Granulosa Cell Tumor Monitoring and Treatment. Outline: 1. Surgery 2. Adjuvant 3. Chemo 4. Hormonal 5. Investigational. Whole Genome Sequencing

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1 Potential Conflicts of Interest capped at a level befitting an academic role Lo B. Serving Two Masters 2010;362: Granulosa Cell Tumor Monitoring and Treatment Richard T. Penson, MD, MRCP Clinical Director Medical Gynecologic Oncology Genentech, Inc. Research DSMC Chair DARA BioSciences, Inc. Consultant DARA BioSciences, Inc. Research Funding MGI PHARMA, INC. Research Funding Lilly and Company. Consultant Bayer HealthCare Pharma. Research Funding GlaxoSmithKline. Scientific Advisory Board CuraGen Corporation. Research Funding PDL BioPharma, Inc. Research Funding ImClone Systems, Inc. Research Funding Abbott Laboratories. Scientific Advisory Board Endocyte, Inc. Research Funding AstraZeneca. Research Funding Eisai Inc. ResearchFunding. Genetic Aberrations in Ovarian Carcinomas Gene Amplification 1q22 RAB25 3q26 PRKCI, EVI1 and PIK3CA 5q31 FGF1 8q24 MYC 19q PIK3R1 and AKT2 20p ND 20q13.2 AURKA Gene deletion 4q, 5q, 16q, 17p, 17q, Xp&q - Gene ND Mutation (Activation) KRAS (15%) BRAF (12%) CTNNB1 (12%) CDKN2A (10%) APC (9%) PIK3CA (8%) KIT (7%) SMAD4 (7%) Loss of Heterozygosity (Inactivation) 17p13 and 17q21 (>50%) ARHI, PEG3, PLAGL1, RPS6KA2, TP53, BRCA1, BRCA2 1p, 3p, 5q, 5q, 6q, 7q and 8q (<30%) PTEN, OPCML and WWOX Bast, Hennessy, & Mills. Nature Reviews Cancer 2009;9: (Inactivation) TP53 (62%) BRCA1 (5%) BRCA2 (<5%) PTEN (3-8%) ARID1A (33-46%) New Engl J Med Hypomethylation (Activation) IGF2 and SAT2 Promoter methylation (Inactivation) ARHI, DAPK1, MLH1, ICAM1, BRCA1, BRCA2, MUC2, CDKN2A, RASSF1, SOCS1 Whole Genome Sequencing Mod. Levanon K, Crum C, Drapkin R. JCO 2008;26:

2 Forkhead Transcription Factor FOXL2 orkhead transcription factor FOXL2 N Engl J Med. 2009;360: Coffee bean nuclei Call-Exner Bodies

3 Granulosa Cell Tumor: Individualized and Personalized Care Diagnosis, Surgery and First Line Therapy Symptoms Pelvic/abd pain Urinary Bloating Early satiety Markers Abnormal US Complex Cyst >5 cm Advanced Disease Likely optimally cytoreducible Diagnostic Laparotomy Staging Diagnostic Laparotomy Debulking Adjuvant Chemotherapy Carboplatin Paclitaxel Or BEP Consider Clinical trial Intraperitoneal Chemotherapy Substituting weekly paclitaxel or docetaxel Granulosa Cell Tumor: Individualized and Personalized Care Treatment of Recurrence Rising Inhibin Potentially Platinum Resistant Rec. < 6 months Carefully consider Rx Palliative Chemotherapy Asymptomatic - Too Early Multifocal >5 cm disease - Too Late Tailor to Toxicity Consider Peg. Lipo. Doxorubicin Bevacizumab cost & risk of GIP vs. longer Gemcitabine PFS Weekly topotecan, Clinical trial Weekly paclitaxel Serous PARPi GOG 9923 Pemetrexed Endometrioid Pi3K mtor inhibitor GOG 86P Clear cell Antiangiogenic GOG 254 Mucinous GI regimen / antiangiogenic GOG 241 Low Grade MEK or b-raf inhibitor GOG 239 Advanced Disease Older Significant comorbidities Sick Stage IV Neoadjuvant Chemotherapy Carboplatin Paclitaxel or Carboplatin If responding If not Interval Cytoreduction Personalize Care Potentially Platinum Sensitive Rec. > 6 months Platinum based Combination Chemotherapy Options Secondary Cytoreduction IF Few mets and pt Fit Carboplatin and Peg. Lipo. Doxorubicin or Gemcitabine or Weekly Paclitaxel Clinical Trial and monitoring

