Nuevas Tecnologías aplicadas a la Oncología · 2019-07-16 · • PET – Body (FDG) – Pelvis...
Transcript of Nuevas Tecnologías aplicadas a la Oncología · 2019-07-16 · • PET – Body (FDG) – Pelvis...
Hernán Cortes-Funes Instituto de Investigación Hospital 12 de Octubre
Madrid
Nuevas Tecnologías aplicadas a la Oncología
Incrementar Efectividad Reducir Toxicidad
TAC RM PET
Proton
Therapy
Imagen Molecular
Nanotechnology
(CF3)180
Cirugía Robotica
Agentes c/dianas específicas
Genomica
Evolucion de tratamiento del Cancer
TECNOLOGIAS DIAGNOSTICAS
- Técnicas de Imagen
- Plataformas Genéticas (Medicina Personalizada)
- Biopsia Líquida
TECNOLOGIAS TERAPEUTICAS
- Tratamientos Biológicos
- Inmunoterapia
- Nuevos Tecnologías Quirúrgicas
- Avances en Radioterapia:
Terapia de Protones
Nuevas Tecnologías aplicadas a la Oncología
TECNOLOGIAS DIAGNOSTICAS
- Técnicas de Imagen
- Plataformas Genéticas (Medicina Personalizada)
- Biopsia Líquida
TECNOLOGIAS TERAPEUTICAS
- Tratamientos Biológicos
- Inmunoterapia
- Nuevos Tecnologías Quirúrgicas
- Avances en Radioterapia:
Terapia de Protones
Nuevas Tecnologías aplicadas a la Oncología
• TAC (Tórax, Abdomen , Pelvis, Cráneo)
– Contraste oral i.v
– Angio-TAC
– Screening Ca de Pulmón (dosis bajas)
• RM (Cerebral, Columna, Pelvis, Tórax, Abdomen)
– Contraste (gadolinio)
– Angio RM
• PET – Body (FDG)
– Pelvis (Colina)
• PET-RM (gadolinio)
Técnicas de Imágen Importante saber realizar cada solicitud conocer su utlidad
• El cribado con TAC de fumadores y exfumadores en 3 rondas anuales reduce la mortalidad por cáncer de pulmón en un 20% cuando se compara con el cribado con radiografía de tórax.
• El cribado no ha demostrado reducir la estadificación de los casos de cáncer de pulmón detectados después de la primera ronda
TAC a dosis bajas y sin contraste National Lung Screening Trial (2011)
TAC a dosis bajas sin contraste National Lung Screening Trial (2011)
PET-RMN Técnica novedosa de Utilidad Limitada y muy costoso. Existe aún poca experiencia
TECNOLOGIAS DIAGNOSTICAS
- Técnicas de Imagen
- Plataformas Genéticas (Medicina Personalizada)
- Biopsia Líquida
TECNOLOGIAS TERAPEUTICAS
• Nuevos tratamientos Quirúrgicos
- Tratamientos Biológicos
- Inmunoterapia
- Avances en Radioterapia:
Terapia de Protones
Nuevas Tecnologías aplicadas a la Oncología
Evolucion de La Oncología
• Mayor incidencia y mayor curación de los tumores • Diagnóstico más correctos (instrumentación mas
compleja) • Mayor atención al pronóstico (clínico; patológico;
genético-molecular) • Tratamientos cada vez mas complejos
• Quimioterapia, Hormonoterapia • Agentes contra nuevas dianas moleculares • Cirugía mas racional y con nuevas técnicas • Nuevos tratamientos Inmunológicos • Radioterapia mas precisa
• Tratamientos multidisciplinares • Tratamientos individualizados
The promise of personalized therapy
Presented By Michael Birrer at 2015 ASCO Annual Meeting
Source: Cell , Volume 144, Issue 5, Pages 646-674 (DOI:10.1016/j.cell.2011.02.013)
Composición del entramado celular de los tumores sólidos y su micro-entorno (estroma)
Therapeutic targeting of the hallmarks of Cancer
Hanahan D & Weinberg RA. Cell 144, March 4, 2011
Methods
