Download consejo genético, dianas terapéuticas y biopsia líquida

UN NUEVO ESCENARIO PARA LA
COLABORACIÓN CIRUJANO-PATÓLOGO:
CONSEJO GENÉTICO, DIANAS
TERAPÉUTICAS Y BIOPSIA LÍQUIDA
JULIAN SANZ
Función de la Anatomía Patológica
DATOS
CLINICOS
IHQ
SEGUIMIENTO/
CRIBADO
TRATAMIENTO
INDIVIDUALIZADO
PACIENTE
MOLECULAR
CLASIFICACION
Y ESTADIAJE
M-E
DIAGNOSTICO
PRECOZ
OTROS
DIAGNOSTICO HISTOPATOLOGICO
TRATAMIENTO
Medicina de Precisión
“Tumores morfológicamente idénticos pueden
tener comportamiento clínico diverso y distinta
respuesta al tratamiento”
Indice
I.
II.
III.
IV.
V.
Conceptos moleculares y morfológicos de
relevancia clínica.
Síndromes hereditarios
Biomarcadores de dianas terapéuticas.
Inmunoterapia
Biopsia líquida
I .- Conceptos
Múltiples mutaciones
Selección natural: Un
driver?
Heterogeneidad
Transcriptomica próstata
The hallmarks of cancer
“Adicción” a una vía proliferativa”
4
5
3
2
6
1
Hanahan and Weinberg, Cell 2000.
Hanahan and Weinberg, Cell. 2011,
Jan;144(5):646-74.
Diferentes pathways para el mismo tumor
Slide 8.37
Clasificación molecular
A.- Lung cancer mutation consortium
PCR/ dasatinib
IHQ,FISH/ crizotinib
FISH/crizotinib
Nuevas:
Ros1 fusions 1% FISH
RET fusions 1% FISH
2%
7%
17%
PCR/ TKIs
22%
B.-
The consensus molecular subtypes of colorectal cancer: (2015)

