Ovarian Cancer Biomarkers: Current Options and Future Promise

As more effective, less toxic cancer drugs reach patients, the need for accurate and reliable cancer diagnostics and prognostics has become widely appreciated. Nowhere is this need more dire than in ovarian cancer; here most women are diagnosed late in disease progression. The ability to sensitively and specifically predict the presence of early disease and its status, stage, and associated therapeutic efficacy has the potential to revolutionize ovarian cancer detection and treatment. This article reviews current ovarian cancer diagnostics and prognostics and potential biomarkers that are being studied and validated. Some of the most recent molecular approaches being used to identify genes and proteins are presented, which may represent the next generation of ovarian cancer diagnostics and prognostics.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Correspondence: Marsha A. Moses, PhD, Program in Vascular Biology and Department of Surgery, 12.214, Karp Family Research Building, Children's Hospital Boston and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115. E-mail: marsha.moses@childrens.harvard.edu

These authors contributed equally to this work.

  • 1.

    American Cancer Society. Cancer Facts & Figures 2007. Atlanta: American Cancer Society; 2007.

  • 2.

    van NagellJRJrDePriestPDReedyMB. The efficacy of transvaginal sonographic screening in asymptomatic women at risk for ovarian cancer. Gynecol Oncol2000;77:350356.

    • Search Google Scholar
    • Export Citation
  • 3.

    ChenDXSchwartzPELiXG. Evaluation of CA 125 levels in differentiating malignant from benign tumors in patients with pelvic masses. Obstet Gynecol1988;72:2327.

    • Search Google Scholar
    • Export Citation
  • 4.

    EngelJEckelRSchubert-FritschleG. Moderate progress for ovarian cancer in the last 20 years: prolongation of survival, but no improvement in the cure rate. Eur J Cancer2002;38:24352445.

    • Search Google Scholar
    • Export Citation
  • 5.

    OmuraGABradyMFHomesleyHD. Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience. J Clin Oncol1991;9:11381150.

    • Search Google Scholar
    • Export Citation
  • 6.

    YoungRCWaltonLAEllenbergSS. Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials. N Engl J Med1990;322:10211027.

    • Search Google Scholar
    • Export Citation
  • 7.

    BristowRETomacruzRSArmstrongDK. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol2002;20:12481259.

    • Search Google Scholar
    • Export Citation
  • 8.

    ParamasivamSTripconyLCrandonA. Prognostic importance of preoperative CA-125 in International Federation of Gynecology and Obstetrics stage I epithelial ovarian cancer: an Australian multicenter study. J Clin Oncol2005;23:59385942.

    • Search Google Scholar
    • Export Citation
  • 9.

    NIH consensus conference. Ovarian cancer. Screening, treatment, and follow-up. NIH Consensus Development Panel on Ovarian Cancer. JAMA1995;273:491497.

    • Search Google Scholar
    • Export Citation
  • 10.

    RiedingerJMBonnetainFBasuyauJP. Change in CA 125 levels after the first cycle of induction chemotherapy is an independent predictor of epithelial ovarian tumour outcome. Ann Oncol2007;18:881885.

    • Search Google Scholar
    • Export Citation
  • 11.

    SabbatiniPMooneyDIasonosA. Early CA-125 fluctuations in patients with recurrent ovarian cancer receiving chemotherapy. Int J Gynecol Cancer2007;17:589594.

    • Search Google Scholar
    • Export Citation
  • 12.

    BastRCJrSiegalFPRunowiczC. Elevation of serum CA 125 prior to diagnosis of an epithelial ovarian carcinoma. Gynecol Oncol1985;22:115120.

    • Search Google Scholar
    • Export Citation
  • 13.

    NiloffJMKnappRCSchaetzlE. CA125 antigen levels in obstetric and gynecologic patients. Obstet Gynecol1984;64:703707.

  • 14.

    LeTHopkinsLFaughtW. The lack of significance of Ca125 response in epithelial ovarian cancer patients treated with neoadjuvant chemotherapy and delayed primary surgical debulking. Gynecol Oncol2007;105:712715.

    • Search Google Scholar
    • Export Citation
  • 15.

    MooreRGBrownAKMillerMC. The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol Oncol2008;108:402408.

    • Search Google Scholar
    • Export Citation
  • 16.

