Post on 21-Oct-2018
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
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
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
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
“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 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 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
Endometrioid and Clear Cell Tumors develop from Ovarian Endometriosis
Endometriosis
Retrograde
menstruation
Borderline
tumor
Carcinoma
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