Diapositiva 1 - Bases Biológicas del Cáncer y Terapias

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
LA VÍA MAPK…
RTK
RAS
RAF
MEK
ERK
LA VÍA MAPK…
RTK
RAS
RAF
MEK
ERK
….FAMILIA RAF QUINASA….
A-RAF
B-RAF
C-RAF
Rahman et al. Exper and Mol Path 2014. B-Raf mutation: A key player in molecular biology of cancer
…. y BRAF….
A-RAF
B-RAF
C-RAF
Rahman et al. Exper and Mol Path 2014. B-Raf mutation: A key player in molecular biology of cancer
….B-RAF
Rahman et al. Clin Reviews in Oncology/Hematology 2014. BRAF inhibitors: From laboratory to CT
Importancia BRAF en Cáncer
•FRECUENCIA
•CARACTERÍSTICAS PROPIAS
•IMPLICACIONES TERAPEÚTICAS
Mutaciones BRAF en Cáncer
Davies et al. Nature 2002. Mutations of the Braf gene 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
Mutaciones BRAF en Cáncer
TIPO TUMORAL
% (Aprox.)
TIPO MUTACIÓN
TODOS
7-8%
MELANOMA
40-60%
V600E / V600K
TIROIDES (Papilar)
45%
V600E
COLORECTAL
5-15%
V600E
OVARIO (Seroso bajo
grado/border line)
35%
V600E
SNC (Astrocitomas pilocíticos)
60-80%
V600E / KIAA1549 /
BRAFins598T
PULMÓN NO MICROCÍTICO
1-3%
V600E / G469A
HEPATO/BILIAR
0-22% (pocos estudios)
V600E
LEUCEMIA CÉLULAS PELUDAS
100% (pocos estudios)
V600E
Pakneshan et al. Pathology 2013. Clinicopathological relevance of BRAF mutations in human cancer
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.)
TIPO MUTACIÓN
TODOS
7-8%
MELANOMA
40-60%
V600E / V600K
TIROIDES (Papilar)
45%
V600E
COLORECTAL
5-15%
V600E
OVARIO (Seroso bajo
grado/border line)
35%
V600E
SNC (Astrocitomas pilocíticos)
60-80%
V600E / KIAA1549 /
BRAFins598T
PULMÓN NO MICROCÍTICO
1-3%
V600E / G469A
HEPATO/BILIAR
0-22% (pocos estudios)
V600E
LEUCEMIA CÉLULAS PELUDAS
100% (pocos estudios)
V600E
Pakneshan et al. Pathology 2013. Clinicopathological relevance of BRAF mutations in human cancer
Mutaciones BRAF en Cáncer
TIPO TUMORAL
% (Aprox.)
TIPO MUTACIÓN
TODOS
7-8%
MELANOMA
40-60%
V600E / V600K
TIROIDES (Papilar)
45%
V600E
COLORECTAL
5-15%
V600E
OVARIO (Seroso bajo
grado/border line)
35%
V600E
SNC (Astrocitomas pilocíticos)
60-80%
V600E / KIAA1549 /
BRAFins598T
PULMÓN NO MICROCÍTICO
1-3%
V600E / G469A
HEPATO/BILIAR
0-22% (pocos estudios)
V600E
LEUCEMIA CÉLULAS PELUDAS
100% (pocos estudios)
V600E
Pakneshan et al. Pathology 2013. Clinicopathological relevance of BRAF mutations in human cancer
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 intraepidérmicos, mayor pigmentación, mayor infiltración linfocitaria
BRAF y MELANOMA
Long et al. JCO 2011. Prognostic and clinicopathologic associations of BRAF in metastatic melanoma
BRAF y MELANOMA
Long et al. JCO 2011. Prognostic and clinicopathologic associations of BRAF in metastatic melanoma
BRAF y MELANOMA
RTK
RAS
Vemurafenib
Dabrafenib
RAF
MEK
ERK
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 Y MELANOMA: VEMURAFENIB
BRAF V600E
BRAF V600K
Dacarbazine
Vemurafenib
Dacarbazine
Vemurafenib
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
Median OS
(months)
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
OS, overall survival; PFS, progression-free survival; ORR, overall response rate; NA, not available (cannot be reliably estimated).
