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The Detection of Early Stage The Detection of Early Stage Epithelial Ovarian CancerEpithelial Ovarian Cancer
David A Fishman MDDavid A Fishman MD-- Director NCI Ovarian Cancer Early Detection Program,Director NCI Ovarian Cancer Early Detection Program,ProfessorProfessor-- Ob/Ob/GynGyn, Director, Director-- Gynecologic Oncology and Cancer Prevention and Early Gynecologic Oncology and Cancer Prevention and Early Detection Program New York University School of MedicineDetection Program New York University School of Medicine
Supported by NCI UO1CA85133, Supported by NCI UO1CA85133, NCI P50 CA83639,NCI P50 CA83639, NIH NIH R01 CA89503,R01 CA89503, NIHNIH--RO1CA82562, RO1CA82562, NIH RO1 NIH RO1 CA01015,CA01015, NCI NCI CA125227CA125227--0101, NYU Cancer Institute, , NYU Cancer Institute, Greenberg Foundation, Kaleidoscope of Hope Foundation, 100 WomenGreenberg Foundation, Kaleidoscope of Hope Foundation, 100 Women’’s Hedge Fund s Hedge Fund Foundation, SAC Foundation, NYU School of MedicineFoundation, SAC Foundation, NYU School of Medicine
22%
18%54%
6%
CervixUterineOvaryOther
Estimated Gynecologic Cancer Deaths 2007
27,100 (10%)
Ovary
15,280
The problem:Epithelial Ovarian Carcinoma
• 70-75% women are diagnosed with advanced disease (as in 1960)
• Poor 5-year survival (12-15%) for advanced stage EOC
• 90% 5-year survival for stage I disease-yet often detected serendipitously
• Therefore intentional detection of earlystage disease is critical
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The Cause: Epithelial Ovarian Cancer
The Cause: Epithelial Ovarian Cancer
• Serous (45%)• Mucinous (13%)• Endometrioid (15%)• Clear Cell (3%)• Brenner (2%)• Mixed Carcinoma• Undifferentiated Carcinoma
How to Detect Early Stage EOC???
• Annual CA125 and US do not achieve detection of early stage disease
• Both can provide false security or inappropriate anxiety
• Accuracy approximates 50% for early stage disease
CA125• increased in 80%
postmenopausal women with OVCA, yet at best 50% with Stage I disease.
• many causes of false elevations; fibroids, benign ovarian cysts, pelvic inflammation, pregnancy, ovulation, endometriosis
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Who is at Risk?
• Increased risk based on: personal history, family cancer pedigree, known mutation carrier, prolonged use of infertility Rx
NOCEDP Clinical Experience
•• Formal Genetic evaluation and TestingFormal Genetic evaluation and Testing•• 3D US and Microvascular Index (MVI)3D US and Microvascular Index (MVI)•• Physical examination q 6mPhysical examination q 6m•• Health Services, QOL, EducationHealth Services, QOL, Education•• Ovarian Pap TestOvarian Pap Test-- outpatient 0.9 mm
miniscope• Biomarkers unique to ovarian
carcinogenesis, invasion, metastasis
Clinical Risk Assessment• Nulliparity???? (92% parous > 1 child)• Personal and Family History- critical • Ashkenazi descent ? (why me?)• 38% Jewish women with ovarian carcinoma-
+ BRCA 1 or 2• 20% Jewish women with premenopausal Breast
carcinoma- + BRCA 1 or 2 • All affected Jewish women should be
offered genetic testingAm. J. Human Genetics-2001, 2003, Lancet-2001
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What is Hereditary Cancer?
60% 10%
30%
Hereditary Cancers
52%32%
16%
BRCA1
BRCA2
Other genes
Sporadic
Familial
Hereditary
Who is at Risk for a Hereditary Ovarian Cancer Syndrome?
