clasificaciÓn molecular del cÁncer gÁstrico · ©2016 by american association for cancer...
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CLASIFICACIÓN MOLECULAR DEL CÁNCER GÁSTRICO Alberto Carmona Bayonas
Servicio de Hematología y Oncología Médica Hospital Universitario Morales Meseguer (Murcia)
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La tecnología molecular de alto rendimiento
permite caracterizar el comportamiento biológico
del cáncer con una precisión sin precedentes
Objetivos:
• Identificación de dianas terapéuticas
• Descubrimiento de nuevos biomarcadores
• Modelos pronósticos mixtos clínico-moleculares
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Más allá de Lauren: tres subtipos de tumor
gástrico con correlato génico preciso
Manish A. Shah et al. Clin Cancer Res 2011;17:2693-2701
Proximal Difuso
Distal no difuso
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Tan IB, Ivanova T, Lim KH et al. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology 2011; 141: 476–485, 485 e471–411
Los subtipos ‘intrínsecos’ de Tan et al.,
predicen la respuesta a quimioterapia
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Microarray-based tumor molecular profiling to direct choice of cisplatin plus S-1 or oxaliplatin plus S-1 for advanced gastric cancer: A multicentre, prospective, proof-of-concept phase 2 trial.
ASCO GI 2017
ORR
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Figure 3
Lei et al. Gastroenterology 2013 145, 554-565DOI: (10.1053/j.gastro.2013.05.010)
Identificación de 3 subtipos basados en fenotipo funcional con
posible respuesta específica a terapias
Sensible a
inhibidor de mTOR Sensible a
fluoropirimidinas
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Kaplan-Meier (K-M) curves of progression-free survival (PFS) of the entire cohort of patients with
metastatic gastric cancer treated with RAD001.
Kakoli Das et al. ESMO Open 2016;1:e000009
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Mutually exclusive and co-amplified genomic alterations
Niantao Deng et al. Gut 2012;61:673-684
Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.
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Deng et al. Gut 2012;61:673-684
Alteraciones genómicas de componentes de la vía RTK/RAS en cáncer gástrico
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Co-occurring oncogenic amplifications in ERBB2-amplified GE adenocarcinoma samples
Kim J, et al. Preexisting oncogenic events impact trastuzumab sensitivity in ERBB2-amplified gastroesophageal adenocarcinoma. J Clin Invest 2014; 124: 5145–5158
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Chia NY, Deng N, Das K et al. Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development. Gut 2015; 64: 707–719.
Redes de transcripción complejas
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AJ Bass et al. Nature 000, 1-8 (2014) doi:10.1038/nature13480
Subtipos moleculares del cáncer gástrico del TCGA
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Subdivisiones del cáncer de esófago
J Kim et al. Nature 1–9 (2017) doi:10.1038/nature20805
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AJ Bass et al. Nature 000, 1-8 (2014) doi:10.1038/nature13480
La secuenciación de nueva generación del TCGA permite
la descripción del paisaje mutacional del cáncer gástrico
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AJ Bass et al. Nature 000, 1-8 (2014) doi:10.1038/nature13480
Las alteraciones genéticas somáticas en RHOA y ARHGAP6/26
son recurrentes en tumores genómicamente estables
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AJ Bass et al. Nature 000, 1-8 (2014) doi:10.1038/nature13480
Alteraciones en número de copias en subtipo ‘CIN’
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AJ Bass et al. Nature 000, 1-8 (2014) doi:10.1038/nature13480
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Chen, Tao, Xiao-Yue Xu, and Ping-Hong Zhou. "Emerging molecular classifications and therapeutic implications for gastric cancer." Chinese journal of cancer 35.1 (2016): 49.
Implicaciones de la clasificación del TGCA para terapias individualizadas
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Setia, Namrata, et al. "A protein and mRNA expression-based classification of gastric cancer." Modern Pathology (2016).
Intentos de clasificación pragmática con técnicas
disponibles en práctica clínica rutinaria
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Cristescu, Razvan, et al. "Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes." Nature medicine 21.5 (2015): 449-456.
Clasificación molecular del ACRG
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Cristescu, Razvan, et al. Nature medicine 21.5 (2015): 449-456.
Predicción de OS y patrón recaída
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Stromal-based phenotypes differ in protein expression profiles and overall patient survival in
TCGA and ACRG gastric cancer cohorts.
Mark T. Uhlik et al. Cancer Res 2016;76:2573-2586
©2016 by American Association for Cancer Research
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Mark T. Uhlik et al. Cancer Res 2016;76:2573-2586; Kodama, Michiyo, et al. Clinical Cancer Research 14.22 (2008): 7205-7214.
Clasificación estromal con diferente
sensibilidad a antiangiogénicos
Herramienta incorrecta?
Sistema complejo
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Chia, N. Y., and P. Tan. "Molecular classification of gastric cancer." Annals of Oncology (2016): mdw040.
• Estudios en fase preliminar
• No definición de consenso
• Datos clínicos pendientes
• Efectos terapéuticos en
diferentes subclases
• Modelos útiles para selección de
terapia adyuvante
• Integración con variables
clásicas
• ¿Cómo implementarlas?
Reflexiones finales
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GRACIAS
Servicio de Hematología y Oncología Médica del Hospital Morales Meseguer de Murcia