Bases biológicas del cáncer de ovario en el siglo XXI

Transcription

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

2 Epithelial Ovarian Tumors WHO Serous Mucinous Endometrioid Clear cell Transitional Squamous Benign 60% BL 10% Ca 30%

3 Ovarian Carcinomas WHO 1973 Serous Mucinous Endometrioid Clear cell

4 Ovarian Carcinomas WHO 1973 Serous Mucinous Endometrioid Clear cell

5 HG- Serous Genomic chaos P53, BRCA Mucinous Abnormal RAS ERBB2 LG-Serous MAPK pathway (KRAS, BRAF) Endometrioid Abnormal PTEN,PI3K,AKT signaling Clear cell A disease of ARID1A

6 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

7 New classification: Frequency HG serous LG serous Clear cell Endometrioid Mucinous Unclassifiable

8 Serous Carcinoma (High-grade)

9 HEREDITARY SUSCEPTIBILITY TO OVARIAN CANCER BRCA2 (30%) Lifetime risk 15-30% BRCA1 (65%) Lifetime risk 30-60% HNPCC (7%) Hereditary (10%) Rebbeck TR, Lynch HT, et al. NEJM 2002 Sporadic (90%)

10 Fallopian Tube Fimbria (STIC)

11 Serous Tubal Intraepithelial Carcinoma STIC p53

12 How about less than STIC?

13 P53 Signature

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15 Normal P53 P53 signature BRCA1 STIC Hereditary : BRCA1 mutation constitutive Normal P53 P53 signature BRCA1 STIC Sporadic : BRCA1 methylation/mutation new event

16 HGSC Pathogenetic Model DDL Bowtell Nature Rev Cancer 2010

17 Chromosomes from six ovarian cancers showing: chromosomal instability A B C X X D E X X F X X

18 Folate Receptor Farletuzumab Tumor Cell VEGF Bevacizumab VEGF Trap Endothelial Cell VDA Combretastain PI3Kinase/AKT mtor inhibitors Ras/Raf/MEK inhibitors Src inhibitors Saracatinib Aurora kinase inhibitors MLN8237 PI3K/AKT mtor Ras/Raf/MEK Src Nucleus PDGFR Imatinib BIBF 1120 HER2/EGFR/IGFR Erlotinib Gefitinib Trastuzumab Pertuzumab AMG479 Angiopoietin AMG 386 VEGFR Sorafenib Sunitnib Cediranib Pazopanib BIBF 1120 Tie2 receptor FGFR BIBF 1120 PARP inhibitors Olaparib AG BSI-201 ABT-888 MK-4827 PARP HR-mediated DNA repair Normal Cell CELL SURVIVAL DNA Replication Tumor Cell (BRCA defficient) CELL DEATH Integrin Volociximab ANGIOGENESIS SB Kaye, 2011 Impaired HR-mediated DNA repair

19 Origin of HGSC: where and how?

20 SET High-grade Serous Carcinomas Soslow RA. et al. Mod Pathol. 2012

21 Differences between SET and Classic High-grade Serous Carcinomas 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 More responsive Less responsive inhibitors Howitt BE. et al. AJSP. 2015

22 Histologic Types of Ovarian Carcinomas Serous high grade Serous low grade Clear cell Endometrioid Mucinous

23 Low-grade High-grade

24 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

25 Serous Borderline Tumor SBT + Low-grade serous carcinoma

26 Mutational Analysis Tumor Subtype BRAF Mutation KRAS Mutation Serous Borderline Tumor 0-40% 40% Low-grade SC 5% 20-40% High-grade SC 0% 0-14%

27 Histologic Types of Ovarian Carcinomas Serous high grade Serous low grade Clear cell Endometrioid Mucinous

28 Mucinous glands Carcinoma Cystadenoma Borderline

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30 Anglesio, J Path 2013

31 Endometrioid and Clear Cell Tumors develop from Ovarian Endometriosis Retrograde menstruation Endometriosis Carcinoma Borderline tumor

32 Ovarian Atypical Endometriosis Endometrioid or Clear Cell Carcinomas 15-32% of cases

33 Endometriosis (Animal models) Mice harboring K-ras benign lesions endometriosis Deletion of PTEN invasive endometrioid carcinoma Dinulescu DM, et al. Nat Med 2005

34 Genetic Alterations of Endometrioid Carcinomas of the Ovary Beta-Catenin 20-40% ARID1A 30% PTEN 15-20% PIK3CA 20% MSI 15% K-RAS 4-35% TP53 10%

35 ARID1A (SWI/SNF) (Diverse functions) AKT signaling PIK3CA signaling Epithelial-mesenchymal transition (EMT) Cell cycle progression Apoptosis DNA damage repair Cancer metabolism

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38 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

39 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 New York: Springer- Verlag; 1968.