Post on 26-Sep-2018
BRAF:
MÁS ALLÁ DEL
TRATAMIENTO DEL
MELANOMA MALIGNO
Juan Carlos Torrego García
Oncología Médica. H.U. Río Hortega. Valladolid
INTRODUCCIÓN
INTRODUCCIÓN
1.- Concepto BRAF
2.- Importancia BRAF
3.- BRAF en distintos tumores
4.- Fármacos antiBRAF
5.- Mecanismos de resistencia
6.- Conclusiones
….FAMILIA RAF QUINASA….
Rahman et al. Exper and Mol Path 2014. B-Raf mutation: A key player in molecular biology of cancer
A-RAF
B-RAF
C-RAF
…. y BRAF….
Rahman et al. Exper and Mol Path 2014. B-Raf mutation: A key player in molecular biology of cancer
A-RAF
B-RAF
C-RAF
….B-RAF
Rahman et al. Clin Reviews in Oncology/Hematology 2014. BRAF inhibitors: From laboratory to CT
•FRECUENCIA
•CARACTERÍSTICAS PROPIAS
•IMPLICACIONES TERAPEÚTICAS
Importancia BRAF en Cáncer
Davies et al. Nature 2002. Mutations of the Braf gene in human cancer
Mutaciones BRAF en Cáncer
Mutaciones BRAF en Cáncer
TIPO TUMORAL % (Aprox.)
TODOS 7-8%
MELANOMA 40-60%
TIROIDES (Papilar) 45%
COLORECTAL 5-15%
OVARIO (Seroso bajo grado/border line)
35%
SNC (Astrocitomas pilocíticos) 60-80%
PULMÓN NO MICROCÍTICO 1-3%
HEPATO/BILIAR 0-22% (pocos estudios)
LEUCEMIA CÉLULAS PELUDAS 100% (pocos estudios)
Pakneshan et al. Pathology 2013. Clinicopathological relevance of BRAF mutations in human cancer
Mutaciones BRAF en Cáncer
TIPO TUMORAL % (Aprox.)
TODOS 7-8%
MELANOMA 40-60%
TIROIDES (Papilar) 45%
COLORECTAL 5-15%
OVARIO (Seroso bajo grado/border line)
35%
SNC (Astrocitomas pilocíticos) 60-80%
PULMÓN NO MICROCÍTICO 1-3%
HEPATO/BILIAR 0-22% (pocos estudios)
LEUCEMIA CÉLULAS PELUDAS 100% (pocos estudios)
Pakneshan et al. Pathology 2013. Clinicopathological relevance of BRAF mutations in human cancer
TIPO MUTACIÓN
V600E / V600K
V600E
V600E
V600E
V600E / KIAA1549 / BRAFins598T
V600E / G469A
V600E
V600E
Inhibidores BRAF
FÁRMACO TIPO DIANA TIPO EC
VEMURAFENIB I V600E / BRAFWT / CRAF Melanoma III
DABRAFENIB I V600E / BRAFWT / CRAF Melanoma III
LGX 818 I V600E Melanoma I
PLX4720 I V600E / BRAFWT / CRAF Preclinical
SB-590885 I V600E / BRAFWT / CRAF Preclinical
SORAFENIB II V600E / BRAFWT / CRAF RET/cKIT/VEGF/FGF/Flt3
Hepatocarcinoma Renal Tiroides
III III III
REGORAFENIB II V600E / BRAFWT / CRAF RET/KIT/VEGF/FGF/PDFG
Colorectal GIST
III III
XL-281 II V600E / BRAFWT / CRAF Colorectal I/II
RAF265 II V600E / BRAFWT / CRAF Ckit/VEGF/PDGF
Melanoma II
ARQ736 ¿? V600E / BRAFWT / CRAF Sólidos I
Inhibidores BRAF
FÁRMACO TIPO DIANA TIPO EC
VEMURAFENIB I V600E / BRAFWT / CRAF Melanoma III
DABRAFENIB I V600E / BRAFWT / CRAF Melanoma III
LGX 818 I V600E Melanoma I
PLX4720 I V600E / BRAFWT / CRAF Preclinical
SB-590885 I V600E / BRAFWT / CRAF Preclinical
SORAFENIB II V600E / BRAFWT / CRAF RET/cKIT/VEGF/FGF/Flt3
Hepatocarcinoma Renal Tiroides
III III III
REGORAFENIB II V600E / BRAFWT / CRAF RET/KIT/VEGF/FGF/PDFG
Colorectal GIST
III III
XL-281 II V600E / BRAFWT / CRAF Colorectal I/II
RAF265 II V600E / BRAFWT / CRAF Ckit/VEGF/PDGF
Melanoma II
ARQ736 ¿? V600E / BRAFWT / CRAF Sólidos I
Mutaciones BRAF en Cáncer
TIPO TUMORAL % (Aprox.)