BRAF Y MELANOMA: DABRAFENIB
Hauschild et al. Lancet 2012. ASCO 2013. Dabrafenib in BRAF-mutated metastasic melanoma: a phase III RCT
BRAF y MELANOMA
Vemurafenib
Dafrafenib
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
BRAF y MELANOMA
Vemurafenib
Dabrafenib
Trametinib
RTK
RAS
RAF
MEK
ERK
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
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
Chapman et al. NEJM 2011. Improved survival with vemurafenib in melanoma BRAFV600E mutation
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
Invasión extratiroidea
Afectación ganglionar
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.
BRAF y CA. TIROIDES
TNM avanzado
Persistencia/recurrencia
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.
BRAF y CA. TIROIDES
Conclusion: “….BRAF mutation V600E should be
considered as a poor prognostic marker in CPT”
TNM avanzado
Persistencia/recurrencia
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.
BRAF y CA. TIROIDES
DECISION Trial
SLP
SORAFENIB
10,8 meses
PLACEBO
5,8 meses
HR:0,59 (0,45-0,76)
p><0,0001
“Progression-free
survival improved in
all prespecified
clinical and genetic
biomarker
subgroups,
irrespective of
mutation
status”
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
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
Estadios
Mucinosos
Grado
Proximal
Chen et al. PlosOne 2014. BRAFV600E Mutation and Its Association with Clinicopathological
Features of Colorectal Cancer: A Systematic Review and Meta-Analysis
BRAF y CA. COLORECTAL
MSI+
CIMP+
MLH1+
Chen et al. PlosOne 2014. BRAFV600E Mutation and Its Association with Clinicopathological
Features of Colorectal Cancer: A Systematic Review and Meta-Analysis
BRAF y CA. COLORECTAL
MSI+
CIMP+
Conclusion: ”Could be used to supplement standard clinical
MLH1+
and pathologìcal staging and could be considered as a poor
prognostic marker CCR”
Chen et al. PlosOne 2014. BRAFV600E Mutation and Its Association with Clinicopathological
Features of Colorectal Cancer: A Systematic Review and Meta-Analysis
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
Conclusion: “BRAF mutation does not appear to be a
predictive biomarker in this setting, but is a marker of poor
prognosis”
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
Conclusion: “BRAF mutation does not appear to be a
predictive biomarker in this setting, but is a marker of poor
prognosis”
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
Conclusion: “BRAF mutation does not appear to be a
predictive biomarker in this setting, but is a marker of poor
prognosis”
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
Conclusion: “BRAF mutation does not appear to be a
predictive biomarker in this setting, but is a marker of poor
prognosis”
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
CORRECT Trial
SG
REGORAFENIB
6,4 meses
PLACEBO
5 meses
status
bRAF¿?”
“…..
HR:0,77 (0,64-0,94)
P=0,0052
Grothet et al. Lancet 2013. “Regorafenib monotherapy for previously treated metastaticcolorectal cancer
(CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial”
BRAF y OTROS TUMORES
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
Pakneshan et al. Pathology 2013. Clinicopathological relevance of BRAF mutations in human cancer
MECANISMOS DE RESISTENCIA
RTK
RAS
RAF
MEK
ERK
MECANISMOS DE RESISTENCIA
Vemurafenib
Dabrafenib
RTK
RAS
RAF
MEK
ERK
MECANISMOS DE RESISTENCIA
RTK
RAS
RTK
RAF
MEK
ERK DEPENDIENTE
ERK
ERK INDEPENDIENTE
MECANISMOS DE RESISTENCIA
ERK DEPENDIENTE
ERK INDEPENDIENTE
Pakneshan. Pathology 2013. Clinicopathological relevance of BRAF mutations in human cancer
MECANISMOS DE RESISTENCIA
6
7
1 Mutación NRAS
2 Amplificacion
1
6 Sobreexpresión
/splicing BRAF
3 Amplificación /
PDGFR/HER
3
7 Sobreexpresión
2
8
mutación CRAF
4 Mutación MEK
5 Sobrexpresión
CyclinD / COT
4
IGF-R1
8 MutPTEN/PI3K
9 +PGC1alfa mitoc.
5
9
0
0 Sobreexpresión
HGF
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
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
Inhibidores BRAF
April et al. Clin Can Research 2013. BRAF in Melanoma: Current Strategies and Future Directions.
CONCLUSIONES
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…
TIPO TUMORAL
CLÍNICOPATOLÓGICAS
PRONÓSTICO
PREDICTIVO
MELANOMA
No (edad)
No
Sí
TIROIDES PAPILAR
Sí
Sí
No
COLORECTAL
Sí
Sí
No (¿?)
¡¡MUCHAS GRACIAS!!