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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

Ovarian Cancerin the Genomics Era

Christina M. Annunziata, MD, PhD

Medical Oncology Branch

National Cancer Institute

Bethesda, MD


Ovarian cancer

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


Ovarian cancer prognostic factors

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


Treatment for newly diagnosed ovarian cancer
Treatment for Newly Diagnosed Ovarian Cancer

  • Complete surgical staging

  • Optimal reductive surgery

  • Chemotherapy

  • Clinical Trials


The state of treatment for newly diagnosed ovarian cancer
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



The state of treatment for newly diagnosed ovarian cancer1
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


Optimal cytoreduction
Optimal Cytoreduction

0 cm

Proportion surviving

0-1 cm

1-2 cm

>2 cm

Time since initial surgery (years)


The state of treatment for newly diagnosed ovarian cancer2
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


Timeline of treatment and outcome for advanced ovarian cancer
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


Representative Chemotherapy Agents CancerPlatinum 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 ----


GOG 172: The new Standard of Care CancerEpithelial 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)


Gog 172 the new standard of care
GOG 172: The new Standard of Care Cancer

Median survival = 65.6 mo

Median survival = 49.7 mo


Ovarian cancer in the genomics era1

Ovarian Cancer Cancerin the Genomics Era

Preclinical studies


Translational oncology observation hypothesis experiment trial result analysis
Translational Oncology CancerObservationHypothesisExperiment / TrialResultAnalysis


Integrated genomic analyses of ovarian carcinoma

Integrated genomic analyses of ovarian carcinoma Cancer

The Cancer Genome Atlas Research Network*

Nature 474: 609-615


Background CancerThe 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.


Methods CancerSample 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.


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


Methods
Methods Cancer



Genome copy number abnormality CancerCopy 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).


Gene and mirna patterns molecular subtype and outcome prediction
Gene and miRNA patterns: CancerMolecular subtype and outcome prediction






TCGA findings CancerTCGA: large-scale integrative 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


TCGA findings Cancer“Remarkable degree of 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.


TCGA – what next? CancerNew 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 ...


The state of treatment for newly diagnosed ovarian cancer3
The State of Treatment for CancerNewly Diagnosed Ovarian Cancer

  • Complete surgical staging

  • Optimal reductive surgery

  • Chemotherapy

  • Clinical Trials: targeted therapies


Translational oncology observation hypothesis experiment trial result analysis1
Translational Oncology CancerObservationHypothesisExperiment / TrialResultAnalysis


Phase ii trial of the oral parp inhibitor olaparib in brca deficient advanced ovarian cancer

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

From genomic aberration to pathway


Parp inhibition brca mutant cancers
PARP inhibition: BRCA-mutant cancers BRCA-deficient advanced ovarian cancer

PARP

inhibitor

Replicating cells

Cancer cell with BRCA deficiency

Normal cell

Repair by Homologous Recombination

No effective repair(No HR pathway)

CELL DEATH

Survival


Phase ii trial of the oral parp inhibitor olaparib in brca deficient advanced ovarian cancer1
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


Phase ii trial of the oral parp inhibitor olaparib in brca deficient advanced ovarian cancer2
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%).


Phase ii trial of the oral parp inhibitor olaparib in brca deficient advanced ovarian cancer3
Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer

Audeh, et al. Lancet 376:245 – 251 (2010)


Phase ii trial of the oral parp inhibitor olaparib in brca deficient advanced ovarian cancer4
Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced ovarian cancer


Phase ii trial of the oral parp inhibitor olaparib in brca deficient advanced ovarian cancer5
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.”