TODOS 7-8%
MELANOMA 40-60%
TIROIDES (Papilar) 45%
COLORECTAL 5-15%
OVARIO (Seroso bajo grado/border line)
35%
SNC (Astrocitomas pilocíticos) 60-80%
PULMÓN NO MICROCÍTICO 1-3%
HEPATO/BILIAR 0-22% (pocos estudios)
LEUCEMIA CÉLULAS PELUDAS 100% (pocos estudios)
Pakneshan et al. Pathology 2013. Clinicopathological relevance of BRAF mutations in human cancer
TIPO MUTACIÓN
V600E / V600K
V600E
V600E
V600E
V600E / KIAA1549 / BRAFins598T
V600E / G469A
V600E
V600E
Mutaciones BRAF en Cáncer
TIPO TUMORAL % (Aprox.)
TODOS 7-8%
MELANOMA 40-60%
TIROIDES (Papilar) 45%
COLORECTAL 5-15%
OVARIO (Seroso bajo grado/border line)
35%
SNC (Astrocitomas pilocíticos) 60-80%
PULMÓN NO MICROCÍTICO 1-3%
HEPATO/BILIAR 0-22% (pocos estudios)
LEUCEMIA CÉLULAS PELUDAS 100% (pocos estudios)
Pakneshan et al. Pathology 2013. Clinicopathological relevance of BRAF mutations in human cancer
TIPO MUTACIÓN
V600E / V600K
V600E
V600E
V600E
V600E / KIAA1549 / BRAFins598T
V600E / G469A
V600E
V600E
BRAF y MELANOMA
•INCIDENCIA: 40-60%
•TIPO MUTACIÓN:
- V600E: 65-75%
- V600K: 20-30%
- Otras: 5%
• CLÍNICO/AP:
- Exposición intermitente al sol > crónica
- Edades más jóvenes < 55 años
- Cutáneo (40-60%) > Mucosas (7%) > Uveal (0%)
- Tronco (60-65%) > Extremidades -CyC (45-50%) > Mano/pie (28%)
- Extensión superficial (63%), nodular (50%), léntigo maligno
(20%), lentiginoso acral (13%).
- AP: Engrosamiento epidermis-incremento melanocitos intra-
epidérmicos, mayor pigmentación, mayor infiltración linfocitaria
Long et al. JCO 2011. Prognostic and clinicopathologic associations of BRAF in metastatic melanoma
BRAF y MELANOMA
BRAF y MELANOMA
Long et al. JCO 2011. Prognostic and clinicopathologic associations of BRAF in metastatic melanoma
RAF
MEK
RTK
ERK
RAS
BRAF y MELANOMA
Vemurafenib Dabrafenib
BRAF Y MELANOMA: VEMURAFENIB
Mc Arthur et al. Lancet Oncol 2014. Safety and efficacy vemurafenib in BRAF V600E and BRAF
V600K mutation positive melanoma (BRIM3): a extended follow-up of a phase III study
BRAF Y MELANOMA: VEMURAFENIB
Mc Arthur et al. Lancet Oncol 2014. Safety and efficacy vemurafenib in BRAF V600E and BRAF
V600K mutation positive melanoma (BRIM3): a extended follow-up of a phase III study
BRAF V600E BRAF V600K
Dacarbazine Vemurafenib Dacarbazine Vemurafenib
Median OS
(months)
10.0
(95% CI: 8.0, 14.0)
13.3
(95% CI:11.9, 14.9)
7.6
(95% CI: 6.1, 16.6)
14.5
(95% CI: 11.2, NA)
Median
PFS
(months)
1.6 6.9 1.7 5.9
Best ORR
(%)
11 59 4 45
OS, overall survival; PFS, progression-free survival; ORR, overall response rate; NA, not available (cannot be reliably estimated).
