Transcript Document

New Developments in Biology and
Targets of
Epithelial Ovarian Cancer
Michael Birrer
Ian McNeish
Ovarian Cancer
Historic Perspective
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All serous tumors thought to arise from surface
epithelium/inclusion cysts.
75% patients present with advanced stage disease.
80% respond to chemotherapy.
Vast majority of patients relapse and eventually develop
drug resistant disease.
Minimal increase in overall survival over last 30 years.
All patients treated with surgery and chemotherapy.
New Development in
Biology
Origins
Integrating the models of serous
carcinogenesis – a binary model
Levanon, Crum, and Drapkin, JCO, 2008
How does it affect screening?
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Is the target lesion a 1mm lesion in the
fallopian tube?
How rapidly do these progress?
What about tumors arising from the
surface of the ovary?
How does it affect
treatment?
Two types of Serous Tumors?
Surface Epithelium versus
Fallopian tube
Are they biologically the same?
Is Ovarian Cancer a
Homogenous Disease?
Histology
ENDOMETRIUM OVARY
OVARIAN AND ENDOMETRIAL CANCER
SUBTYPES
SEROUS
ENDOMETRIOID
CLEAR CELL
OVARIAN & ENDOMETRIAL CANCER
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OVARIAN ENDO & SEROUS
ENDOMETRIAL ENDO &
SEROUS
OVARIAN CLEAR CELL
ENDOMETRIAL CLEAR CELL
Zorn et. al. Clinical Cancer Research 2005
CLEAR CELL CANCER
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OVARIAN
ENDOMETRIAL
RENAL
Zorn et. al. Clinical Cancer Research 2005
Clinical Impact of Genomic
Characterization of Clear Cell Cancers
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Remove clear cell tumors from ovarian
cancer phase III trials.
Create clear cell specific phase II trials.
Utilize understanding of molecular
pathways of clear cell cancers from other
organs to better treat ovarian cancer.
Expression Profiling of Clear
Cell Tumors of the Ovary
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15 clear cell cancers of the ovary
Whole genome profiling
Supervised clustering
Pathway identification
Clear Cell Ovarian Cancer HIF1 alpha Pathway
Angiogenesis
Cell Migration
Glycolysis
HIF1alpha degradation
Cell Cycle Progression
Is ovarian cancer a
homogenous
disease?
Grade
Unsupervised Hierarchical Clustering of Serous
Ovarian Cancers
Ovarian Cancer
Papillary Serous Ovarian Tumors
High Grade
P53Normal Cells
P53+
LMP/Low Grade
B-raf, ras
Bonome et al Cancer Research 2005
Low Grade Phase II Trials
GOG 239 AZ MEK Inhibitor
What About Papillary Serous Ovarian Cancer?
90% of ovarian cancers are papillary serous tumors.
All tumors high grade tumors treated with surgery
and chemotherapy.
Activated pathways remain unknown.
Figure 5">
Tothill, R. W. et al. Clin Cancer Res 2008;14:5198-5208
Copyright ©2008 American Association for Cancer Research
Gene signatures predicts survival only
for suboptimally debulked tumors
Optimally Debulked
Suboptimally Debulked
Co-regulated Signaling Events In Sub-optimal Patient Subgroups
TCGA
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200 high grade serous ovarian cancers
6000 genes sequenced
Expression profiling
Copy number differences
Methylation status
Future Directions
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Histo/grade specific trials and regimens.
Identification of sub-groups of patients
based upon genomic patterns and
activated pathways.
Future Challenges
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Validation of prognostic and predictive
biomarkers.
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Identification and validation of small molecule
inhibitors targeting pathways
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Larger numbers of carefully annotated specimens
FFPE technologies
Integrated biomarkers will be mandated.
Molecular basis for resistance
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Recurrent tumor biopsies should be a requirement.
Michael J. Birrer M.D. Ph.D.
Professor of Medicine Harvard Medical School
Director Gynecologic Medical Oncology
Massachusetts General Hospital