therefore,
the only ones to be pursued, the ones of exclusive
significance?”
![Page 111: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/111.jpg)
![Page 112: Antonio Llombart Bosch Prof Emerito, Univ Valencia Presidente …files.sld.cu/scap/files/2019/11/PATOLOGIA-DE-PRECISION... · 2019-11-20 · A.Evans et al., Arch Pathol Lab Med. 2018;](https://reader033.vdocuments.co/reader033/viewer/2022041602/5e319dc833cfa4019d55e4a5/html5/thumbnails/112.jpg)
500 AÑOS DE LA FUNDACION DE LA CIUDAD DE LA HABANA