A very robust analysis of the tumor’s biology and potential clinically actionable targets is enabled by a Multi-platform, technology independent analysis
• Mutational Analysis by Sanger Sequencing (n=6), Next
Generation Sequencing (n=44), FISH (n=2) and PCR (n=1) • Gene Copy Number by FISH (Fluorescent in Situ
Hybridization) / CISH (Chromogenic In Situ Hybridization) (n=7)
• MGMT Methylation by PCR (n=1) • Protein Expression Analysis by Immunohistochemistry
(IHC) (n=17 biomarkers)
Gatalica et al. ASCO 2013
Sanger sequencing
• DNA is fragmented
• Cloned to a plasmid vector
• Cyclic sequencing reaction
• Separation by electrophoresis
• Readout with fluorescent tags
‘Sanger sequencing’ has been the only DNA sequencing method for 30 years but…
…hunger for even greater sequencing throughput and more economical sequencing technology…
NGS has the ability to process millions of sequence reads in parallel rather than 96 at a time (1/6 of the cost)
Objections: fidelity, read length, infrastructure cost, handle large volum of data
.
• Roche/454 FLX
• Illumina Solexa Genome Analyzer
• Applied Biosystems SOLiDTM System
• Ion Torrent
• Helicos HeliscopeTM
Sequencing Procedures
Personalized Anticancer Therapy An Evolving Continuum From Tumor Genetic Information to Novel Therapeutic Targets and Treatments
TIMER
Plataformas Institucionales (Centros de Investigación). Instrumentación (Illumina, Quiagen..) Generalmente para proyectos de investigación •España (Institutos de I+D en Sanidad pública y algunos privados) •USA (MSKCC, Mayo Clinic, MD Anderson. …) •ENCODE (Encyclopedia of DNA Elements – NIH), regulatory
Plataformas Genomicas
Plataformas Comerciales •Foundation Medicine, NGS, Comprehensive Genomic Profiling •Sysmex
Oncobeam single gene test (9 pannels) Oncobeam multiple gene test (13 pannels) CTC, ctDNA test Sysmex, Guardant Health
•Caris Molecular Intelligence MI Profile (multipl platform for therapeutic decision MI Profile plus , NGS for additional biomarkers
•Genomica, Clart CMA Biosequence (España, emplea varias metodologías) Cancer de Mama
Oncotype DX (Genomic Health – Palex) Mammaprint (Synphony) Agendia Prosigna PAM 50 (Nanostring)
Plataformas Genomicas
Pancreatic cancer new drug development based on genomic alterations
Tumor heterogeneity in the primary tumor and in metastatic spread: therapeutic resistance
Multiregion sequencing and Intratumor heterogeneity NEJM 2012;366:883
Cedido por EDR
Biopsia Líquida
Biopsia Líquida
Cedido por EDR
ADN CIRCULANTE
ADN Libre y ADN Circulante
• ADN libre circulantes (cfDNA) – Se eleva en procesos inflamatorios, en heridas, menstrución, ejercicio
y cáncer (0-1.000 ng/ml (media 180 ng/ml)
– Vida media en plasma, 16 minutos
– En Individuos sanos 1 ng ADN / ml
• ADN tumoral Circulante (ctDNA – Representa entre el 0.01 al 60 % del cfDNA
– Son pequeños fragmentos <120 pares de bases
– Se eliminan por el rión
– Se pueden determinar mutaciones, traslocaciones, metiaciones…
Fraction of patients with detectable ctDNA
Cedido por EDR
Cedido por EDR
Cedido por EDR
Cedido por EDR
Applications of Liquid Biopsies (ctDNA)
• Early detection • Assessment of molecular heterogeneity of overall
disease • Identification of genetic determinants for
