UN NUEVO ESCENARIO PARA LA COLABORACIÓN CIRUJANO-PATÓLOGO:

CONSEJO GENÉTICO, DIANAS

TERAPÉUTICAS Y BIOPSIA LÍQUIDA

JULIAN SANZ

Función de la Anatomía Patológica

DIAGNOSTICO HISTOPATOLOGICO

IHQ

M-E

OTROS

MOLECULAR

DATOS CLINICOS

TRATAMIENTO

PACIENTE

SEGUIMIENTO/ CRIBADO

TRATAMIENTO INDIVIDUALIZADO

CLASIFICACION Y ESTADIAJE

DIAGNOSTICO PRECOZ

Medicina de Precisión

“Tumores morfológicamente idénticos pueden

tener comportamiento clínico diverso y distinta respuesta al tratamiento”

Indice

I. Conceptos moleculares y morfológicos de relevancia clínica.

II. Síndromes hereditarios III. Biomarcadores de dianas terapéuticas. IV. Inmunoterapia V. Biopsia líquida

Transcriptomica próstata

Múltiples mutaciones Selección natural: Un

driver? Heterogeneidad

I .- Conceptos

The hallmarks of cancer

1

“Adicción” a una vía proliferativa”

Hanahan and Weinberg, Cell 2000. Hanahan and Weinberg, Cell. 2011, Jan;144(5):646-74.

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3

4

5

6

Slide 8.37

Diferentes pathways para el mismo tumor

Clasificación molecular

17% 7%

22%

2%

A.- Lung cancer mutation consortium

FISH/crizotinib

IHQ,FISH/ crizotinib

PCR/ TKIs

PCR/ dasatinib Nuevas: Ros1 fusions 1% FISH RET fusions 1% FISH

B.-

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.

The consensus molecular subtypes of colorectal cancer: (2015)

Nature Medicine 2015; 21: 1350–1356

* Adjusted for stage, MSI, BRAF mut, adjuvant chemotherapy, and stratified by dataset.

Perez-Villamil et al, BMC 2012

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

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

II Síndromes hereditarios

Incidencia Lynch: 1/300

Síndromes hereditarios

• Modifican el cribado del cáncer. Consejo genético.

• Implicaciones pronósticas y terapéuticas. Modifica los procedimientos quirúrgicos

• Modifica el seguimiento

- Tratamiento oncológico:

a) Sin Biomarcador de respuesta terapéutica en el tumor y/o paciente

b) Con biomarcador “predictor” de respuesta

III- Biomarcadores

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) FDA-approved indication(s)

Erlotinib (Tarceva) EGFR (HER1/ERBB1) Non-small cell lung cancer

Pancreatic cancer

Everolimus (Afinitor) mTOR • Pancreatic neuroendocrine tumor

• Renal cell carcinoma

• Nonresectable subependymal giant cell astrocytoma + tuberous sclerosis

• Breast cancer (HR+, HER2-)

Gefitinib (Iressa) EGFR (HER1/ERBB1) • NSCLC( EGFR exon 19 del or L858Rmut)

Imatinib (Gleevec) KIT, PDGFR, ABL 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 Thyroid cancer

Nivolumab (Opdivo) PD-1 • 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

Regorafenib (Stivarga) KIT, PDGFRβ, RAF, RET, VEGFR1/2/3 • Colorectal cancer

• Gastrointestinal stromal tumors

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

- Guías clínicas SEAP-SEOM - Programas de calidad - Centros de Referencia

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BIOMARCADOR CÁNCER FÁRMACO HER2 (FISH/IHQ) Mama

Estómago Trastuzumab Lapatinib Trastuzumab

KIT y PDGFRA (mutación) GIST Imatinib KRAS y NRAS (mutación) Colo-rectal Panitumumab

Cetuximab EGFR (mutación) Pulmón

(adenocarcinoma) Gefitinib Erlotinib

ALK (FISH/IHQ) Pulmón (adenocarcinoma)

Crizotinib

BRAF (mutación/IHQ) Melanoma Vemurafenib

¿Dónde? Anatomía Patológica Otro Servicio Desconocido

KIT 78,9% 15,5% 5,7% KRAS 76,3% 23,7% HER2 98,3% 1,7% EGFR 79,3% 20,7% BRAF 73% 25% 2%

• Cáncer de mama: – Her2 (FISH) – Recept Estrog y Prog. (IHQ) – Ki67 (IHQ)

• Cáncer de pulmón

– EGFR (PCR) – EMLA4-Alk (FISH, IHQ) – Ros1 – PDL1

• Cáncer de colon

– K-ras y Nras (PCR)

• Melanoma: – bRaf (PCR, IHQ) – PD1/PDL1

• GIST:

– C-kit y PDGFRa (PCR)

1. Al diagnóstico: En Primario o metástasis: Para

decidir tratamiento

2. Tras neoadyuvancia: Para valorar respuesta

3. Para decidir adyuvancia

4. Tras tratamiento selectivo; resistencia….: para valorar nuevos tratamientos

5. En Biopsia líquida

III- Biomarcadores

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

• Landscapes of Human

Breast and Colorectal Cancers

• Laura D. Wood et al.

EEj NGS: • -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.

Frank Macfarlane

Burnet (1899–1985).

Immunosurvilliance Immunosenescence Immunoediting: elimination, equilibrium, escape.

1Cancer immunity:

William Coley, 1880s, New York surgeon, Coley toxins

IV- Inmunoterapia

A.-

B.-

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CD56+, CD3+

CD56+, CD3-

Chemical microenvironment

CD117

CD1a

Role of Lymphocytes

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External Validation (n=162)

Hazard Ratio: 3.359, Log-Rank: P=0.001

Low risk expression profile

High risk expression profile

Dise

ase-

free

surv

ival

Cluster “High risk” (112) ——

Cluster “Low risk” (50) ——

Development series (n=84) Years

A 50-gene “immune” expression profile classifies early-stage NSCLC (n=246) into low and high recurrence risk”

Sanz-Ortega J et al, CTO 2014.

Firma génica HCSC “50 genes”

B and plasma cells: Maduration Recruiting Memory cells Proliferation Anti-apoptosis

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

Firma 50 genes: Inmunidad B sobre-expresada en Low-risk

Lung cancer

• 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

Immunoscoring NSCLC for prognosis (RFS)

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….

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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.