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


• 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




- Biopsia Líquida


• Nuevos tratamientos Quirúrgicos


- Inmunoterapia


Terapia de Protones


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)

http://www.cell.com/abstract/S0092-8674(11)00127-9

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

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

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




- Biopsia Líquida



- Inmunoterapia

- Nuevos Tecnologías quirúrgicas


Terapia de Protones


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 ??




- Biopsia Líquida



- Inmunoterapia

- Nuevas Tecnologías Quirúrgicas

- Avances en Radioterapia

Terapia de Protones


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

09

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

Nuevas Tecnologías aplicadas a la Oncología · 2019-07-16 · • PET – Body (FDG) – Pelvis...

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