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European Studies– Ovarian Cancer

European Studies– Ovarian Cancer. Definition Primary/Acquired Histopathology Heterogeneity Trials Future Directions. 100. 90. 80. 70. Overall Logrank test: p=0.001. 60. 50. 40. 30. 20. 10. 0. (years). 0. 1. 2. 3. 4. 5. 6. 7. 8. O. N. Number of patients at risk :.

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European Studies– Ovarian Cancer

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  1. European Studies– Ovarian Cancer Definition Primary/Acquired Histopathology Heterogeneity Trials Future Directions

  2. 100 90 80 70 Overall Logrank test: p=0.001 60 50 40 30 20 10 0 (years) 0 1 2 3 4 5 6 7 8 O N Number of patients at risk : 268 338 266 179 127 91 74 54 9 CP 243 342 292 221 167 126 105 76 6 TP Overall Survival Update with 6.5 years median follow-up B. Baron, March 2002

  3. Dose dense chemotherapy Carboplatin AUC6 +weekly paclitaxel 80 mg/m2/week Katsumata et al Lancet 2009

  4. Overall Survival ICON and EORTC combined (n = 925) HR = 0.68, p=0.01 95%CI (0.51, 0.92) Absolute difference At 5 year=8% (74% 82%) 95%CI (2%, 11%)

  5. Carboplatin vs Carbo/paclitaxel – Early ovarian cancer Adams et al BJOG 2010

  6. What Is Ovarian Cancer? Picture clipping

  7. 100 80 60 40 20 0 0 – 6 7 – 12 13 – 18 > 18 Interval from previous treatment, mo Relationship of Treatment-Free Interval & Response to Therapy • Independent Predictors of Response (Eisenhauer) • Serous Histology p=0.009 • No. of Disease Sites (<3) p=0.003 • Tumour size (<5cm) p=0.001 • Time since last chemo p=0.008 • <6 vs>6 months Response rate, % Blackledge et al.Br J Cancer 1989; 59: 650-653

  8. 1000 100 Survival Response • 957 ( days ) rate (%) 800 80 Overall survival • • 600 60 60 • Response • 393 rate • 400 40 • • • • • • 217 33 339 • • • • 200 20 • • - Progression • 174 9 free survival • • 90 0 0 0 - 3 /Pr 0 - 3 3 - 6 6 - 9 9 - 12 12 - 18 >18 GINECO. ASCO 2002 TFI ( months ) Treatment-Free Interval and Efficacy

  9. Breast Cancer Subtyping Her2 +ve Luminal A Luminal B Triple negative/ Basal Normal like

  10. % of mutation frequency ND ND Kuo et al 2009

  11. PersonalisedMedicine Molecular signature 1-90 genes/ER/kras/ b-raf /ECM Surrogate marker CA125 PET imaging Platinum sensitive BRCAmut or - like

  12. Relative survival – ovarian cancer subtypen=8704 7RCTs Mackay et al 2010

  13. Mucinous vs Serous Ovar 3, ICON5 and GOG182 had central path review

  14. PPM1D amplification in OCCA Tumours • PPM1D Amplified in 10% of OCCA tumours • Potential therapeutic target in a subset of OCCAs with wt p53 Tan et al CCR 2009

  15. Tp53 and Drug Resistance Shang Oncogene 2010

  16. Lee et al 2007 J Pathol

  17. BRCA1/2 alterations and outcome Henessey et al JCO 2010

  18. Genetic Alterations - EOC

  19. Bowtell D 2010

  20. Tothill et al 2008

  21. Selection of Targeted Therapy _ Ovarian Cancer

  22. Mucinous Ovarian Cancer (MeOC) • Carboplatin+paclitaxel x 6 cycles • vs Oxaliplatin 150mg/m2+capcitabine 1000mg/m2 Chemotherapy and 2 X 2 with bevacizumab

  23. OVAR 16/LUPTS Carboplatin AUC6 Primary endpoint: OS Secondary endpoint: PFS Arm A Paclitaxel 175 mg/m2 Placebo? Sub-optimally debulked Stage III/ IV OC Carboplatin AUC6 Arm B Paclitaxel 175 mg/m2 1:1:1 Randomization BBIF 1120 Stratification variables: PS (0-1 vs 2), stage (III vs IV) 15 months* Cycles (q3wk)* * Taxane consolidation therapy prohibited

  24. OVAR pazopanib Carboplatin AUC6 Primary endpoint: OS Secondary endpoint: PFS Arm A Paclitaxel 175 mg/m2 Placebo? Stage I/II OC Carboplatin AUC6 Arm B Paclitaxel 175 mg/m2 2:1 Randomization Pazopanib Stratification variables: PS (0-1 vs 2), stage (III vs IV) 15 months* Cycles (q3wk)* * Taxane consolidation therapy prohibited

  25. Summary and Future Directions • Greater understanding of molecular basis of ovarian cancers • Heterogeneity • intertumoural and intratumoural • Histopathology • Immunochemistry • stroma • mutation/CNA • Matching drugs to targets • systems biology • multidisciplinary working • education/training • EUTROC - www.eutroc.org

  26. Bowtell D 2010

  27. PARP phase 2 trials

  28. Mechanism of PARPi

  29. BRCAness Hennessy et al 2010

  30. Merlo et al.Nature Reviews Cancer advance online publication; published online 16 November 2006 | doi:10.1038/nrc2013

  31. Cisplatin + Paclitaxel IV vs IPOverall Survival Armstrong et al. NEJM 2006; 354 (1): 34-43

  32. Weekly ( dose dense) paclitaxel Patients were randomly assigned to receive carboplatin to an AUC 6 with either paclitaxel at 180 mg/m2 on day 1 or paclitaxel at 80 mg/m2on days 1, 8, and 15. The treatments were repeated every 3 weeks for six cycles. The study had 0.8 power to detect 5 months increase in median PFS at 0.05 two-sided alpha. Results: Of 637patients who underwent randomization, 631were eligible. After median follow-up of 29 m PFS in the c-TC group and dd-TC group overall survival at 2 years was 77.7% and 83.6%, respectively (P=0.05). Isonishi et al ASCO 2008 was 17.1 and 27.9m , (P=0.0014)

  33. IP Therapy Weekly paclitaxel Paclitaxel Cisplatin Aggressive Surgery Combination Chemotherapy Survival (mo) Paclitaxel/Carboplatin Ovarian CancerSurvival after Treatment

  34. Copy Number Analysis by Platinum Sensitive (Blue) and Resistant (Red) Ovarian Cancer Cases n=89 serous tumours Etemadmoghadam et al Clin Can Res 2009

  35. Ovarian Surface Epithelium

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