    RosenDGWangLAtkinsonJN. Potential markers that complement expression of CA125 in epithelial ovarian cancer. Gynecol Oncol2005;99:267277.

    • Search Google Scholar
    • Export Citation
  • 17.

    WongKKChengRSMokSC. Identification of differentially expressed genes from ovarian cancer cells by MICROMAX cDNA microarray system. Biotechniques2001;30:670675.

    • Search Google Scholar
    • Export Citation
  • 18.

    KimJHSkatesSJUedeT. Osteopontin as a potential diagnostic biomarker for ovarian cancer. JAMA2002;287:16711679.

  • 19.

    BrakoraKALeeHYusufR. Utility of osteopontin as a biomarker in recurrent epithelial ovarian cancer. Gynecol Oncol2004;93:361365.

  • 20.

    BaoLHSakaguchiHFujimotoJ. Osteopontin in metastatic lesions as a prognostic marker in ovarian cancers. J Biomed Sci2007;14:373381.

  • 21.

    YeBSkatesSMokSC. Proteomic-based discovery and characterization of glycosylated eosinophil-derived neurotoxin and COOH-terminal osteopontin fragments for ovarian cancer in urine. Clin Cancer Res2006;12:432441.

    • Search Google Scholar
    • Export Citation
  • 22.

    DiamandisEPYousefGM. Human tissue kallikreins: a family of new cancer biomarkers. Clin Chem2002;48:11981205.

  • 23.

    YousefGMScorilasAKatsarosD. Prognostic value of the human kallikrein gene 15 expression in ovarian cancer. J Clin Oncol2003;21:31193126.

    • Search Google Scholar
    • Export Citation
  • 24.

    BorgonoCAKishiTScorilasA. Human kallikrein 8 protein is a favorable prognostic marker in ovarian cancer. Clin Cancer Res2006;12:14871493.

    • Search Google Scholar
    • Export Citation
  • 25.

    BorgonoCAGrassLSoosaipillaiA. Human kallikrein 14: a new potential biomarker for ovarian and breast cancer. Cancer Res2003;63:90329041.

    • Search Google Scholar
    • Export Citation
  • 26.

    LuoLYKatsarosDScorilasA. Prognostic value of human kallikrein 10 expression in epithelial ovarian carcinoma. Clin Cancer Res2001;7:23722379.

    • Search Google Scholar
    • Export Citation
  • 27.

    TanakaYKobayashiHSuzukiM. Reduced bikunin gene expression as a factor of poor prognosis in ovarian carcinoma. Cancer2003;98:424430.

  • 28.

    TanakaYKobayashiHSuzukiM. Upregulation of bikunin in tumor-infiltrating macrophages as a factor of favorable prognosis in ovarian cancer. Gynecol Oncol2004;94:725734.

    • Search Google Scholar
    • Export Citation
  • 29.

    MatsuzakiHKobayashiHYagyuT. Plasma bikunin as a favorable prognostic factor in ovarian cancer. J Clin Oncol2005;23:14631472.

  • 30.

    DrapkinRvon HorstenHHLinY. Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. Cancer Res2005;65:21622169.

    • Search Google Scholar
    • Export Citation
  • 31.

    HellstromIRaycraftJHayden-LedbetterM. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res2003;63:36953700.

  • 32.

    NagyJAMasseEMHerzbergKT. Pathogenesis of ascites tumor growth: vascular permeability factor, vascular hyperpermeability, and ascites fluid accumulation. Cancer Res1995;55:360368.

    • Search Google Scholar
    • Export Citation
  • 33.

    YamamotoSKonishiIMandaiM. Expression of vascular endothelial growth factor (VEGF) in epithelial ovarian neoplasms: correlation with clinicopathology and patient survival, and analysis of serum VEGF levels. Br J Cancer1997;76:12211227.

    • Search Google Scholar
    • Export Citation
  • 34.

    HeflerLAZeillingerRGrimmC. Preoperative serum vascular endothelial growth factor as a prognostic parameter in ovarian cancer. Gynecol Oncol2006;103:512517.

    • Search Google Scholar
    • Export Citation
  • 35.

    RudlowskiCPickartAKFuhljahnC. Prognostic significance of vascular endothelial growth factor expression in ovarian cancer patients: a long-term follow-up. Int J Gynecol Cancer2006;16(Suppl 1):183189.