BRAF Y MELANOMA: VEMURAFENIB
Mc Arthur et al. Lancet Oncol 2014. Safety and efficacy vemurafenib in BRAF V600E and BRAF
V600K mutation positive melanoma (BRIM3): a extended follow-up of a phase III study
BRAF Y MELANOMA: DABRAFENIB
Hauschild et al. Lancet 2012. ASCO 2013. Dabrafenib in BRAF-mutated metastasic melanoma: a phase III RCT
BRAF y MELANOMA
Chapman et al. NEJM 2011. Improved survival with vemurafenib in melanoma BRAFV600E mutation
Hauschild et al. Lancet 2012. Dabrafenib in BRAF-mutated metastasic melanoma: a phase III RCT
Vemurafenib
Dafrafenib
RAF
MEK
RTK
ERK
RAS
BRAF y MELANOMA
Vemurafenib Dabrafenib
Trametinib
BRAF Y MELANOMA: DABRAFENIB+TRAMETINIB
Flaherty et al.NEJM 2012.Combined BRAF and MEK Inhibition in Melanoma BRAF V600 Mutated
BRAF Y MELANOMA: DABRAFENIB+TRAMETINIB
Daud A Oral Presentation SMR 2013
TOXICIDAD: VEMURAFENIB
Chapman et al. NEJM 2011. Improved survival with vemurafenib in melanoma BRAFV600E mutation
Vemurafenib, n=337 Dacarbazine, n=287
Adverse events All Grade 3 Grade ≥4 All Grade 3 Grade ≥4
Arthralgia 56 6 – 4 1 –
Rash 41 9 – 2 – –
Fatigue 46 3 – 35 2 –
Photosensitivity 41 4 – 5 – –
LFTs 26 10 1 6 2 –
Cutaneous SCC 19 19 – <1 <1 –
Keratoacanthoma 11 10 – <1 <1 –
Skin papilloma 28 <1 – <1 <1 –
Nausea 38 2 – 45 2 –
Neutropenia <1 – <1 12 6 3
TOXICIDAD: DABRAFENIB
Hauschild et al. Lancet 2012. ASCO 2013. Dabrafenib in BRAF-mutated metastasic melanoma: a phase III RCT
TOXICIDAD: DABRAFENIB+TRAMETINIB
Flaherty et al.NEJM 2012.Combined BRAF and MEK Inhibition in Melanoma BRAF V600 Mutated
TOXICIDAD
Anforth et al. The Lancet Oncology 2013. Cutaneous toxicities of RAF inhibitors
BRAF y CA. TIROIDES
•INCIDENCIA: 45% en Carcinoma Papilar Tiroideo (CPT)
•TIPO MUTACIÓN: V600E (posible papel iniciador en CPT)
•DIAGNÓSTICO:
- DD con patología benigna / otros carcinomas. Valor marginal (sobre PAAF…)
- Tall cell variante > convencional > variante folicular
- AP: Crecimiento infiltrativo, cels. eosinofílicas, no encapsulados
- Extensión extratiroidea, afectación ganglionar, TNM más avanzado
- Mayor riesgo persistencia/recurrencia
•PRONÓSTICO: “Should be considered a poor prognostic marker”
•PREDICTIVO: - Sugiere peor respuesta a radioIo (pérdida de captación)
- NO valor predictivo de respuesta a terapias biológicas
BRAF y CA. TIROIDES
Kim et al. Cancer 2012. The association of the BRAF(V600E) mutation with prognostic factors and
poor clinical outcome in papillary thyroid cancer: a meta-analysis.
Invasión extratiroidea Afectación ganglionar
BRAF y CA. TIROIDES
Kim et al. Cancer 2012. The association of the BRAF(V600E) mutation with prognostic factors and
poor clinical outcome in papillary thyroid cancer: a meta-analysis.