1. MSI Immune : hypermutated, MSI, strong immune activation;

2. Canonical :chromosomally unstable, WNT and MYC activation;

3. Metabolic :epithelial, evident metabolic dysregulation;

4. Mesenchymal :TGFβ active, stromal invasion, angiogenesis.
Perez-Villamil et al, BMC 2012
* Adjusted for stage, MSI, BRAF
mut, adjuvant chemotherapy, and
stratified by dataset.
Nature Medicine 2015; 21: 1350–1356
Using Multiplexed Assays of Oncogenic Drivers in Lung
Cancers to Select Targeted Drugs
Mark G. Kris, et al. JAMA. 2014;311(19):1998-2006.
14 Hospitales
1007 adenocarcinomas de pulmón
II Síndromes hereditarios
Predisposición genética al
cáncer
•
•
•
•
•
•
•
•
•
•
•
•
•
Birt-Hogg-Dubé Syndrome
Breast/Gynecologic Cancers, Hereditary.
Carney-Stratakis Syndrome
Colon Cancer, Hereditary Nonpolyposis or Lynch
Syndrome
Cowden Syndrome
Li-Fraumeni
Multiple Endocrine Neoplasia Type 1).
Multiple Endocrine Neoplasia Type 2A, 2B
(Sipple Syndrome)
Polyposis, Familial Adenomatous and Attenuated
Familial Adenomatous Polyposis
Polyposis, Familial Juvenile
Polyposis, MYH-Associated
Renal Cell Cancer, Hereditary Papillary
Von Hippel-Lindau Syndrome
Incidencia Lynch: 1/300
Síndromes hereditarios
• Modifican el cribado del cáncer. Consejo
genético.
• Implicaciones pronósticas y terapéuticas.
Modifica los procedimientos quirúrgicos
• Modifica el seguimiento
III- Biomarcadores
- Tratamiento oncológico:
a) Sin Biomarcador de respuesta terapéutica en el tumor
y/o paciente
b) Con biomarcador “predictor” de respuesta
FDA-approved
-Signal transduction inhibitors
-Angiogenesis
-Targeted therapies helping the immune
system to destroy cancer cells
monoclonal antibody (mAb)
small-molecule (S-m)
Agent
Target(s)
FDA-approved indication(s)
Ado-trastuzumab emtansine (Kadcyla)
HER2 (ERBB2/neu)
•
Breast cancer (HER2+)
Afatinib (Gilotrif)
EGFR (HER1), HER2 (ERBB2/neu)
•
NSCLC(EGFR exon 19 del ,L858R)
Aldesleukin (Proleukin)
Renal cell carcinoma
Melanoma
Axitinib (Inlyta)
KIT, PDGFRβ, VEGFR1/2/3
•
Renal cell carcinoma
Bevacizumab (Avastin)
VEGF ligand
•
Cervical cancer
•
Colorectal cancer
•
Fallopian tube cancer
•
Glioblastoma
•
Non-small cell lung cancer
•
Ovarian cancer
•
Peritoneal cancer
•
Renal cell carcinoma
Cabozantinib (Cometriq)
FLT3, KIT, MET, RET, VEGFR2
•
Medullary thyroid cancer
Ceritinib (Zykadia)
ALK
•
Non-small cell lung cancer (ALK +)
Cetuximab (Erbitux)
EGFR (HER1/ERBB1)
•
Colorectal cancer (KRAS wild type)
•
Squamous cell cancer head and neck
Cobimetinib (Cotellic)
MEK
•
Melanoma (BRAF V600E V600Kmut)
Crizotinib (Xalkori)
ALK, MET
•
Non-small cell lung cancer (ALK +)
Dabrafenib (Tafinlar)
BRAF
•
Melanoma (with BRAF V600 mutat)
Denosumab (Xgeva)
RANKL
Giant cell tumor of the bone
Dinutuximab (Unituxin)
B4GALNT1 (GD2)
Pediatric neuroblastoma
Agent
Target(s)
Erlotinib (Tarceva)
EGFR (HER1/ERBB1)
FDA-approved indication(s)
Non-small cell lung cancer
Pancreatic cancer
Everolimus (Afinitor)
mTOR
Gefitinib (Iressa)
EGFR (HER1/ERBB1)
Imatinib (Gleevec)
KIT, PDGFR, ABL
•
Pancreatic neuroendocrine tumor
•
Renal cell carcinoma
•
Nonresectable subependymal giant cell
astrocytoma + tuberous sclerosis
•
Breast cancer (HR+, HER2-)
•
NSCLC( EGFR exon 19 del or L858Rmut)
GI stromal tumor (KIT+)
Dermatofibrosarcoma protuberans
Multiple hematologic malignancies
Ipilimumab (Yervoy)
CTLA-4
•
Melanoma
Lapatinib (Tykerb)
HER2 (ERBB2/neu), EGFR (HER1)
•
Breast cancer (HER2+)
Lenvatinib (Lenvima)
VEGFR2
Nivolumab (Opdivo)
PD-1
Thyroid cancer
•
Melanoma
•
Non-small cell lung cancer
Olaparib (Lynparza)
PARP
•
Ovarian cancer (with BRCA mutation)
Palbociclib (Ibrance)
CDK4, CDK6
•
Breast cancer (ER+, HER2-)
Panitumumab (Vectibix)
EGFR (HER1/ERBB1)
•
Colorectal cancer (KRAS wild type)
Pazopanib (Votrient)
VEGFR, PDGFR, KIT
•
Renal cell carcinoma
Pembrolizumab (Keytruda)
PD-1
Melanoma
Non-small cell lung cancer (PD-L1+)
Pertuzumab (Perjeta)
HER2 (ERBB2/neu)
•
Breast cancer (HER2+)
Agent
Target(s)
FDA-approved indication(s)
Ramucirumab (Cyramza)
VEGFR2
•
Colorectal cancer
•
Gastric cancer or Gastroesophageal
junction (GEJ) adenocarcinoma
•
Non-small cell lung cancer
•
Colorectal cancer
•
Gastrointestinal stromal tumors
Regorafenib (Stivarga)
KIT, PDGFRβ, RAF, RET, VEGFR1/2/3
Sipuleucel-T (Provenge)
Prostate cancer
Sonidegib (Odomzo)
Smoothened
•
Basal cell carcinoma
Sorafenib (Nexavar)
VEGFR, PDGFR, KIT, RAF
•
Hepatocellular carcinoma
•
Renal cell carcinoma
•
Thyroid carcinoma
Temsirolimus (Torisel)
mTOR
•
Renal cell carcinoma
Trametinib (Mekinist)
MEK
•
Melanoma (BRAF V600 mutation)
Trastuzumab (Herceptin)
HER2 (ERBB2/neu)
•
Breast cancer (HER2+)
•
Gastric cancer (HER2+)
Vandetanib (Caprelsa)
EGFR (HER1/ERBB1), RET, VEGFR2
Medullary thyroid cancer
Vemurafenib (Zelboraf)
BRAF
•
Melanoma (BRAF V600 mutation)