targeted therapy • Evaluation of early treatment response • Monitoring of minimal residual disease • Assessment of evolution of resistance in real time
Cedido por EDR
TECNOLOGIAS DIAGNOSTICAS
- Técnicas de Imagen
- Plataformas Genéticas (Medicina Personalizada)
- Biopsia Líquida
TECNOLOGIAS TERAPEUTICAS
- Tratamientos Biológicos
- Inmunoterapia
- Nuevos Tecnologías quirúrgicas
- Avances en Radioterapia:
Terapia de Protones
Nuevas Tecnologías aplicadas a la Oncología
Existen dos líneas en el desarrollo de nuevas Terapias para algunos tumores avanzados
Target Huésped
Target tumor
Inmunoterapia Terapias dirigidas
Frecuencia relativa de mutaciones en pacientes con Adenocarcinoma de Pulmón
Paik P K et al. JCO 2011;29:2046-2051
Las Características Moleculares en CNMP pueden predecir la respuesta o la resistencia a terapias dirigidas
Results in EGFR mutation positive and negative patients
EGFR mutation positive EGFR mutation negative
HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 No. events gefitinib: 97 No. events Chemo: 111
Gefitinib (n=132) Carboplatin / paclitaxel (n=129)
HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001 No. events gefitinib: 88 No. events Chemo: 70
132 71 31 11 3 0 129 37 7 2 1 0
108 103
0 4 8 12 16 20 24
Gefitinib C / P
0.0
0.2
0.4
0.6
0.8
1.0
Prob
abilit
y of
pro
gres
sion
-free
sur
viva
l
At risk : 91 4 2 1 0 0 85 14 1 0 0 0
21 58
0 4 8 12 16 20 24 0.0
0.2
0.4
0.6
0.8
1.0
Prob
abilit
y of
pro
gres
sion
-free
sur
viva
l
Gefitinib (n=91) Carboplatin / paclitaxel (n=85)
Months Months
Gefitinib CR/PR Rate 71% CBP/PTX CR/PR Rate 47%
Gefitinib CR/PR Rate 1% CBP/PTX CR/PR Rate 24%
PFS with maintenance Erlotinib in EGFR mutation+ and wild-type groups
1.0
0.8
0.6
0.4
0.2
0
Time (weeks)
1.0
0.8
0.6
0.4
0.2
0
Time (weeks) 0 8 16 24 32 40 48 56 64 72 80 88 96 0 8 16 24 32 40 48 56 64 72 80 88 96
Interaction p<0.001
PFS
prob
abili
ty
Log-rank p<0.0001 HR=0.10 (0.04–0.25)
Erlotinib (n=199) Placebo (n=189)
Erlotinib (n=22) Placebo (n=27)
Log-rank p=0.0185 HR=0.78 (0.63–0.96)
EGFR mutation+ EGFR wild-type
Brugger, et al. WCLC 2009
miR-18b
miR-19a, -19b
miR-19a, -19b miR-106a, -106b, -93, -17-5p, -20a, -20b, -192
PTEN ATM
ERBB2 HRAS KRAS
PIK3CA AKT1 TP53
AKT1 CCDN1 ERBB2 HRAS KRAS MYC
PIK3CA
APC ATM NF1
PTEN RB1 LKB1 TP53
AKT1 APC
ERBB2 PIK3CA
TERT
HRAS KRAS MYC
PIK3CA PTEN LKB1 TP53
ATM PTEN TP53
miR-106a, -106b, -19b, -20b, -93
miR-19a, -19b, -93
miR-25
miR-19a, -363
miR-363*
miR-106a, -106b, -19b, -20b, -93
miR-18b
miR-19b, -92
miR-363*, -192
miR-93
miR-19a, -363 miR-19a, -19b
miR-19a, -19b, -93
miR-363*
miR-106a, -106b, -19b, -20b, -93
miR-19b, -92
miR-19b, -92
miR-363*
miR-93
miR-19a, -19b miR-17-3p
miR-19a, -19b
miR-19b, -92
miR-106a, -106b, -19b, -20b, -93
miR-19a, -19b, -93
miR-363 miR-19a, -19b
miR-17-3p
miR-93 miR-17-5p, -20a, 20b, 106b, -93
miR-17-3p
miR-363
miR-19a, -19b, -93
Principales genes implicados en la génesis del adenocarcinoma de pulmón
Melanoma Avanzado Vemurafenib (Zelboraf)
Tratamientos Inmunológicos (Inmunoterapia)
Objetivo de la inmunoterapia
Basis for Immune therapy – Immune Escape
Presented by: Tanguy Seiwert Melero I et al. Clin Cancer Res 2013;19:997-1008
• Expression of PD-L1 on
a) tumor cells &
b) macrophages
can suppress immune
surveillance.