TNM avanzado Persistencia/recurrencia
BRAF y CA. TIROIDES
Kim et al. Cancer 2012. The association of the BRAF(V600E) mutation with prognostic factors and
poor clinical outcome in papillary thyroid cancer: a meta-analysis.
TNM avanzado Persistencia/recurrencia
Conclusion: “….BRAF mutation V600E should be
considered as a poor prognostic marker in CPT”
BRAF y CA. TIROIDES
Brose et al. The Lancet Oncol 2014. Sorafenib in radioactive iodine-refractory, locally advanced or
metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial
“Progression-free
survival improved in
all prespecified
clinical and genetic
biomarker
subgroups,
irrespective of
mutation
status”
DECISION Trial SLP
SORAFENIB 10,8 meses
PLACEBO 5,8 meses
HR:0,59 (0,45-0,76) p><0,0001
BRAF y CA. COLORECTAL
•INCIDENCIA: 5%-15%
•TIPO MUTACIÓN: V600E
•CLÍNICA/AP:
- Vía alternativa tumorogénesis: activación aberrante MAPK
- metilación CIMP (CpG), metilación MLH1, MSI+ (DD con Sdr. Lynch)
- Adenoma serrado
- Sexo femenino, >60 años, colon proximal.
- TNM más avanzado, grado III, histología mucinosa.
•PRONÓSTICO: “Could be used to supplement standard clinical and pathologìcal
staging and could be considered as a poor prognostic marker CCR”
•PREDICTIVO: NO concluyente
BRAF y CA. COLORECTAL
Chen et al. PlosOne 2014. BRAFV600E Mutation and Its Association with Clinicopathological
Features of Colorectal Cancer: A Systematic Review and Meta-Analysis
Estadios
Grado
Mucinosos
Proximal
BRAF y CA. COLORECTAL
Chen et al. PlosOne 2014. BRAFV600E Mutation and Its Association with Clinicopathological
Features of Colorectal Cancer: A Systematic Review and Meta-Analysis
MLH1+
CIMP+
MSI+
BRAF y CA. COLORECTAL
Chen et al. PlosOne 2014. BRAFV600E Mutation and Its Association with Clinicopathological
Features of Colorectal Cancer: A Systematic Review and Meta-Analysis
MLH1+
CIMP+
MSI+
Conclusion: ”Could be used to supplement standard clinical
and pathologìcal staging and could be considered as a poor
prognostic marker CCR”
BRAF y CA. COLORECTAL
Bokemeyer el al. Eur J Cancer 2012. Addition of cetuximab to chemotherapy as first-line treatment for
KRAS wild-type metastati colorectal cancer: pooled analysis of CRYSTAL and OPUS random trials
BRAF y CA. COLORECTAL
Bokemeyer el al. Eur J Cancer 2012. Addition of cetuximab to chemotherapy as first-line treatment for
KRAS wild-type metastati colorectal cancer: pooled analysis of CRYSTAL and OPUS random trials
Conclusion: “BRAF mutation does not appear to be a
predictive biomarker in this setting, but is a marker of poor
prognosis”
BRAF y CA. COLORECTAL
Bokemeyer el al. Eur J Cancer 2012. Addition of cetuximab to chemotherapy as first-line treatment for
KRAS wild-type metastati colorectal cancer: pooled analysis of CRYSTAL and OPUS random trials
Conclusion: “BRAF mutation does not appear to be a
predictive biomarker in this setting, but is a marker of poor
prognosis”
BRAF y CA. COLORECTAL
Bokemeyer el al. Eur J Cancer 2012. Addition of cetuximab to chemotherapy as first-line treatment for
KRAS wild-type metastati colorectal cancer: pooled analysis of CRYSTAL and OPUS random trials
Conclusion: “BRAF mutation does not appear to be a
predictive biomarker in this setting, but is a marker of poor
prognosis”
BRAF y CA. COLORECTAL
Bokemeyer el al. Eur J Cancer 2012. Addition of cetuximab to chemotherapy as first-line treatment for
KRAS wild-type metastati colorectal cancer: pooled analysis of CRYSTAL and OPUS random trials
Conclusion: “BRAF mutation does not appear to be a
predictive biomarker in this setting, but is a marker of poor
prognosis”
BRAF y CA. COLORECTAL
Grothet et al. Lancet 2013. “Regorafenib monotherapy for previously treated metastaticcolorectal cancer
(CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial”
“….. status
bRAF¿?”