• Any person with a personal history or family history of:– Breast, Colon, or Uterine cancer diagnosis under the age of 50– Ovarian cancer diagnosed at any age– Male breast cancer at any age– Multiple primary cancers: (i.e. breast and ovarian cancer, bilateral
breast cancer, ovarian and uterine cancer, colon and uterine cancer)– 2 or more family members with the same or related cancer
diagnosis in the family– Ashkenazi Jewish ancestry (with breast or ovarian cancer)– Relatives of mutation carrier
A BRCA Mutation Increases Breast and Ovarian Cancer Risks
Lancet 1994;343:692-695NEJM 1997;336:1401-1408AJHG 2003;72:1117-1130AJHG 1995;56:265-271Science 2003: 643-646
20
40
60
80
100
Breast cancerby age 50
Breast cancerby age 70
Ovarian cancerby age 70
2%
Up to 50%
7%
Up to 87%
Ris
k of
Can
cer
(%)
<2%
Up to 44%
General PopulationBRCA Mutation
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A BRCA Mutation Increases Risk of Second Cancer
JNCI 1999;15:1310-6JCO 1998;16:2417-25
Lancet 1998;351:316-21JCO 2004;22:2328-35
Lancet 1994;3343:692-5
0
20
40
60
Ovarian Cancer Breast Cancerafter 5 yrs
Breast Cancer by age 70
General PopulationBRCA Mutation
16% Up to 11%
Up to 27%
Up to 11%
Up to 64%
Ris
k of
Can
cer (
%)
* no statistic available
*
Risks in Men With a BRCA Mutation
JCO 2004;22: 735-42
5
10
15
20
25
Breast Cancer Prostate Cancer
General PopulationBRCA Mutation
<1%
7% 7%
20%
Ris
k of
Can
cer (
%)
Management/ Surveillance
Yearly beginning at age 25-35
Yearly beginning at age 40
Mammogram
Yearly (6 months after mammo) beginning at age 25
PRNBreast U/S and/or MRI
2-4 x/yr beginning at age 25
Every 1-3yrs beginning at age 20 and yearly at age 40
Clinical Breast Exam
Monthly beginning at age 18
Monthly beginning at age 18
Self Breast Exam
High RiskGeneral Population
Breast Screening
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Management/ Surveillance
Colonoscopy every 3-5 yrs beginning at age 40
Colonoscopy every 5-10 years beginning at age 50*
Colon
Concurrent transvaginalultrasound with color Doppler, pelvic exam, and CA-125 2x/yr
Not routinely recommended
Ovarian
High RiskGeneral Population
Other Screening
Management/ Surveillance• Surgical Options
– Prophylactic Bilateral Salpingo-Oophorectomy• Reduces the risk for Ovarian cancer by 96%• Reduces the risk for Breast Cancer by 50-68%
– Prophylactic Mastectomy: Reduces the risk for breast cancer by 90%
• Tamoxifen:– Affected: reduces contralateral Br ca by 75%– Unaffected: BRCA2: 62%; High Risk: 45%
• Oral Contraceptives: Reduces the risk for Ovarian Cancer by 60% (if used for >5yrs)
Other Hereditary Cancer Syndromes Associated with Breast or Ovarian Cancer
• HNPCC: Hereditary Non-Polyposis Colorectal Cancer:– Colon Cancer (75%); Endometrial (39%); Ovarian
(5-10%); Others- GI area• Li-Fraumeni:
– Leukemia; breast; brain tumor; adrenocorticalcarcinoma; bone and soft tissue sarcoma; early onset adenocarcinomas or other childhood cancers.