• In mouse models antibodies blocking PD-1 / PD-L1 interaction lead to tumor rejection
• Clinical prognosis correlates with presence of TILs and PD-L1 expression in multiple cancers.
[TITLE]
Presented By Jedd D. Wolchok, MD, PhD at 2013 ASCO Annual Meeting
ORR by PD-L1 Expression in Patients with Solid Tumors
Rx Antibody Testing Method N PD-L1 + RR PD-L1 - RR
Nivolumab[1]
Manual staining – 5H1 5% cutoff
Tumor staining 49 13/31
42% 0/18 0%
Nivolumab[2]
Dako automated 5% cutoff
Tumor staining 38 7/17
41% 3/21 14%
MPDL3280A[3]
Automated Roche Dx IHC
1% cutoff Tumor immune cell staining
103 13/36 36%
9/67 13%
Ipi/Nivo[4] Dako automated
5% cutoff Tumor staining
56 8/14 57%
17/42 40%
1. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454. 2. Grosso J, et al. ASCO 2013. Abstract 3016. 3. Herbst RS, et al. ASCO 2013. Abstract 3000. 4. Sznol M, et al. ASCO 2014. LBA9003.
Ipilimumab: irRC Identifies Survivors in Patients with Progressive Melanoma
Wolchok JD, et al. Clin Cancer Res. 2009;15:7412-7420.
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
0
Prop
ortio
n Al
ive
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
Mos
CR/PR/SD (by WHO criteria) irPR/irSD (by the irRC) PD and unknown response
Tumors Shown to Respond to Anti-PD1 or Anti-PD-L1 Therapy
• Melanoma
– Pembrolizumab approved by the US FDA in September 2014 for unresectable or metastatic disease with progression following ipilimumab and, if appropriate, a BRAF inhibitor
• NSCLC SCLC • RCC (Atezoluzumab)
• Urothelial Tumors
• Head and Neck cancer
• Lymphomas
• Breast ??
• Gliomas ??
TECNOLOGIAS DIAGNOSTICAS
- Técnicas de Imagen
- Plataformas Genéticas (Medicina Personalizada)
- Biopsia Líquida
TECNOLOGIAS TERAPEUTICAS
- Tratamientos Biológicos
- Inmunoterapia
- Nuevas Tecnologías Quirúrgicas
- Avances en Radioterapia
Terapia de Protones
Nuevas Tecnologías aplicadas a la Oncología
Nuevos Tratamientos Quirúrgicos Cirugía Robotica (Da Vinci)
Nuevos Tratamientos Radioterápicos
- Terapia con Fotones: IMRT, IGRT, SBRT, IORT, Cyberknife, Gammaknife…
- Terapia con Haz de Protones (PBT)
HISTORY
07
Proton Therapy has been used to treat more than 137,000 patients from 1954 to 2014 for a wide range of cancer indications worldwide according to PTCOG.
