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Ovarian Cancer in the Genomics Era

Ovarian Cancer in the Genomics Era. Christina M. Annunziata, MD, PhD Medical Oncology Branch National Cancer Institute Bethesda, MD. Stage Description Incidence Survival I Confined to ovaries 20% 90% II Confined to pelvis 5% 65% III Spread IP or nodes 58% 45%

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Ovarian Cancer in the Genomics Era

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  1. Ovarian Cancerin the Genomics Era Christina M. Annunziata, MD, PhD Medical Oncology Branch National Cancer Institute Bethesda, MD

  2. Stage Description Incidence Survival I Confined to ovaries 20% 90% II Confined to pelvis 5% 65% III Spread IP or nodes 58% 45% IV Distant metastases 17% <5% Ovarian Cancer

  3. Stage Extent of Cytoreduction Histology and Grade Performance Status p53 Status Vital Organ Function Physiologic Age Platinum+Taxane Primary Therapy Intraperitoneal therapy Information from Second-Look Surgery Genotype BRCA1/2 VEGF Production Ovarian Cancer: Prognostic Factors

  4. Treatment for Newly Diagnosed Ovarian Cancer • Complete surgical staging • Optimal reductive surgery • Chemotherapy • Clinical Trials

  5. The State of Treatment for Newly Diagnosed Ovarian Cancer • Complete surgical staging • Full assessment of abdomen and pelvis • Random biopsy of visually negative areas • Lymph node dissection (except Stage I) • Optimal reductive surgery • Chemotherapy • Clinical Trials

  6. Surgical staging of ovarian cancer www.cancerfacts.com

  7. The State of Treatment for Newly Diagnosed Ovarian Cancer • Complete surgical staging • Optimal reductive surgery • Stage I, II - Complete removal of all disease • Stage III, IV - Residual disease < 1 cm • Chemotherapy • Clinical Trials

  8. Optimal Cytoreduction 0 cm Proportion surviving 0-1 cm 1-2 cm >2 cm Time since initial surgery (years) www.mayoclinicproceedings.com

  9. The State of Treatment for Newly Diagnosed Ovarian Cancer • Complete surgical staging • Optimal reductive surgery • Chemotherapy • Platinum = cisplatin or carboplatin AND • Taxane = paclitaxel or docetaxel • Intraperitoneal if Stage III, optimal reduction • Clinical Trials

  10. Timeline of Treatment and Outcome for Advanced Ovarian Cancer ALKYLATORS CISPLATIN/ALKYLATOR COMBINATIONS INTRA- PERITONEAL 1960 1980 2000 1970 1990 CISPLATIN PACLITAXEL/ CARBOPLATIN 0 5% 15% 35% 40% 1960 1970 1980 1990 2000 5 YR SURVIVAL ADVANCED DISEASE

  11. Representative Chemotherapy AgentsPlatinum Paclitaxel Topotecan Gemcitabine DoxilTarget: DNA b-tubulin Topo-I RN-reductase, Nucleotide pool Topo-IIMechanism:DNA adduct formation TubulinAggregation Stabilize DNA-TopoDNA synth DNA Schedule:Independent Dependent(toxicity)Dependent(efficacy) Dependent Phosporylation Prolonged clearanceResistance:GSH, tolerance, retention MDR-MRP, tubulin mutations Topo-I, BCRP RN-reductase MDR-MRP Topo-IIPlatinumInteraction:N/A Platelet Sparing ---- Enhanced Toxicity ----

  12. GOG 172: The new Standard of CareEpithelial Ovarian Cancer, Optimal Stage III, No prior therapy, Well balanced arms1. Intravenous therapy, Cisplatin 75 mg/m2Paclitaxel 135 mg/m2 (24 h), 83% completed 6 cycles2. Intraperitoneal therapy, Cisplatin 100 mg/m2 IP d1Paclitaxel 135 mg/m2 (24 h) IV d1Paclitaxel 60 mg/m2 IP d8, 42% completed 6 cycles Open: 23-Mar-98Closed: 29-Jan-01Accrual: 416 pts (evaluable)

  13. GOG 172: The new Standard of Care Median survival = 65.6 mo Median survival = 49.7 mo Armstrong, NEJM 2006

  14. Ovarian Cancerin the Genomics Era Preclinical studies

  15. Translational OncologyObservationHypothesisExperiment / TrialResultAnalysis

  16. Integrated genomic analyses of ovarian carcinoma The Cancer Genome Atlas Research Network* Nature 474: 609-615

  17. Background The Cancer Genome Atlas (TCGA) Clinically annotated HGS-OvCa samplesIdentify molecular abnormalities that influence pathophysiology,affect outcome and constitute therapeutic targets. Microarray analyses: 489 HGS-OvCa tumours, mRNA expression,microRNA (miRNA) expression, DNA copy number and DNA promoter methylation for and Whole exome DNA sequence: 316 samples.