• Cowden:– Breast, thyroid, endometrial
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REVIEW of RED FLAGS FOR HBOC
• Early age onset breast cancer• Bilateral breast cancer or both breast and
ovarian cancer in same individual (regardless of age)
• Both breast and ovarian cancer occurring in one family regardless of age
• Member of BRCA mutation family• Ashkenazi Jewish
Ovarian Cancer Syndromes
• Site-specific ovarian• Breast-Ovarian• Lynch type II - hereditary
nonpolyposis colorectal cancer (HNPCC) – 9- 12%
• Mutations of unknown significance
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Risk Assessment• Formal pedigree analysis and genetic
testing and counseling by a team including board certified geneticists and gynecologic oncologists identified 981 women
• 919 BRCA1/2 +, 62 + pedigree assessment
• Prophylactic surgery consisted of a laparoscopic BSO, peritoneal washings, and comprehensive evaluation of pelvis and abdomen
Demographics• 981 High Risk women• 517 BRCA 1 + (55%)• 402 BRCA 2+ (39%)• 62 BRCA- (5%) yet pedigree c/w
Inherited Cancer Syndrome• Evaluation from 1990-present• Average Clinical follow-up 5 years
BRCA 1• 517 women• 7 Gynecologic malignancies
–PPC- 2- Stage IIIC and IIIB–FT- 2- Stage IIB and IIIB–OVCa- 3- 1-Stage IA, 2-IIIA
–No PPC in all women s/p BSO
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BRCA 2• 402 women• 3 Gynecologic Malignancies
–PPC- 1 Stage IIIB–FT- 1 Stage IIIA–OVCA- 1 Stage IB
–No PPC in women s/p BSO
Cancer Detection• 971 Benign • 3 Primary Peritoneal Cancer- all Stage III• 3 Fallopian Tube Cancer- Stage II/III(2)• 4 Ovarian Cancer- 2- Stage I, 2- Stage III• 10 Cancers –
– 2- Stage I– 1- Stage II – 7- Stage III
Abdominal UltrasoundThe Role of US
Best Visualization of the Fetus and Adnexa
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Three Dimensional Ultrasound
Can Treat & Res 2002
Recent Advances In Ultrasound• Power Doppler Energy- improved
specificity as secondary test (83-92%)• 3-Dimensional volume acquisition and
power Doppler- identifies architectural and vascular changes in observed mass, increases specificity from 54% to 75% as a secondary test
• Microvascular Imaging (MVI)- capillaries visualized with nanoparticles
Gyn Onc 2001, Gyn Onc 2002, Lancet 2003
Simple ovarian cyst demonstrating peripheral flow
Vaginal U/S with Color DopplerVaginal U/S with Color Doppler
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Complex adnexal mass with multiple septations with central flow suggestive of malignancy
serous cystadenocarcinoma - confirmed by pathology
3-D U/S Power Doppler
Gyn Onc 2002
NOCEDP• 47,356 gynecologic U/S on
13,646 asymptomatic high-risk women (normal exam and U/S)
• 297 aberrant masses identified• 127 surgical interventions • 113 benign tumors, 14 cancers
AJOG 2005
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NOCEDP• 14 asymptomatic gynecologic cancers
detected (4 fallopian tube, 4 primary peritoneal, 2 epithelial ovarian carcinoma, 2 uterine, 2 metastatic Br)
• all Stage III/IV (A, B, and C) except uterine (both stage1A G1)
• all normal US and PE 12 and 6 months prior to abnormal scan
• FT/PPC - normal ovaries
Conclusion• US was effective in detecting
asymptomatic advanced stage adnexal disease
• US is ineffective as an independent modality in the detection of early stage EOC in the high-risk population
The Future:Microvascular Imaging
• Combination of high resolution ultrasound with vascular mapping and quantification of aberrant capillary influx from pre-existing host venules stimulated by tumor neovascularization
• IV contrast agents (micro- and nanoparticles) to illuminate the extravasation associated with the influx of new “leaky” vessels
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Demonstration of normal ovarian vascularization (left) as compared to a morphologically “normal” ovary with Stage I EOC (papillary serous) (right). Note the significant increase in tumor vascularity as well as RBC extravasation throughout the parenchyma, both of which were perfused by contrast agents and therefore detected by contrast sonography. (H&E stain, x200 magnification)
• Designed to increase the backscatter of the echoes coming from the blood
• 1-10μ microbubbles can pass through the smallest capillaries.
