1. Michael Birrer Ian McNeish New Developments in Biology and Targets of Epithelial Ovarian Cancer

2. Ovarian Cancer Historic Perspective All serous tumors thought to arise from surface epithelium/inclusion cysts. All serous tumors thought to arise from surface epithelium/inclusion cysts. 75% patients present with advanced stage disease. 75% patients present with advanced stage disease. 80% respond to chemotherapy. 80% respond to chemotherapy. Vast majority of patients relapse and eventually develop drug resistant disease. Vast majority of patients relapse and eventually develop drug resistant disease. Minimal increase in overall survival over last 30 years. Minimal increase in overall survival over last 30 years. All patients treated with surgery and chemotherapy. All patients treated with surgery and chemotherapy.

3. New Development in Biology Origins

4. Integrating the models of serous carcinogenesis – a binary model Levanon, Crum, and Drapkin, JCO, 2008

5. How does it affect screening? Is the target lesion a 1mm lesion in the fallopian tube? Is the target lesion a 1mm lesion in the fallopian tube? How rapidly do these progress? How rapidly do these progress? What about tumors arising from the surface of the ovary? What about tumors arising from the surface of the ovary?

6. How does it affect treatment? Two types of Serous Tumors? Surface Epithelium versus Fallopian tube Are they biologically the same?

7. Is Ovarian Cancer a Homogenous Disease? Histology

8. OVARIAN AND ENDOMETRIAL CANCER SUBTYPES SEROUS ENDOMETRIOID CLEAR CELL OVARY ENDOMETRIUM

9. OVARIAN & ENDOMETRIAL CANCER OVARIAN ENDO & SEROUS ENDOMETRIAL ENDO & SEROUS OVARIAN CLEAR CELL ENDOMETRIAL CLEAR CELL Zorn et. al. Clinical Cancer Research 2005

10. CLEAR CELL CANCER OVARIAN ENDOMETRIAL RENAL Zorn et. al. Clinical Cancer Research 2005

11. Clinical Impact of Genomic Characterization of Clear Cell Cancers Remove clear cell tumors from ovarian cancer phase III trials. Remove clear cell tumors from ovarian cancer phase III trials. Create clear cell specific phase II 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. Utilize understanding of molecular pathways of clear cell cancers from other organs to better treat ovarian cancer.

12. Expression Profiling of Clear Cell Tumors of the Ovary 15 clear cell cancers of the ovary 15 clear cell cancers of the ovary Whole genome profiling Whole genome profiling Supervised clustering Supervised clustering Pathway identification Pathway identification

13. Cell Cycle Progression Glycolysis HIF1alpha degradation Angiogenesis Clear Cell Ovarian Cancer HIF1 alpha Pathway Cell Migration

14. Is ovarian cancer a homogenous disease? Grade

15. Unsupervised Hierarchical Clustering of Serous Ovarian Cancers

16. Ovarian Cancer Normal Cells Papillary Serous Ovarian Tumors LMP/Low Grade High Grade P53- P53+ B-raf, ras Bonome et al Cancer Research 2005

17. Low Grade Phase II Trials GOG 239 AZ MEK Inhibitor

18. 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.

19. Copyright ©2008 American Association for Cancer Research Tothill, R. W. et al. Clin Cancer Res 2008;14:5198-5208 Figure 5">

20. Optimally Debulked Suboptimally Debulked Gene signatures predicts survival only for suboptimally debulked tumors

21. Co-regulated Signaling Events In Sub-optimal Patient Subgroups

22. TCGA 200 high grade serous ovarian cancers 200 high grade serous ovarian cancers 6000 genes sequenced 6000 genes sequenced Expression profiling Expression profiling Copy number differences Copy number differences Methylation status Methylation status

23. Future Directions Histo/grade specific trials and regimens. Histo/grade specific trials and regimens. Identification of sub-groups of patients based upon genomic patterns and activated pathways. Identification of sub-groups of patients based upon genomic patterns and activated pathways.

24. Future Challenges Validation of prognostic and predictive biomarkers. Validation of prognostic and predictive biomarkers. Larger numbers of carefully annotated specimens Larger numbers of carefully annotated specimens FFPE technologies FFPE technologies Identification and validation of small molecule inhibitors targeting pathways Identification and validation of small molecule inhibitors targeting pathways Integrated biomarkers will be mandated. Integrated biomarkers will be mandated. Molecular basis for resistance Molecular basis for resistance Recurrent tumor biopsies should be a requirement. Recurrent tumor biopsies should be a requirement.

25. Michael J. Birrer M.D. Ph.D. Professor of Medicine Harvard Medical School Director Gynecologic Medical Oncology Massachusetts General Hospital