    • Search Google Scholar
    • Export Citation
  • 36.

    DehavenKTaylorDDGercel-TaylorC. Comparison of serum vascular endothelial growth levels between patients with and without ovarian malignancies. Int J Gynecol Cancer2002;12:715719.

    • Search Google Scholar
    • Export Citation
  • 37.

    MorGVisintinILaiY. Serum protein markers for early detection of ovarian cancer. Proc Natl Acad Sci U S A2005;102:76777682.

  • 38.

    VisintinIFengZLongtonG. Diagnostic markers for early detection of ovarian cancer. Clin Cancer Res2008;14:10651072.

  • 39.

    MaattaMTalvensaari-MattilaATurpeenniemi-HujanenT. Matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) and their tissue inhibitors (TIMP-1 and TIMP-2) in differential diagnosis between low malignant potential (LMP) and malignant ovarian tumours. Anticancer Res2007;27:27532758.

    • Search Google Scholar
    • Export Citation
  • 40.

    MurthiPBarkerGNowellCJ. Plasminogen fragmentation and increased production of extracellular matrix-degrading proteinases are associated with serous epithelial ovarian cancer progression. Gynecol Oncol2004;92:8088.

    • Search Google Scholar
    • Export Citation
  • 41.

    PoriesSEZurakowskiDRoyR. Urinary metalloproteinases: non-invasive biomarkers for breast cancer risk assessment. Cancer Epidemiol Biomarkers Prev2008;17:10341042.

    • Search Google Scholar
    • Export Citation
  • 42.

    RauvalaMTurpeenniemi-HujanenTPuistolaU. The value of sequential serum measurements of gelatinases and tissue inhibitors during chemotherapy in ovarian cancer. Anticancer Res2006;26:47794784.

    • Search Google Scholar
    • Export Citation
  • 43.

    RoyRWewerUMZurakowskiD. ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage. J Biol Chem2004;279:5132351330.

    • Search Google Scholar
    • Export Citation
  • 44.

    ChanLWMosesMAGoleyE. Urinary VEGF and MMP levels as predictive markers of 1-year progression-free survival in cancer patients treated with radiation therapy: a longitudinal study of protein kinetics throughout tumor progression and therapy. J Clin Oncol2004;22:499506.

    • Search Google Scholar
    • Export Citation
  • 45.

    FernandezCAYanLLouisG. The matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancer patients. Clin Cancer Res2005;11:53905395.

    • Search Google Scholar
    • Export Citation
  • 46.

    MosesMAWiederschainDLoughlinKR. Increased incidence of matrix metalloproteinases in urine of cancer patients. Cancer Res1998;58:13951399.

    • Search Google Scholar
    • Export Citation
  • 47.

    SmithERZurakowskiDSaadA. Urinary biomarkers predict brain tumor presence and response to therapy. Clin Cancer Res2008;14:23782386.

  • 48.

    YanLBorregaardNKjeldsenL. The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. J Biol Chem2001;276:3725837265.

    • Search Google Scholar
    • Export Citation
  • 49.

    SuzukiSMooreDHIIGinzingerDG. An approach to analysis of large-scale correlations between genome changes and clinical endpoints in ovarian cancer. Cancer Res2000;60:53825385.

    • Search Google Scholar
    • Export Citation
  • 50.

    KiechleMJacobsenASchwarz-BoegerU. Comparative genomic hybridization detects genetic imbalances in primary ovarian carcinomas as correlated with grade of differentiation. Cancer2001;91:534540.

    • Search Google Scholar
    • Export Citation
  • 51.

    ChengKWLahadJPKuoWL. The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nat Med2004;10:12511256.

  • 52.

    BirrerMJJohnsonMEHaoK. Whole genome oligonucleotide-based array comparative genomic hybridization analysis identified fibroblast growth factor 1 as a prognostic marker for advanced-stage serous ovarian adenocarcinomas. J Clin Oncol2007;25:22812287.

    • Search Google Scholar
    • Export Citation
  • 53.

    TsudaHItoYMOhashiY. Identification of overexpression and amplification of ABCF2 in clear cell ovarian adenocarcinomas by cDNA microarray analyses. Clin Cancer Res2005;11:68806888.

    • Search Google Scholar
    • Export Citation
  • 54.

    SchwartzDRKardiaSLSheddenKA. Gene expression in ovarian cancer reflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas. Cancer Res2002;62:47224729.