Proton Therapy 1
NOWADAYS
Technology 1
08
PROTON THERAPY ADVANTAGES
PROTON THERAPY AND CONVENTIONAL RADIOTHERAPY
. Proton Therapy (PT) is an alternative to standard radiotherapy for tumor sterilization with a proven record for reduced side-effects – up to 60% less than standard photon radiotherapy – and the promise of higher effectiveness in terms of tumor recurrence. Uniquely, Proton Therapy is the tool enabling the delivery of the desired high radiation dose to the tumor while sparing surrounding healthy tissue • Effective, precise targeting. Less and more precise radiation than conventional radiotherapy reducing side effects and damages to healthy tissue • Proven Treatment. Proton Therapy is an approved therapy that has been used to treat more than 137,000 patients from 1954 to 2014 for a wide range of cancer indications according to PTCOG. • Ultimate Technology. Proton Therapy technology is a paramount example of human technological achievement in terms of sophistication and performance, much like the CERN particle accelerator for fundamental physics research in Geneva.
Proton Therapy delivers less and more targeted radiation to side areas and healthy tissues than radiotherapy, reducing the likelihood of side effects. In contrast to conventional radiation therapy, proton beams deliver the majority of their destructive energy within a small range inside the tumor, known as the Bragg peak.
(SPREAD OUT BRAGG PEAK)
DRAFT. PREPARED TO CLINICA UNIVERSITARIA DE NAVARRA (CUN)
Proton Therapy Centre Europe Map
Protons - low energy Protons – high energy Carbons
Avances en Radioterapia Terapia con Haz de Protones
Orbital Rhabdomyosarcoma
X-Rays Protons/Ions Courtesy T. Yock, N. Tarbell, J. Adams
Technology 1
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X-Ray •High radio sensitivity. •No cell-targeting affects the normal tissue as the X-Rays pass through. •Most energy is released outside the tumor damaging healthy tissue. •Deeper tumors embedded in important organs cannot be targeted by radiation therapy because of life threatening damage. •Treatment sessions (“fractions”) 5 days a week for 5-8 weeks. •Immediate and long-term side effects •Elevated post-treatment cancer risk . •1% chance of developing radiation-induced cancer •Affects the normal tissue it passes through on its way into the body: starting at skin level, all tissues on the way to the tumor absorb the X-rays and only a fraction of the energy will eventually reach the tumor itself. •X-rays pass through the body like a bullet, continually loosing energy as they pass and damaging the tissue behind the tumor as well. •Based on the physical properties of the X-ray beams, we will always need to use higher energy levels to kill a tumor than actually is required by the tumor, as most of the energy will be lost on its way in.
No cell-targeting, high energy loss & elevated post-treatment cancer risk.
IMRT/ TrueBeam • Reduces healthy tissues exposure by
targeting cells from multiple angles. • Affected volume of tissue is much
smaller and more conformal. • Increased number of X-ray beams are
necessary resulting in a much larger volume of non-targeted tissue receiving low radiation doses.
• More non-targeted tissue receives low radiation doses .
• Integral dose is redistributed over a larger volume of non-targeted tissue but total amount of radiation applied may be higher.
• Increase of risk of second cancers as a late onset side effect .
• New radiation technique, historical data remains a subject of ongoing research.
Cell-targeted , high risk of second cancer & more healthy tissue exposure.
Proton Beam Radiation Therapy Proton therapy is an advanced form of radiotherapy that uses a high-energy proton beam for cancer treatment. •It provides of greater control and precision and superior management of treatment. •Protons lose relatively little energy along the beam path until the end of their range, at which point they lose the majority of their energy. •Each proton full treatment course requires on average 26 treatment sessions (“fractions”) of an average 20 minutes per fraction, which allow the optimal dose to be given with the least damage to normal tissues. •The radiation dose can be increased to the tumor without affecting normal tissues allowing the dose to go beyond that possible for conventional photon radiation. •Overall effects lead to the potential for fewer harmful side effects, more direct impact on the tumor, and increased tumor control.