Nf b deregulation and targeting

NF- BRCA-deficient advanced ovarian cancerB: Deregulation and Targeting

A Genomic approach to Ovarian Cancer


Schematic of nf b signaling
Schematic of NF- BRCA-deficient advanced ovarian cancerB signaling


Defining the Ovarian Cancer-specific IKK BRCA-deficient advanced ovarian cancer gene signature using IKK inhibitor and IKK shRNA


Ikk gene signature is coordinately expressed in primary ovarian cancers
IKK BRCA-deficient advanced ovarian cancer gene signature is coordinately expressed in primary ovarian cancers


High ikk activity associates with worse survival in ovarian cancer
High IKK BRCA-deficient advanced ovarian canceractivity associates with worse survival in ovarian cancer


Intersecting pathways cooperate with nf b in ovarian cancer
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)



TNF: NF-kB activation or apoptosis? cancerNormal cells:SMAC released from mitochondria, inhibiting cIAP 1 & removing blockade to activated caspase function apoptotic cell deathTumor cells: apoptosis is dysregulated due to low SMAC or upstream blockade e.g overexpression of IAPs

X

SMAC

SMAC


TNF: NF-kB activation or apoptosis? cancerHigh immunohistochemical expression of TNFα in ovarian tumor & stroma Increased TNF-α serum concentrations reported in patients with endometrial carcinomaTNFα may activate NF-kB in the presence of IAP (Inhibitors of Apoptotic Proteins), but trigger apoptosis in its absence


New Hypothesis: cancerThe intersection of the NF-κB and caspase pathways provides a novel point of therapeutic intervention, where pro-survival signals can be switched to pro-apoptotic killing of cancer cells


Tnf a enhances smac mimetic killing
TNF cancera enhances SMAC mimetic killing



The state of treatment for newly diagnosed ovarian cancer4
The State of Treatment for cancerNewly Diagnosed Ovarian Cancer

Complete surgical staging

Optimal reductive surgery

Chemotherapy

Clinical Trials


Phase 2 study of SMAC-mimetic for relapsed ovarian cancer SMAC mimetic administered IV on days 1, 8, 15 of 28 day cycle 18g needle biopsy prior to start, and after 2 cycles CT scan restaging every 2 cycles


Primary Objectives Dual endpoint efficacy (GOG criteria):objective response (confirmed complete response [CR] of any duration or confirmed partial response [PR] of any duration defined by RECIST version 1.1 criteria)progression-free survival lasting greater than 6 months, in patients with relapsed platinum refractory or resistant ovarian cancer, primary peritoneal cancer, fallopian tube cancer treated with TL32711 at 47mg/m2


Correlative Studies on paired pre- and post-treatment tumor biopsies & on archival tissue. Immunohistochemistry for measurement of TNF alpha and TRAIL (NIH Core Facility)Gene expression profiling of NF-kappaB signature (Annunziata lab) Apoptosis gene signature (TetraLogic Pharmaceuticals)Response biomarkers:cIAP1 & cIAP2 (immediate targets of TL37211), with degradation of cIAP1 & 2 protein post-treatment activated caspase-8 – a measure of extrinsic pathwayPARP cleavage – a measure of activated caspase-3 and ultimate apoptosis pathway activation (both extrinsic and intrinsic pathways).


Correlative Studies on blood specimens biopsies & on archival tissue. PBMCCleaved caspase 3/7 levels in PBMCsCleaved PARP levels in PBMCscIAP1/2 levels in PBMCsPlasmaTNF alpha, TRAILIL-6, IL-8


Translational oncology observation hypothesis experiment trial result analysis2
Translational Oncology biopsies & on archival tissue. ObservationHypothesisExperiment / TrialResultAnalysis


Future directions back to bench
Future directions biopsies & on archival tissue. (…back to bench)


Future directions back to bench1

What sequence of SMAC mimetic in combination biopsies & on archival tissue.

achieves maximal tumor cell death and

correlates with proteomic changes in apoptosis and NF-kB pathways

Biomarkers will be used in future clinical trials

Future directions (…back to bench)


Clinical application: Indvidualized therapy Therapeutic agents targeting each critical pathway can be tested for their ability to overcome molecularly defined cancers Ultimately, the benefit of signature-directed therapy will be assessed by prospectively profiling individual patients and allocating therapy based on the molecular defects identified at the bench


Medical Ovarian Cancer Team Anne Noonan, MDElise C. Kohn, MDJung-Min Lee, MDNicole Houston, RNJessica Hearn, RNMOB Fellows and Nursing Staff Translational scientists:Lidia Hernandez, MSMarianne Kim, PhDCarrie House, PhDEthan SagherBridget Hill


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