BIOE 301Lecture FifteenBioengineering and Ovarian CancerStatistics on Ovarian Cancer United States: Incidence: 22,430 Mortality: 15,280 Worldwide: Incidence: 190,000 Mortality: 114,000Global Burden of Ovarian CancerRisk factors Age Most ovarian cancers develop after menopause Personal or family history of breast, ovarian, endometrial, prostate or colon cancer. Reproductive history Increases with the more lifetime cycles of ovulation that awoman has undergone. Thus, women who haveundergone hormonal treatment for infertility, never usedbirth control pills, and who never became pregnant are athigher risk for ovarian cancerPathophysiologyScreening of Ovarian Cancer Pelvic and rectal exam CA125 test Transvaginal sonographyTransvaginal SonographyDiagnostic LaparoscopyComplication Rate = 0.5 – 1%Detection and Treatment Screening Pelvic exam CA125 test Transvaginal ultrasound Diagnosis Diagnostic laparoscopy Treatment: Surgery, radiation therapy, chemotherapy 5 year survival Localized disease: 93% (20% diagnosed at this stage)Screening Scenarios Scenario #1: Screen 1,000,000 women with CA125 p = .0001 (100 cancers) Se=35%, Sp=98.5% Cost = $30 Follow with laparoscopy Complication rate = 1% Cost=$2,000 TP=35 FP=14,999 Complications=150 PPV =0.23% NPV =99.99% Cost per cancer found = $1,716,200Screening Scenarios Scenario #2: Screen 1,000,000 women with transvaginal US P = .0001 (100 cancers) Se=100%, Sp=96% Cost = $150 Follow with laparoscopy Complication rate = 1% Cost=$2,000 TP=100 FP=39,996 Complications=401 PPV =0.25% NPV =100% Cost per cancer found = $300,672Screening Scenarios Scenario #3: Screen 1,000,000 women >age 50 with TVUS P = .0005 (500 cancers) Se=100%, Sp=96% Cost = $150 Follow with laparoscopy Complication rate = 1% Cost=$2,000 TP=500 FP=39,980 Complications=405 PPV =1.24% NPV =100% Cost per cancer found = $60,670Screening Scenarios Scenario #3 cont.: Screen 1,000,000 women > age 50 with TVUS P = .0005 (500 cancers) Se=100%, Sp=??% Cost = $150 How high does Sp need to be for PPV to reach 25%? Sp = 99.985%Does Ultrasound Screening Work? Two studies of over 10,000 low-risk women: The positive predictive value was only 2.6% Ultrasound screening of 100,000 women over age 45 would: Detect 40 cases of ovarian cancer, Result in 5,398 false positives Result in over 160 complications from diagnostic laparoscopy Jacobs I. Screening for early ovarian cancer. Lancet; 2:171-172, 1988.Ongoing Clinical Trials United Kingdom 200,000 postmenopausal women CA 125 level plus transvaginal ultrasound examination Transvaginal ultrasound alone No screening United States: 37,000 women (aged 55–74) Annual CA 125 level and transvaginal ultrasound examination No screening Europe: 120,000 postmenopausal women No screening, Transvaginal ultrasound at intervals of 18 months Transvaginal ultrasound at intervals of 3 yearshttp://www.mja.com.au/public/issues/178_12_160603/and10666_fm.pdfChallengeBetter screening methods to detect early stages of ovarian cancerCancer Screening Exams Cellular Changes Pap smear Serum Proteins PSA CA125 OvaCheck Genetic Changes HPV DNANew Screening Tool Current screening tests look for 1 protein: CA125 PSA Many serum proteins Can complex fingerprint predictive of cancer can be identified? PROTEOMICS: Don’t try to understand disease mechanisms Use proteomics to analyze patterns made by all proteins in the blood, without even knowing what they areHow do we measure serum proteins? Mass Spectrometry: Serum proteins are vaporized, given an electric charge and propelled down a tube How fast they make the trip depends on their mass Produces graph that shows distribution of masses in the sample Use computer program to analyze patterns and distinguish blood from patients with cancer and from those withoutProteomics: Mass SpectrometerMass/ChargeComparative AnalysisUseful M/Z:534989211122512465Data AnalysisTraining ValidationOvaCheck Quest Diagnostics and LabCorp: Will analyze blood samples sent by doctors, rather than sell test kits to doctors and hospitals Tests performed at a central location do not require F.D.A. approval Will be available in a few months Cost: $100-$200Response Dr. Eleftherios P. Diamandis, head of clinical biochem at Mount Sinai Hospital in Toronto. "If you don't know what you're measuring, it's a dangerous black-box technology… They are rushing into something and it could be a disaster.“ Dr. Nicole Urban, head of gynecologic cancer research at the Fred Hutchinson Cancer Research Center in Seattle. "Certainly there's no published work that would make me tell a woman she should get this test.“ Dr. Beth Karlan, director of gynecologic oncology at Cedars-Sinai Medical Center "Before you mass-market to the uninformed, fearful population, it should be peer-reviewed," When asked whether she would recommend her patients not get tested, she said: "It doesn't matter what I recommend. They are going to do it anyway." http://www.ovarian.org/press.asp?releaseID=263Gene Expression Analysis Human Genome 30,000 unique genes Which genes are active? DNA Microarrays Tool to study gene expression Which genes are turned on or off as cells grow, divide, respond to hormones, etcWhat is a DNA Microarray? Glass slide Large number of DNA fragments Each contains nucleotide sequence to probe for a specific gene Short oligos synthesized on surface of glass wafer Large DNA fragments generated by PCR and spotted onto slide by robot Each gene has unique physical address on slideHow Do We Use a DNA Microarray? Extract mRNA from cells under study Convert mRNA to cDNA Label cDNA with fluorescent probe Incubate labeled cDNA with microarray Wash slide to remove unbound cDNA Scan slide with laser scanning fluorescence microscope Determine which genes are expressed in test sampleDNA MicroarraysFrom: Molecular Biology of the CellNew screening technologies New screening technologies Proteomics DNA
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