Sonographic Contrast AgentsMicrobubble Destruction
• At diagnostic output levels, bubble can expand a few times original radius
• Most stabilizing coatings give way, leaving a free bubble to dissolve
• After insonification at normal imaging levels, most agents are destroyed
• This can be avoided with new sensitive imaging modes, or can be used to advantage Animation adapted from Dr. K Ferrara, UC Davis.
© Becher H and Burns PN, Handbook of Contrast Echocardiography,Springer 2000,
www.Sunnybrook.utoronto.ca/EchoHandbook/
5μ
Sonographic contrast agents can diffuse into the leaky capillary beds associated with tumor neovascularization
which translates into enhanced sonographic visualization of early stage EOC.
Tumor EnhancementMicrobubble Tumor Perfusion
0
2
4
6
8
10
12
0 2 4 6 8 10 12 14Seconds after injection
Sig
nal i
nten
sity
Mouse 4b with LLC tumor
MVI Quantification
QLAB Software (Version 2)
In vivo model demonstrating sonographic detection of aberrant tumor vascularity. Time activity curve showing time to peak and full-width half maximum points used to quantify
perfusion.
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Mass Spectrometry as a Discovery Tool for Mass Spectrometry as a Discovery Tool for Cancer BiomarkersCancer Biomarkers
•• Low resolution mass spectrometry profiles Low resolution mass spectrometry profiles segregate cancer from nonsegregate cancer from non--cancer controlcancer control•• Sensitivity 100% and specificity 95% Sensitivity 100% and specificity 95%
•• Low molecular weight archive Low molecular weight archive
•• Small proteins associate with high abundance Small proteins associate with high abundance carrier proteins carrier proteins
•• Extraction and analysis of carrierExtraction and analysis of carrier--bound peptides a bound peptides a rich source of novel biomarkers rich source of novel biomarkers
More specialized knowledge required…?Limited m/z range? (5-12,000 – XL to 40,000)High resolution (>9000 at m/z 1500)High mass accuracy (>50 ppm - external cal)Able to conduct CID of peptides
WCX2 ProteinChip Array
Ciphergen SELDI-TOF MS ABI QSTAR Pulsar QqTOF MS
WCX2 ProteinChip Array
Validation and Implementation of SELDI-QqTOF for Diagnostic Proteomics
Widely accessibleExtensive m/z range (5-300,000)Low Resolution (~ 100-200)Low Mass Accuracy (~1000 ppm)
EDRN 2002
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m /z2 0 0 0 6 0 0 0 8 0 0 0 1 0 0 0 0 1 2 0 0 04 0 0 0
1 0 0
2 0 0
0
3 0 0
4 0 0
Inte
nsity
(cps
)
3 8 8 3 .5 73 9 7 7 .7 6 4 0 7 1 .8 1
4 4 6 7 .2 2
7 7 6 6 .0 2
7 9 5 5 .3 8
8 1 4 2 .9 8
8 3 3 3 .5 98 6 0 2 .8 3
8 9 3 3 .4 67 1 9 3 .7 8
0
2 5
5 0
7 5
1 0 0
m /z2 0 0 0 6 0 0 0 8 0 0 0 1 0 0 0 0 1 2 0 0 04 0 0 0
3 8 8 5 .3
4 0 7 2 .8
4 4 7 1 .9
7 7 7 1 .4
7 9 2 3 .0
8 1 4 9 .8
8 9 4 5 .7
1 0 2 7 6
Rel
ativ
e In
tens
ity
A .
B .
C o n r a d s e t a l., F ig . 1
Comparison of the mass spectra from control serum prepared on a WCX2 Protein Chip array and analyzed with a PBS-II TOF (panel A) or a Qq-TOF mass spectrometer (panel B).