Control & precision (cell-targeting), little energy loss & fewer side-effects.
COMPARISON Advantages of Proton Therapy vs Radiation:
DRAFT. PREPARED TO CLINICA UNIVERSITARIA DE NAVARRA (CUN)
Proton Therapy vs Conventional Radiotherapy
08
Brain Tumors -This image show the areas of the brain and the spinal cord exposed to radiation during treatment and the amount of radiation receiving the
surrounding normal tissues.
Left Breast Cancer Areas of the chest wall exposed to radiation during treatment and the amount of radiation
receiving the surrounding normal organs (lung and heart)
Inoperable Lung Cancer – Curative PBT
Localized Prostate Cancer Curative PBT
IBA 1 ROOM MODEL: PROTEUS ONE
11
Tumors Indication (approved or accepted) 1
08
Tumors of the eye
Uveal malignant melanoma
Macular degeneration
Choroid hemangioma
Vascular malformations & Benign tumors
A-V malformations
Acoustic neurinoma
Pituitary adenomas
Meningeomas
Childrens Tumors
Meduloblastoma
Craniopharyngioma
Juvenile pilocytic astrocytomas, (JPA)
Low malignant gliomas
Ependymoma
Breast Cancer
Adjuvant to surgery left breast tumors
Malignant CNS disease
Skull base tumors (chordomas, chondrosarcomas)
Chordomas (Clivus and sacrum)
Low grade glioma (situated close to structures sensitive to radiation)
Head and Neck Tumors
Tumors of the sinuses
Nasopharyngeal carcinoma
Particular tumors of the oropharynx, hypopharynx and larynx
Tumors of the salivary glands
Tumors with unfavorable histology, as adenoid cystic carcinomas, sarcomas, melanomas or esthesioneuroblastoma
Lung Cancer
Curative treatment in T1-2N0 stage tumors that are inoperable
Tumors Indication (selective) 1
08
Prostate
Localized and locally progressed prostate tumors (T1-T3b, N0, M0)
Adjuvant or salvage radiotherapy after radical prostatectomy
Malignant CNS disease
High grade glioma (especially situated close to structures sensitive to radiation)
Specific types of brain metastasis
Pancreatic tumors
Inoperable or postoperative
Isolate metastasis
Inoperable liver or other sites
Lung Cancer
T3-4 N0 and T1-4 N1-3 locally progressed tumors if surgery is not possible
Stage IIIB Palliative in locally progressed tumors with concomitant chemotherapy
Head and Neck Tumors
Paraspinal tumors
Tumors of the oropharynx, hypopharynx and larynx (selective)
Tumors of the salivary glands
Tumors with unfavorable histology, such as adenoid cystic carcinomas, sarcomas, melanomas or esthesioneuroblastoma
Carcinoma of the esophagus
Preoperative or radical radiotherapy
Hepatocellular carcinoma
Inoperable lesions
Rectal carcinoma
If surgery is impossible or refused
Childrens Tumors
Localized Lymphomas
Soft tissue & Ewing sarcoma,
Oncología Actual
• Diagnóstico por el órgano del primitivo
• Clasificación Histológica • Tratamiento > Prevención • Tratamientos Tóxicos y
Complejos • Pronósticos Subóptimo • Monitorización Anatómica TNM, Respuestas clásicas
(RC, RP, RG...), intentos erradicadores
• Diagnóstico por su alteración genética
• Clasificación molecular • Prevención > Tratamiento • Terapias no tóxicas y simples • Pronóstico adecuado • Monitorización genético-
molecular: sobrevida, estabilizaciones, (Plataformas genéticas Farmacogenomica, Biopsia líquida)
• Incorporación de nuevas terapias: la Inmunología, PBT.
Oncología del Futuro
Evolución de la Oncología
MUCHAS GRACIAS