Medicina de Precisión en Cáncer renal · PDL-1 is prognostic in RCC PDL-1 expression is...
Transcript of Medicina de Precisión en Cáncer renal · PDL-1 is prognostic in RCC PDL-1 expression is...
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Medicina de Precisión en Cáncer renal
Julio Lambea Sorrosal
Servicio de Oncología Médica
Hospital Clínico Lozano Blesa Zaragoza
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Definición de Medicina de Precisión
• Se trata de una aproximación a la prevención de padecer una enfermedad y laprobabilidad de respuesta a los tratamientos médicos que están condicionadospor nuestros genes y el ambiente al que estamos expuestos como resultado denuestro entorno y estilo de vida.
• La integración de los datos genómicos y de otras ciencias ómicas con el conjuntode datos clínicos del paciente y su entorno, permite una práctica clínica adaptada alas características individuales de cada paciente, en lo que se denomina MedicinaPersonalizada de Precisión (MPP).
US National Institutes of Health (NIH)
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CHALLENGES
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Algo más que localización tumoral
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Biopsias líquidas
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• Biomarcadores para inmunoterapia: PD-L1
• Transcriptomas tumorales distintos definen
la respuesta a tratamientos distintos
(atezolizumab-bevacizumab).
• Valor pronóstico de alteraciones genéticas
• Firmas génicas que orientan a inmunoterapia
CÁNCER RENAL
.
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PDL-1 is prognostic in RCC
PDL-1 expression is associated with:
➢Impaired antitumor immunity
➢More aggressive disease
➢High tumor grade
➢Shorter survival
In the COMPARZ trial PDL-1+ (HS<55) was associated with worse OS in both arms (p=0.003):
➢Pazopanib: 15.1 vs 36.6 months
➢Sunitinib: 15,3 vs 27,3 months
A combined analysis of the METEOR and CABOSUN positive PD-L1 expression in Tumor Cells (TCs) had poorer
PFS and OS.
Thompson, Proc NAtl Acad Sci 2004; Thompson, Clin Can Res 2007; Thopmson,
Cancer Res 2006; Frigola, Clin Can Res 2011; Choueiri, Ann Oncol 2014; Choueiri, Clin
Can Res 2015.
Choueiri, ESMO 2018.
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1L Combination Therapy Trials of Approved Agents
Presented By Rana McKay at 2019 ASCO Annual Meeting
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PDL-1 is also prognostic in TKI treated
Escudier ESMO 2017; Motzer NEJM 2018.
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Overall Survival in Key Subgroups
KEYNOTE-426: OS and PFS BY PDL-1
JAVELIN 101: PFS BY PDL-1
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IMMOTION 150:Transcriptome Map of Angiogenesis and Immune-
Associated Genes in RCC Tumors
PD-L1 IHC
IC0
IC1
IC2
IC3
Immune, Antigen Presentation
Myeloid Inflammation
3
-3
2
-2
-1
1
0
Angiogenesis
PD-L1 IHC
(e.g., CD34, KDR, VEGFA)
(e.g. CD8A, IFNG, PSMB8)
(e.g. IL6, PTGS2, IL8)
McDermott D, et al. IMmotion150 biomarkers: AACR 2017
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Angiogenesis gene signature: VEGFA, KDR, ESM1, PECAM1, ANGPTL4, CD34.Angiogenesis High: ≥ median expression, Angiogenesis Low: < median expression.
Atezolizumab + Bevacizumab Demonstrated Improved PFS vs Sunitinib in the AngiogenesisLow Subset
Angiogenesis Low
Atezo + bev (n = 43)
Atezo (n = 44)
Sunitinib (n = 45)
Angiogenesis High
Atezo + bev (n = 45)
Atezo (n = 42)
Sunitinib (n = 44)
HR (95% CI)
Angiogenesis Low Angiogenesis High
Atezo + bev vssunitinib
0.58 (0.35, 0.98) 1.36 (0.78, 2.36)
Atezo vs sunitinib 0.75 (0.45, 1.25) 1.45 (0.81, 2.60)
Angiogenesis
24
McDermott D, et al. IMmotion150 biomarkers: AACR 2017
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T-effector Gene Signature: CD8A, EOMES, PRF1, IFNG, CD274. High: ≥ median expression, Low: < median expression.
Addition of Bevacizumab to Atezolizumab is Associated With Improved Benefit in T-effectorHigh/Myeloid InflammationHigh
Subgroup
T-effectorHighMyeloidHigh
Atezo + bev (n = 20)
Atezo (n = 23)
Sunitinib (n = 24)
T-effectorHighMyeloidLow
Atezo + bev (n = 23)
Atezo (n = 23)
Sunitinib (n = 19)
25
McDermott D, et al. IMmotion150 biomarkers: AACR 2017
Myeloid Inflammation
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➢ Expression of genes of the VEGF-dependent angiogenesis pathway was significantly higher in IMDC good
risk patients compared with IMDC Intermediate/Poor patients
Tumor molecular characteristics in ccRCC patients with IMDC Good and
Intermediate/Poor risk.
Beuselinck, ESMO 2018.
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IMDC favorable risk: Angiogenic profile??
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NO SE OBSERVAN DIFERENCIAS
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Derivation of the 26-gene JAVELIN Renal 101 signature
Presented By Toni Choueiri at 2019 ASCO Annual Meeting
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Slide 12
Presented By Toni Choueiri at 2019 ASCO Annual Meeting
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PFS according to expression of select genes
Presented By Toni Choueiri at 2019 ASCO Annual Meeting
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• La Medicina de precisión puede generar una mejor
selección de los tratamientos y una disminución del
coste.
• Continúa la búsqueda de Biomarcadores de respuesta a
inmunoterapia: PD-L1…..
• Transcriptomas tumorales distintos y firmas génicas
definen la respuesta a tratamientos distintos
(atezolizumab-bevacizumab, avelumab-axitinib).
• Valor pronóstico de alteraciones genéticas
CONCLUSIONES
.
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GRACIAS