    • Search Google Scholar
    • Export Citation
  • 55.

    ZornKKBonomeTGangiL. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res2005;11:64226430.

    • Search Google Scholar
    • Export Citation
  • 56.

    SpentzosDLevineDARamoniMF. Gene expression signature with independent prognostic significance in epithelial ovarian cancer. J Clin Oncol2004;22:47004710.

    • Search Google Scholar
    • Export Citation
  • 57.

    BerchuckAIversenESLancasterJM. Patterns of gene expression that characterize long-term survival in advanced stage serous ovarian cancers. Clin Cancer Res2005;11:36863696.

    • Search Google Scholar
    • Export Citation
  • 58.

    SpentzosDLevineDAKoliaS. Unique gene expression profile based on pathologic response in epithelial ovarian cancer. J Clin Oncol2005;23:79117918.

    • Search Google Scholar
    • Export Citation
  • 59.

    JazaeriAAAwtreyCSChandramouliGV. Gene expression profiles associated with response to chemotherapy in epithelial ovarian cancers. Clin Cancer Res2005;11:63006310.

    • Search Google Scholar
    • Export Citation
  • 60.

    DressmanHKBerchuckAChanG. An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer. J Clin Oncol2007;25:517525.

    • Search Google Scholar
    • Export Citation
  • 61.

    LeeRCFeinbaumRLAmbrosV. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell1993;75:843854.

    • Search Google Scholar
    • Export Citation
  • 62.

    GarzonRFabbriMCimminoA. MicroRNA expression and function in cancer. Trends Mol Med2006;12:580587.

  • 63.

    LuJGetzGMiskaEA. MicroRNA expression profiles classify human cancers. Nature2005;435:834838.

  • 64.

    IorioMVVisoneRDi LevaG. MicroRNA signatures in human ovarian cancer. Cancer Res2007;67:86998707.

  • 65.

    ZhangLHuangJYangN. microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci U S A2006;103:91369141.

  • 66.

    ShellSParkSMRadjabiAR. Let-7 expression defines two differentiation stages of cancer. Proc Natl Acad Sci U S A2007;104:1140011405.

  • 67.

    PetricoinEFArdekaniAMHittBA. Use of proteomic patterns in serum to identify ovarian cancer. Lancet2002;359:572577.

  • 68.

    KozakKRAmneusMWPuseySM. Identification of biomarkers for ovarian cancer using strong anion-exchange ProteinChips: potential use in diagnosis and prognosis. Proc Natl Acad Sci U S A2003;100:1234312348.

    • Search Google Scholar
    • Export Citation
  • 69.

    RaiAJZhangZRosenzweigJ. Proteomic approaches to tumor marker discovery. Arch Pathol Lab Med2002;126:15181526.

  • 70.

    YeBCramerDWSkatesSJ. Haptoglobin-alpha subunit as potential serum biomarker in ovarian cancer: identification and characterization using proteomic profiling and mass spectrometry. Clin Cancer Res2003;9:29042911.

    • Search Google Scholar
    • Export Citation
  • 71.

    ZhangZBastRCJrYuY. Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer. Cancer Res2004;64:58825890.

    • Search Google Scholar
    • Export Citation
  • 72.

    MooreLEFungETMcGuireM. Evaluation of apolipoprotein A1 and posttranslationally modified forms of transthyretin as biomarkers for ovarian cancer detection in an independent study population. Cancer Epidemiol Biomarkers Prev2006;15:16411646.

    • Search Google Scholar
    • Export Citation
  • 73.

    Gortzak-UzanLIgnatchenkoAEvangelouAI. A proteome resource of ovarian cancer ascites: integrated proteomic and bioinformatic analyses to identify putative biomarkers. J Proteome Res2008;7:339351.

    • Search Google Scholar
    • Export Citation
  • 74.

    BaggerlyKAMorrisJSCoombesKR. Reproducibility of SELDI-TOF protein patterns in serum: comparing datasets from different experiments. Bioinformatics2004;20:777785.

    • Search Google Scholar
    • Export Citation
  • 75.

    RansohoffDF. Rules of evidence for cancer molecular-marker discovery and validation. Nat Rev Cancer2004;4:309314.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 116 102 10
PDF Downloads 55 51 5
EPUB Downloads 0 0 0