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Bases biológicas del cáncer de ovario en el siglo XXI Iñigo Espinosa, M.D. Clínica Universidad de Navarra

Bases biológicas del cáncer de ovario en el siglo XXI · Clínica Universidad de Navarra . Epithelial Ovarian Tumors _____ Serous Mucinous Endometrioid Clear cell Transitional Squamous

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Bases biológicas del cáncer de ovario en el

siglo XXI

Iñigo Espinosa, M.D.

Clínica Universidad de Navarra

Epithelial Ovarian Tumors _________________________________________________________________________________________

Serous

Mucinous

Endometrioid

Clear cell

Transitional

Squamous

Benign

60% BL

10% Ca 30%

WHO 1973-2014

Ovarian Carcinomas _________________________________________________________________________________________

Serous

Mucinous

Endometrioid

Clear cell

WHO 1973

Ovarian Carcinomas _________________________________________________________________________________________

Serous

Mucinous

Endometrioid

Clear cell

WHO 1973

• HG-

Serous

Genomic chaos

P53, BRCA

• Clear cell – A disease of

ARID1A

• Endometrioid Abnormal

PTEN,PI3K,AKT

signaling

• Mucinous Abnormal RAS

ERBB2

• LG-Serous MAPK pathway

(KRAS, BRAF)

These types differ from each

other with respect to:

1. Risk factors and precursor lesions 2. Patterns of spread 3. Molecular genetic alterations 4. Response to chemotherapy 5. Outcome

New classification: Frequency

HG serous

LG serous

Clear cell

Endometrioid

Mucinous

Unclassifiable

Serous Carcinoma (High-grade)

HEREDITARY SUSCEPTIBILITY

TO OVARIAN CANCER

BRCA2 (30%)

BRCA1 (65%)

HNPCC (7%)

Hereditary (10%)

Sporadic (90%)

Lifetime risk 30-60%

Lifetime risk 15-30%

Rebbeck TR, Lynch HT, et al. NEJM 2002

Fallopian Tube Fimbria (STIC)

Serous Tubal “Intraepithelial” Carcinoma

STIC

p53

How about less than “STIC”?

P53 Signature

P53 signature P53 signature TIC TIC Normal Normal P53 P53 BRCA1 BRCA1

P53 signature P53 signature TIC TIC Normal Normal P53 P53

Sporadic : BRCA1 methylation/mutation new event

Hereditary : BRCA1 mutation constitutive

P53 signature P53 signature TIC STIC Normal Normal P53 P53 BRCA1 BRCA1

P53 signature P53 signature TIC STIC Normal Normal P53 P53

BRCA1

Sporadic :

Hereditary : BRCA1 mutation constitutive

HGSC – Pathogenetic Model

DDL Bowtell Nature Rev Cancer 2010

Chromosomes from six ovarian cancers showing:

chromosomal instability

1 2 3

4 5

6 7 8

9 10 11

12 13 14 15

16 17 18

19 20

21 22 X

1 2 3

4 5

6 7 8

9 10 11

12 13 14

15 16 17 18

19 20

21 22 X

1 2 3

4 5

6 7 8

9 10 11

12 13 14 15

16 17 18

19 20

21 22 X

1 2

3 4 5

6 7 8

9 10 11

12 13 14 15

16 17 18

19 20

21 22 X

1 2 3

4 5

6 7 8 9

10 11 12

13 14 15

16 17 18

19 20 21

22 X

1 2 3

4 5

6 7 8

9 10 11

12 13 14 15

16 17 18

19 20

21 22 X

A B

C D

E F

Tumor Cell Folate Receptor

Farletuzumab

Endothelial Cell

PI3Kinase/AKT mTOR inhibitors

Ras/Raf/MEK inhibitors

Src inhibitors Saracatinib

Aurora kinase inhibitors

MLN8237

PARP

inhibitors Olaparib

AG-014699

BSI-201

ABT-888

MK-4827

PI3K/AKT mTOR

Src

Ras/Raf/MEK

Nucleus

PARP DNA Replication

Normal Cell Tumor Cell (BRCA defficient)