  18. MethodsSample inclusion criteriaNewly diagnosed patientsovarian serous adenocarcinomano prior treatmentregardless of surgical stage or histologic gradeEach frozen tumor specimen had to have a companion normal tissue specimen, which could be adjacent normal tissue, peripheral lymphocytes, or previously extracted germline DNA.

  19. Methods Clinical data collectionClinical data can be accessed and downloaded from the TCGA Data Portal Demographics,histopathologic informationtreatment detailsoutcome parameters

  20. Clinical data analyses

  21. Methods

  22. Platforms used and data produced

  23. Mutated genes

  24. Genome copy number abnormality Copy number profiles of 489 HGS-OvCa, compared with profiles of 197 glioblastoma multiforme (GBM) tumours. Copy number increases (red) and decreases (blue) are plotted as a function of distance along the normal genome (vertical axis, divided into chromosomes).

  25. Gene and miRNA patterns: Molecular subtype and outcome prediction

  26. Gene and miRNA patterns: Molecular subtype and outcome prediction. Using a training data set, a prognostic gene signature was defined and applied to a test data set.

  27. Gene and miRNA patterns: Kaplan–Meier analysis of four independent expression profile data sets, comparing survival for predicted higher-risk patients versus lower-riskpatients. Univariate Cox P value for risk index included.

  28. Altered pathways in HGS-OvCa

  29. Altered pathways in HGS-OvCa

  30. Altered pathways in HGS-OvCa

  31. Altered pathways in HGS-OvCa

  32. DiscussionTCGA: large-scaleintegrative view of aberrations in HGS-OvCa Mutational spectrum “surprisingly simple” TP53 predominated = 96% BRCA1 and BRCA2 =22% Seven other significantly mutated genes = 2–6%HGS-OvCa is distinct from other histological subtypes Clear-cell: few TP53; recurrent ARID1A, PIK3CA mutationsEndometrioid: frequent CTNNB1, ARID1A and PIK3CA; fewer TP53Mucinous: prevalent KRAS mutations

  33. Discussion “Remarkable degreeof genomic disarray” “Striking contrast to previous TCGA findings in glioblastoma”Mutations and promoter methylation in putative DNA repair genes (HR) may explain the high prevalence of SCNAs.

  34. Discussion New therapeutic approaches?50% with HR defects : PARP inhibitors commonly deregulated pathways: RB, RAS/PI3K, FOXM1, NOTCH, provide opportunities for therapeutic treatmentInhibitors exist for 22 genes in regions of recurrent amplificationaberrant genes or networks: targeted therapies selected to be effective ...

  35. The State of Treatment for Newly Diagnosed Ovarian Cancer • Complete surgical staging • Optimal reductive surgery • Chemotherapy • Clinical Trials: targeted therapies

  36. Translational OncologyObservationHypothesisExperiment / TrialResultAnalysis

  37. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer American Society of Clinical Oncology, 2009 Presenter: M William Audeh

  38. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer • Olaparib (AZD2281) • novel, orally active PARP inhibitor • synthetic lethality in homozygous BRCA-mut cells • The primary aim of this study was to test the efficacy of olaparib in confirmed BRCA1/BRCA2 carriers with advanced refractory ovarian cancer

  39. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer • Results: 57 enrolled pts • 39 BRCA1 deficient and 18 BRCA2 deficient • 33 evaluable at 400 mg bid and 24 at 100 mg bid • ORR was 33% at 400 mg bd; 12.5% at 100 mg bd • Clinical benefit rate: • ORR and/or confirmed ≥50% decline in CA125 • 57.6% at 400 mg bd and 16.7% at 100 mg bd • Median PFS: 5.8 mo (med duration 9.6 mo) • Toxicity • grade 1/2 nausea (44%); fatigue (35%); anemia (14%) • Grade 3 toxicity occurred infrequently, and comprised primarily nausea (7%) and leukopenia (5%).

  40. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer

  41. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer

  42. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer • Conclusions: Oral olaparib is well tolerated and highly active in advanced, chemotherapy-refractory BRCA-deficient ovarian cancer • Greater activity seen at the higher dose • Toxicity in BRCA1/2 carriers was similar to that seen in non-carriers • “Positive proof of the concept of the activity and tolerability of genetically defined targeted therapy with olaparib in BRCA-deficient ovarian cancers.”

  43. NF-B: Deregulation and Targeting A Genomic approach to Ovarian Cancer

  44. Schematic of NF-B signaling

  45. Defining the Ovarian Cancer-specific IKK gene signature using IKK inhibitor and IKK shRNA

  46. IKK gene signature is coordinately expressed in primary ovarian cancers

  47. High IKKactivity associates with worse survival in ovarian cancer

  48. IGFBP2 outliers Aberrant gene expression indicates key NF-κB regulators

  49. Intersecting pathways cooperate with NF-κB in ovarian cancer • RNAi sensitization screen • shRNA library targeting human kinome (500 kinases) • Combination with IKK inhibitor (sub-lethal dose)

  50. The State of Treatment for Newly Diagnosed Ovarian Cancer • Complete surgical staging • Optimal reductive surgery • Chemotherapy • Clinical Trials

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