CORRECT Trial SG
REGORAFENIB 6,4 meses
PLACEBO 5 meses
HR:0,77 (0,64-0,94) P=0,0052
BRAF y OTROS TUMORES
Pakneshan et al. Pathology 2013. Clinicopathological relevance of BRAF mutations in human cancer
TIPO
TUMORAL
% TIPO
MUTACIÓN
CARACTERÍSTICAS
OVARIO 35% V600E - Serosos bajo grado / borderline - Parece estadios más iniciales (mejor pronóstico?)
SNC 60-80% KIAA1549 – BRAF / V600E / BRAFins598T
- Astrocitomas pilocíticos - Específica - DD astrocitomas pilocíticos vs otros astrocitomas de bajo grado
PULMÓN
NO
MICROCÍTICO
1-3% V600E / G649A - Mayoría adenocarcinomas - Excluyente con mutEGFR - V600E parece asociado a mujeres, agresivo, no tabaco
MECANISMOS DE RESISTENCIA
RAF
MEK
RTK
ERK
RAS
RAF
MEK
RTK
ERK
RAS
MECANISMOS DE RESISTENCIA
Vemurafenib Dabrafenib
RAF
MEK
RTK
ERK
RAS
RTK
ERK DEPENDIENTE ERK INDEPENDIENTE
MECANISMOS DE RESISTENCIA
Pakneshan. Pathology 2013. Clinicopathological relevance of BRAF mutations in human cancer
ERK DEPENDIENTE ERK INDEPENDIENTE
MECANISMOS DE RESISTENCIA
Pakneshan. Pathology 2013. Clinicopathological relevance of BRAF mutations in human cancer
April et al. Clin Can Research 2013. BRAF in Melanoma: Current Strategies and Future Directions
Pritchard et al Clin Can Res 2013. Molecular pathways: MAPK pathway mutations and drug resistance
2
3
4
5
0
8
1
9
7
6
4
3
2
1
Mutación NRAS
Amplificacion
/splicing BRAF
Amplificación /
mutación CRAF
Mutación MEK
Sobrexpresión
CyclinD / COT
Sobreexpresión
PDGFR/HER
Sobreexpresión
IGF-R1
MutPTEN/PI3K
+PGC1alfa mitoc.
Sobreexpresión
HGF
9
8
7
6
0
MECANISMOS DE RESISTENCIA
5
MECANISMOS DE RESISTENCIA
Trunzer et al. JCO 2013. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in
patients with metastasic melanoma
MECANISMOS DE RESISTENCIA
Straussman et al. Nature 2012. Tumor microenvironment induces innate RAF-inhibitor
resistance through HGF secretion
MECANISMOS DE RESISTENCIA
Corcoran et al. Oncotarget 2011. Potential therapeutic strategies to overcome acquired resistance to
BRAF or MEK inhibitors in BRAF mutant cancers
April et al. Clin Can Research 2013. BRAF in Melanoma: Current Strategies and Future Directions.
Inhibidores BRAF
CONCLUSIONES
TIPO TUMORAL CLÍNICO-PATOLÓGICAS
PRONÓSTICO PREDICTIVO
MELANOMA No (edad) No Sí
TIROIDES PAPILAR Sí Sí No
COLORECTAL Sí Sí No (¿?)
1.- Frecuencia global: 7-8% 2.- Importancia variable según tipo tumoral 3.- Influye características AP/clínicas ciertos tumores: papilar tiroides, colorectal. 4.- Valor pronóstico desfavorable en papilar tiroides y colorectal. 5.- Valor predictivo en melanoma frente a inhBRAF (colorectal¿?) 6.- “Basket trials”, muestras AP…
¡¡MUCHAS GRACIAS!!