HR-mediated

DNA repair

CELL

SURVIVAL

CELL

DEATH Impaired

HR-mediated

DNA repair

HER2/EGFR/IGFR Erlotinib

Gefitinib

Trastuzumab

Pertuzumab

AMG479

PDGFR Imatinib

BIBF 1120

VEGFR Sorafenib

Sunitnib

Cediranib

Pazopanib

BIBF 1120

FGFR BIBF 1120

Angiopoietin AMG 386

Integrin Volociximab

Tie2 receptor

VDA Combretastain

ANGIOGENESIS

VEGF Bevacizumab

VEGF Trap

SB Kaye, 2011

Origin of HGSC: where and how?

“SET” High-grade Serous Carcinomas

Soslow RA. et al. Mod Pathol. 2012

“SET” Classic

Histologic pattern Solid, endometrioid, transitional Solid growth with slit-like glandular lumens

Age Younger Older

STIC 23% 67%

BRCA mutation 50% 28%

Behavior Rapidly growing Lag phase from STIC to symptomatic metastatic tumor

Response to chemotherapy and PARP

inhibitors

More responsive Less responsive

Differences between “SET” and Classic High-grade Serous Carcinomas

Howitt BE. et al. AJSP. 2015

Histologic Types of Ovarian Carcinomas

• Serous – high grade

• Serous – low grade

• Clear cell

• Endometrioid

• Mucinous

Low-grade High-grade

Low-Grade Serous Carcinoma (<5% of ovarian carcinomas)

• Progression of SBT (6-7%)

• Relatively chemoresistant

• Median overall survival = 7 yr

Gershenson et al,

Obtet Gynecol 2006

Serous Borderline Tumor SBT + Low-grade serous carcinoma

Serous Borderline Tumor 0-40% 40% Low-grade SC 5% 20-40% High-grade SC 0% 0-14%

Tumor Subtype BRAF Mutation KRAS Mutation

Mutational Analysis

Histologic Types of Ovarian Carcinomas

• Serous – high grade

• Serous – low grade

• Clear cell

• Endometrioid

• Mucinous

Mucinous

glands

Cystadenoma

Borderline

Carcinoma

Anglesio, J Path 2013

Endometrioid and Clear Cell Tumors develop from Ovarian Endometriosis

Endometriosis

Retrograde

menstruation

Borderline

tumor

Carcinoma

Ovarian Atypical Endometriosis Endometrioid or Clear Cell Carcinomas

15-32% of cases

Endometriosis

(Animal models)

· Mice harboring K-ras → benign lesions ≈

endometriosis

· Deletion of PTEN → invasive endometrioid

carcinoma

Dinulescu DM, et al.

Nat Med 2005

Beta-Catenin 20-40%

ARID1A 30%

PTEN 15-20%

PIK3CA 20%

MSI 15%

K-RAS 4-35%

TP53 10%

Genetic Alterations of Endometrioid Carcinomas of the Ovary

ARID1A (SWI/SNF) (Diverse functions)

• AKT signaling • PIK3CA signaling • Epithelial-mesenchymal transition

(EMT) • Cell cycle progression • Apoptosis • DNA damage repair • Cancer metabolism

Summary

• Ovarian cancer is not a homogeneous disease Neither one single type nor two types (“type I/type II”) but at least 5 different diseases

• Different genetic alterations: target therapies

• Some “ovarian cancers” (HGSCs) may originate in the Fallopian tube fimbria

• Endometrioid, clear cell, low-grade serous, and mucinous carcinomas (≈30%) are unrelated to the tube

‘‘Ovarian cancer is not an entity

but a group of diseases’’

Dr. Hans L. Kottmeier

Dr. Lars J. H. Santesson

UICC Monograph Series,

Ovarian Cancer. Vol. 11. pp. 1–8. New York: Springer-

Verlag; 1968.