ERC 2004
PrOTOF 2000PrOTOF 2000™™
MALDI Orthogonal-TOF Mass Spectrometry
prOTOF orthogonal high resolution MALDI TOF detector…
Mass accuracy:
5-10 ppm external calibration
2-5 ppm internal calibration
Mass stability: 10 ppm over several hours using external calibration
Resolution: 10,000-15,000
Detection limits: sub femtomole
Throughput: 15,000 samples/day
Independence of operating parameters
Disposable sample plates
Mass accuracy:
5-10 ppm external calibration
2-5 ppm internal calibration
Mass stability: 10 ppm over several hours using external calibration
Resolution: 10,000-15,000
Detection limits: sub femtomole
Throughput: 15,000 samples/day
Independence of operating parameters
Disposable sample plates
0
25
50
75
100
m/z2000 6000 8000 10000 120004000
3885.34072.8
4471.9
7771.47923.0
8149.8
8945.710276
Rel
ativ
e In
tens
ity
Year 2002= Low Resolution SELDI-TOFLancet 2002
Year 2004= High Resolution SELDI-TOFERC 2004
Year 2005= Ultra High Resolution Orthogonal MALDI-TOF and FT-ICRDirect Accurate Mass Tagging Based IDJNCI 2005
The Rapid Evolution of MS Instrumentation
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Rapid Identification of Biomarkers in Ovarian Cancer Serum Samples:
• Carrier protein-bound affinity enrichment• High resolution MALDI OTOF MS• Decision rule analysis and FTICR de
novo sequencing
Albumin trap Albumin trap and elution of bound proteins/peptidesand elution of bound proteins/peptides
1D protein gel separation and digestion1D protein gel separation and digestion
InIn--gel gel tryptictryptic digestion and excision gel lanesdigestion and excision gel lanes
µµLC MS/MS analysis LC MS/MS analysis Data analysis and repetitive sequencingData analysis and repetitive sequencing
Albumin-Bound Peptide Purification and Biomarker Identification
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7 T Actively ShieldedSuperconducting Magnet
FTMS Data
210L/s
Linear Ion Trap Data
60m3/hr 300L/s 400L/s 210L/s15L/s
Triple Ported Turbo Pump
ECD Assembly
IRMPD Laser Assembly
Finnigan LTQ FT
Accurate mass, isotopically-resolved, differentially-expressed BioXPRESSION processed peptides are selected for LC-MS/MS
De novo sequencing of putative marker peptides…
Peptide Identification from MicrocapillaryReverse-phase Tandem MS
•• Data analysis through the Data analysis through the SequestSequest BioworksBioworks Browser Browser •• European Bioinformatics Institute nonEuropean Bioinformatics Institute non--redundant proteome set redundant proteome set
•• SwissSwiss--ProtProt •• TrEMBLTrEMBL •• EnsemblEnsembl
•• Mascot version 1.9.0 and NCBI BLASTCLUSTMascot version 1.9.0 and NCBI BLASTCLUST
Protein IdentificationProtein Identification
• Over 800 distinct proteins identified in data set
• 618 previously unknown to exist in human sera
• Stage-specific proteins identified• 215 unique to Stage I• 127 unique to Stage III and IV• 30 found in both early and late stage
• 96 of novel proteins identified by ≥ 2 peptide matches• Indicates greater than 99% confidence of correct identification
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AlbuminAlbumin--bound Candidate Biomarkersbound Candidate Biomarkers
Prominent SELDI-TOF ionic species (m/z 6631.7043) identified to correlate with the presence of ovarian cancer were amplified by albumin capture
• 456 Albumin Binding Fragments: Ovarian Cancer
• 3’, 5’ –cyclic-GMP phosphodiesterase• A Chain A, Crystal Structure of Human Apolipoprotein• A Chain A, Transthyretin (Prealbumin)• A1AG Human Alpha 1 Acid Glycoprotein 1 Precursor (AGP 1)• A1AT Human Alpha-1-Antitrypsin Precursor, Alpha-1 Protease
Inhibitor, Alpha-1-Antiproteinase• A1BG Human Alpha 1B Glycoprotein • A2MG Human Alpha 2 Macroglobulin Precursor • ADP-Ribosylation Factor Binding Protein 3, golgi localized gamma ear
containing, ARF binding protein 3, KIAA0154 gene product• AF070710 envelope glycoprotein (Human Immunodeficiency Virus