Vismodegib (Erivedge)
PTCH, Smoothened
•
Basal cell carcinoma
Ziv-aflibercept (Zaltrap)
PIGF, VEGFA/B
•
Colorectal cancer
Terapias dirigidas
BIOMARCADOR
CÁNCER
FÁRMACO
HER2 (FISH/IHQ)
Mama
Estómago
Trastuzumab
Lapatinib
Trastuzumab
KIT y PDGFRA (mutación)
KRAS y NRAS (mutación)
GIST
Colo-rectal
Imatinib
Panitumumab
Cetuximab
EGFR (mutación)
Pulmón
(adenocarcinoma)
Gefitinib
Erlotinib
ALK (FISH/IHQ)
Pulmón
(adenocarcinoma)
Crizotinib
Melanoma
Vemurafenib
BRAF (mutación/IHQ)
¿Dónde?
KIT
KRAS
HER2
EGFR
BRAF
Anatomía Patológica
78,9%
76,3%
98,3%
79,3%
73%
Otro Servicio
Desconocido
15,5%
23,7%
1,7%
20,7%
25%
5,7%
- Guías clínicas
SEAP-SEOM
- Programas de
calidad
- Centros de
Referencia
2%
21
III- Biomarcadores
1. Al diagnóstico:
•
Cáncer de mama:
–
–
–
•
Cáncer de pulmón
–
–
–
–
•
K-ras y Nras (PCR)
Melanoma:
–
–
•
EGFR (PCR)
EMLA4-Alk (FISH, IHQ)
Ros1
PDL1
2. Tras neoadyuvancia: Para
valorar respuesta
3. Para decidir adyuvancia
Cáncer de colon
–
•
Her2 (FISH)
Recept Estrog y Prog. (IHQ)
Ki67 (IHQ)
En Primario o metástasis: Para
decidir tratamiento
bRaf (PCR, IHQ)
PD1/PDL1
GIST:
–
C-kit y PDGFRa (PCR)
4. Tras tratamiento selectivo;
resistencia….: para valorar
nuevos tratamientos
5. En Biopsia líquida
Biopsies after therapy: Intermediate atypical
carcinoma (IAC). Nueva entidad??
•
ASCO Chicago 2015: A new histologic subset of metastatic castration-resistant prostate
cancer (mCRPC) (IAC).
•
IAC had poor survival, with the Kaplan-Meier curves for survival of IAC tracking with
those of patients with small-cell NEPC, and distinct from adenocarcinoma.
•
“Despite being cytologically bland, this is an aggressive cancer similar to that seen with
small-cell NEPC” . “IAC represents 25% of mCRPC biopsies and when combined
with small-cell NEPC accounts for 40% of all samples, comprising the single
largest group of abiraterone- and enzalutamide-refractory patients.”
Plataformas multigénicas/ secuenciación masiva
Mountains and hills: Laura Wood et al : Science 2007; 318 : 1108-1113
Genomic Landscapes of Human Breast and Colorectal Cancers
EEj NGS:
• Landscapes of Human
Breast and Colorectal
Cancers
• Laura D. Wood et al.
• -Ion AmpliseqCancer Hotspot:
To target "hot spot" regions of 50
oncogenes and tumor suppressor genes,
with wide coverage of KRAS, BRAF, and
EGFR genes
• - Comprehensive cancer:
Exons within >400 oncogenes and
tumor suppressor genes
• -BRCA1 y BCA2
• - Oncomine
24
JTO Nov 2015; Gao X et al.
IV- Inmunoterapia
1Cancer immunity:
Immunosurvilliance
Immunosenescence
Immunoediting:
elimination,
equilibrium,
escape.
William Coley, 1880s,
New York surgeon, Coley
toxins
Frank Macfarlane
Burnet (1899–1985).
A.-
B.-
CD117
CD1a
CD56+, CD3CD56+, CD3+
Chemical microenvironment
28
Role of Lymphocytes
29
A 50-gene “immune” expression profile classifies early-stage NSCLC
(n=246) into low and high recurrence risk”
Firma génica HCSC “50 genes”
External Validation (n=162)
Disease-free survival
Low risk expression profile
High risk expression profile
Cluster “High risk” (112) ——
Cluster “Low risk” (50) ——
Development series (n=84)
Years
Sanz-Ortega J et al, CTO 2014.
Hazard Ratio: 3.359, Log-Rank: P=0.001
Firma 50 genes: Inmunidad B sobre-expresada en Low-risk
B-cell-specific transcrtiptional
co-activator (POU2)
TNFR, 17
SLAM7F (CD139), proliferation,
autocrine cytokine
CXCL13, a B-cell-attracting chemokine,
IRF4, B-cell development
CD38: proliferation and survival of B cells
CD27 memory cells
Pim-2 anti-apoptotic
B and plasma cells:
Maduration
Recruiting
Memory cells
Proliferation
Anti-apoptosis
Lung cancer
Immunoscoring NSCLC for prognosis (RFS)
•
•
The leading cause of death in developed countries (1.5 million deaths worlwide per
year).
Combination of radiological imaging, clinical, histopathological and molecular data
for personalyzed treatment.
Targeted therapies have shown a dramatic impact on patients outcome, since 2006.
•
Limited amount of tissue available in most cases.
•
1 mm
Ongoing therapies to avoid cancer avoiding immunity
1) Block immune checkpoints
(inmunotolerancia):
AntiPDL1 (breakthrough):
Anti CTLA-4
2) Accelerating immunity with Agonist Ab:
Anti-OX40, antiCD40
3) Peptide-based vaccines
Ej: A10VAC
4) MDSC suppressor
5) Adoptive Immunity….
34
V.- Biopsia líquida:
-ADN circulante
-Célula tumoral circulante
¿Para qué?:
- Falta de tejido/material insuficiente
- Riesgo de recurrencia
- Cambios moleculares a la progresión
- Mecanismos de resistencia
Conclusiones
• Obligación de reconocer las formas hereditarias:
consejo genético, cribado y tratamientos específicos.
• Muestras para Biomarcadores: al diagnóstico inicial,
progresión, resistencia, biopsia líquida….
• Más neoadyuvancia. Nuevos criterios de adyuvancia,
terapias combinadas.
• Inmunoterapia ya es realidad.