4 CA-125 MUC1, 16, other mucins in gel Modified Gendler 2001

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6 GOG RTM 0602 GOG 264 Chemo naive primary or recurrent sex cord/ stromal tumors of the ovary Randomized phase II Carboplatin/paclitaxel vsbep Sample size: N= patients

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8 Prospective Bevacizumab Trials Relapsed Ovarian Cancer Study Treatment Prior Treatment Setting Efficacy 6-mo PFS ORR GOG 170-D* [n=63] Single agent BV 15 mg/kg q 3 wk Relapsed platinum disease, up to 2 prior regimens 40% 18% NCI 5789** [n=70] BV 10 mg/kg q 2 wks + low dose oral cytoxan Relapsed platinum disease w/ postplatinum maximum of 2 regimens 56% 24% ORBIT*** [n = 44] Single agent BV 15 mg/kg q 3 wk Platinum, and Doxil/topo resistant, up to 3 regimens total 28% 16% GIP 0 2 [3%] 5 [11%] *R Burger et al., ASCO, J Clin Oncol 2007;25:5165 **A Garcia et al., ASCO, J Clin Oncol 2008;26:76 ***S Cannistra et al., ASCO, J Clin Oncol 2007;25:5180 GOG-251: A Phase II Trial Of Bevacizumab For Recurrent Sex Cord-Stromal Tumors Of The Ovary STUDY CHAIR STUDY: Jubilee Brown, M.D. M.D. Anderson Cancer Center SCHEMA: Bevacizumab 15 mg/kg IV Repeat every 21 days until disease progression or adverse effects prohibit further treatment 1. PRIMARY OBJECTIVE: To estimate the anti-tumor activity of bevacizumab by assessing frequency of objective response in patients with recurrent sex cordstromal tumors of the ovary who have measurable disease. 2. SECONDARY OBJECTIVES: To determine the nature and degree of toxicity in these patients. To determine the overall survival and progression-free survival of these patients. 3. TRANSLATIONAL RESEARCH OBJECTIVE: To quantify expression of angiogenic or lymphangiogenic markers in recurrent stromal tumors of the ovary to determine the frequency of alterations and potential utility of biologic agents directed at these proteins for inclusion in future studies.

9 Challenges?. Neumann Safety x Efficacy x PFS OS. Cost med. III cost $72,576 $401,088 per PF- Eisenhauer LYS On the basis of today s results, I Need OS data believe the use of bevacizumab in QoL data standard clinical practice may be ICON-7 premature. Who Decides? Investigators? PJ. National survey of oncologists. Health Aff (Millwood). 2010;29:196. Survival time required for new Rx that cost $70K 45% said 2-4 months $280K >> K per QALY. Patients?? Treasury? Insurance NCCN? Co? ASCO? Avastin May Extend PFS In Ovarian Cancer Patients Media? the cancer drug Avastin [bevacizumab] extends progressionfree survival by 39% in ovarian cancer patients." extended Avastin treatment, it took a median of 14.1 months for the cancer to start worsening, compared with 10.3 months Avastin can help fight relapsed ovarian cancer, this is the first" study "to show it also combats newly diagnosed disease, Burger says." SUMMARY Antiangiogenics Bevacizumab is a great drug Bevacizumab is not for everyone Bevacizumab is going to be the test of cost-effectiveness Richard T Penson MD MRCP rpenson@partners.org