Type 1)• AF077721 Pol Protein (Human Immunodeficiency Virus Type 1)• AF094250 envelope glycoprotein (Human Immunodeficiency Virus
Type 1)• AF099171 protease (Human Immunodeficiency Virus Type 1)• AF190128 Rev (Human Immunodeficiency Virus Type 1)• AJ228172 gp120 (Human Immunodeficiency Virus Type 1)• ALC1 Human Ig Alpha-1 Chain C Region
• Alpha 1 & 2 Hemoglobin, HBA Human Hemoglobin Alpha Chain
• APA1 Human Apolipoprotein A-I Precursor, Apolipoprotein A-I
• APA2 Human Apolipoprotein A-II Precursor, ApolipoproteinA-II
• APC1 Human Apolipoprotein C-I Precursor, Apolipoprotein C-I
• APC3 Human Apolipoprotein C-III Precursor, ApolipoproteinC-III
• LPHUB apolipoprotein B-100 precursor – human• apolipoprotein D, apoD (human, plasma)• apolipoprotein E (homo sapien)• ASNS Human Asparagine Synthetase (glutamine hydrolyzing),
TS11 Cell Cycle Control Protein • AT Human Alpha-1-Antitrypsin (Internal Fragment)• B Chain B, Crystal Structure of A Human Fcg• B Chain B, Crystal Structure of S-Nitroso-Nit• BBHU CFAB Human Complement factor B Precursor, C3/C5
Convertase, Properdin Factor B, Glycine Rich Beta Glycoprotein GBG
• BRS3 Human Bombesin Receptor Subtype 3, Uterine BombesinReceptor
• C Chain C, Human Serum Transferrin, Recombinant• C1HUQB Complement Subcomponent C1q Chain B Precursor• C4HU complement precursor (validated)• Ceruloplasmin, Ferroxidase Human• CFA1 Human Complement Factor I Precursor, C3B• Clusterin, Complement Cytolysis Inhibitor (CLI), SP-40,
Sulfated Glycoprotein 2, testosterone Repressed Prostate Message 2JNCI-2005, JBC-2005
Candidate Biomarkers in Stage I EOCCandidate Biomarkers in Stage I EOC
Zinc finger Zinc finger homeoboxhomeobox ProteinProteinRho GDPRho GDP--dissociation dissociation inhibitor 1inhibitor 1
CHORD containing protein 1CHORD containing protein 1
Vascular nonVascular non--inflamatorinflamator molecule 2molecule 2RB associated factor 600RB associated factor 600cGMPcGMP gated gated cationcation channelchannel
UNC5C UNC5C transmembranetransmembrane receptor 2receptor 2ProtoProto--oncogene TKoncogene TKCentrosomalCentrosomal protein 2protein 2
UbiquitinUbiquitin--activating enzyme E1activating enzyme E1PhosphodiesterasePhosphodiesterase gammagammaCaspaseCaspase recruitment protein 12recruitment protein 12
Tyrosine protein Tyrosine protein kinasekinase CSKCSKPannexinPannexin 22BrCaBrCa antigen NUantigen NU--BRBR--11
Tumor associated Ca signal transducerTumor associated Ca signal transducerMelanoma antigen B4Melanoma antigen B4BRCA 2BRCA 2
TuftelinTuftelin--interacting protein 11interacting protein 11MDM4 proteinMDM4 proteinBAI 1 BAI 1
TransmembraneTransmembrane FLRT1 precursorFLRT1 precursorKinaseKinase suppressor of rassuppressor of ras--11BAGBAG--11
Transcription factor SOXTranscription factor SOX--33JunctophilinJunctophilin 11BaculoviralBaculoviral IAP domain protein 1IAP domain protein 1
TitinTitinInterleukinInterleukin--17 precursor17 precursorAPC proteinAPC protein
TenacinTenacin--RRIGF complexIGF complexAlpha Alpha tectorintectorin
SRp25 nuclear proteinSRp25 nuclear proteinEMILIN precursorEMILIN precursorALK TK receptor precursorALK TK receptor precursorRyanodineRyanodine receptor 3receptor 3Disks largeDisks large--assoc protein 2assoc protein 2AdlicanAdlican TK receptorTK receptor
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Conclusions
• High resolution mass spectral analysis of albumin-enriched serum fraction effectively segregates while Microcapillary HPLC tandem MS identifies novel biomarker candidates• Normal from malignant , Early from late stage
disease• Disease recurrence• Optimization of chemotherapeutics-
chemosensitivity assays
• Lysophospholipds (LPA) -LC/MS/MS• Growth factors (p110, p60)• Proteases (MMPs, Kallikreins) • Proteomics- SELDI/ MALDI-TOF, ABI
QqTOF, ESI-MS • Many other proteins … Prolactin, Leptin,
Osteopontin, IGF-II..
Clinically Relevant Biological Markers for Early Detection
Ovarian Pap Test
• Minimally invasive office laparoscopy- outpatient procedure
• Genomics and proteomics can detect precancer/cancer years before cytology- Prevention
Cont Ob/Gyn 2003, NEJM 2003
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Array CGH Analysis
- 0 .7 5
- 0 .5
- 0 .2 5
0
0 .2 5
0 .5
0 .7 5
0 5 0 0 1 0 0 0 1 5 0 0 2 0 0 0 2 5 0 0 3 0 0 0
D i s t a n c e a l o n g g e n o m e
Freq
uenc
y
Summary of array CGH analyses of 54 serous ovarian cancers. Data are represented from 1pter (left) to 22qter and X (right). Vertical lines indicate chromosome boundaries. Red spots indicate regions that are homozygouslydeleted or highly amplified in some tumors. Regions most frequently increased in copy number are apparent on chromosomes 3q26 (EVI1) and 8q24 (MYC).
FISH assay: EVI1 and MYC for EOC detection
EVI1 FISH Contig (550 kb)
MYC FISH Contg (500 kb)
BRCA1+ Mutation with Normal Cytology
Prophylactic BSO
Normal histology
Abnormal Copy Number of EVI1 and MYC
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Asymptomatic Patient
Serum/Plasma Protein and Lipid Analysis
Diagnostic Imaging-USMVI
Ovarian Pap Test/ Biopsy- Cytopathology- Gene/Protein Profile
Detection of Early Stage Disease
New Paradigm for Cancer Detection
New York Univ. New York Univ. FDAFDANational Cancer InstituteNational Cancer Institute George MasonGeorge MasonMD Anderson Cancer Center MD Anderson Cancer Center Roswell ParkRoswell ParkMayo ClinicMayo Clinic Duke Univ.Duke Univ.Johns Hopkins Johns Hopkins Creighton Univ.Creighton Univ.Yale Univ.Yale Univ. Univ. TorontoUniv. TorontoUniv.CaliforniaUniv.California-- San FranciscoSan Francisco Univ. ArizonaUniv. ArizonaUniv.CaliforniaUniv.California-- Los Angles Los Angles Univ. ChicagoUniv. ChicagoUniv. Southern California Univ. Southern California Northwestern Univ.Northwestern Univ.Univ. Utah Univ. Utah Stanford Univ.Stanford Univ.Univ. PittsburghUniv. Pittsburgh Wayne State Univ.Wayne State Univ.Harvard Univ.Harvard Univ. TuftsTufts-- BaystateBaystateUniv. TexasUniv. Texas-- SouthwesternSouthwestern Univ. MichiganUniv. MichiganPhilips CorpPhilips Corp Univ. HawaiiUniv. HawaiiPerkinPerkin Elmer Univ. AlabamaElmer Univ. AlabamaAustralia, Israel, Hungary, Canada, Japan, Sweden, Finland, Germany, Holland
Collaborating InstitutionsCollaborating Institutions