Clinical Use of Cancer Biomarkers in Epithelial Ovarian Cancer

Objective To present an update of the European Group on Tumor Markers guidelines for serum markers in epithelial ovarian cancer. Methods Systematic literature survey from 2008 to 2013. The articles were evaluated by level of evidence and strength of recommendation. Results Because of its low sensitivity (50–62% for early stage epithelial ovarian cancer) and limited specificity (94–98.5%), cancer antigen (CA) 125 (CA125) is not recommended as a screening test in asymptomatic women. The Risk of Malignancy Index, which includes CA125, transvaginal ultrasound, and menopausal status, is recommended for the differential diagnosis of a pelvic mass. Because human epididymis protein 4 has been reported to have superior specificity to CA125, especially in premenopausal women, it may be considered either alone or as part of the risk of ovarian malignancy algorithm, in the differential diagnosis of pelvic masses, especially in such women. CA125 should be used to monitor response to first-line chemotherapy using the previously published criteria of the Gynecological Cancer Intergroup, that is, at least a 50% reduction of a pretreatment sample of 70 kU/L or greater. The value of CA125 in posttherapy surveillance is less clear. Although a prospective randomized trial concluded that early administration of chemotherapy based on increasing CA125 levels had no effect on survival, European Group on Tumor Markers state that monitoring with CA125 in this situation should occur, especially if the patient is a candidate for secondary cytoreductive surgery. Conclusions At present, CA125 remains the most important biomarker for epithelial ovarian cancer, excluding tumors of mucinous origin.

[1]  I. Brandslund,et al.  Prognostic Impact of Prechemotherapy Serum Levels of HER2, CA125, and HE4 in Ovarian Cancer Patients , 2011, International Journal of Gynecologic Cancer.

[2]  R. Bast,et al.  A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. , 1983, The New England journal of medicine.

[3]  T. Kitanaka,et al.  A randomized study of screening for ovarian cancer: a multicenter study in Japan , 2007, International Journal of Gynecologic Cancer.

[4]  Fake Li,et al.  Does risk for ovarian malignancy algorithm excel human epididymis protein 4 and ca125 in predicting epithelial ovarian cancer: A meta-analysis , 2012, BMC Cancer.

[5]  R. Molina,et al.  Comparison of serum human epididymis protein 4 with cancer antigen 125 as a tumor marker in patients with malignant and nonmalignant diseases. , 2011, Clinical chemistry.

[6]  Chen Yang,et al.  Diagnostic Value of Serum Human Epididymis Protein 4 (HE4) in Ovarian Carcinoma: A Systematic Review and Meta-Analysis , 2012, International Journal of Gynecologic Cancer.

[7]  The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer. , 2003, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[8]  Dirk Timmerman,et al.  Evaluating the risk of ovarian cancer before surgery using the ADNEX model to differentiate between benign, borderline, early and advanced stage invasive, and secondary metastatic tumours: prospective multicentre diagnostic study , 2014, BMJ : British Medical Journal.

[9]  R. Bast CA 125 and the detection of recurrent ovarian cancer , 2010, Cancer.

[10]  P. Zola,et al.  Cancer Antigen 125: Lost to Follow-Up? , 2012, International Journal of Gynecologic Cancer.

[11]  Shuang Yu,et al.  Diagnostic value of HE4 for ovarian cancer: a meta-analysis , 2012, Clinical chemistry and laboratory medicine.

[12]  R. Edwards Tribute to Patrick Steptoe: beginnings of laparoscopy. , 1989, Human reproduction.

[13]  G. Morgante,et al.  Comparison of two malignancy risk indices based on serum CA125, ultrasound score and menopausal status in the diagnosis of ovarian masses , 1999, British journal of obstetrics and gynaecology.

[14]  I. Christensen,et al.  Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass. , 2012, Gynecologic oncology.

[15]  P. Vasey,et al.  ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of epithelial ovarian carcinoma. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[16]  U. Matulonis,et al.  Anti-angiogenic Agents in Ovarian Cancer: Dawn of a New Era? , 2011, Current oncology reports.

[17]  M. Federico,et al.  Significance of early changes in the serum CA-125 antigen level on overall survival in advanced ovarian cancer. , 2006, Gynecologic oncology.

[18]  Corneel Coens,et al.  Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial , 2010, The Lancet.

[19]  P. Dombernowsky,et al.  Serum tumour marker CA 125 in monitoring of ovarian cancer during first-line chemotherapy , 2001, British Journal of Cancer.

[20]  Screening for ovarian cancer: recommendations and rationale. American College of Physicians. , 1994, Annals of internal medicine.

[21]  G. Rustin,et al.  Role of tumour markers in monitoring epithelial ovarian cancer , 2000, British Journal of Cancer.

[22]  H. Blanton To monitor or not to monitor. , 1994, Pediatric dentistry.

[23]  G. Rustin,et al.  Use of CA-125 to define progression of ovarian cancer in patients with persistently elevated levels. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  R. Bast,et al.  The CA 125 tumour-associated antigen: a review of the literature. , 1989, Human reproduction.

[25]  M. Poutanen,et al.  Serum HE4 concentration is not dependent on menstrual cycle or hormonal treatment among endometriosis patients and healthy premenopausal women. , 2012, Gynecologic oncology.

[26]  Giuseppe Lippi,et al.  The ROMA (Risk of Ovarian Malignancy Algorithm) for estimating the risk of epithelial ovarian cancer in women presenting with pelvic mass: is it really useful? , 2011, Clinical chemistry and laboratory medicine.

[27]  P. Dombernowsky,et al.  Serum tumor marker CA 125 for monitoring ovarian cancer during follow-up , 2002, Scandinavian journal of clinical and laboratory investigation.

[28]  Z. Hernádi,et al.  Elevated human epididymis protein 4 concentrations in chronic kidney disease , 2012, Annals of clinical biochemistry.

[29]  Hong Zheng,et al.  Serum HE4 as a Useful Biomarker in Discriminating Ovarian Cancer From Benign Pelvic Disease , 2012, International Journal of Gynecologic Cancer.

[30]  Matthew Burnell,et al.  Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) , 2009, Journal of Family Planning and Reproductive Health Care.

[31]  A. Tailor,et al.  Prospective evaluation of three different models for the pre‐operative diagnosis of ovarian cancer , 2000, BJOG : an international journal of obstetrics and gynaecology.

[32]  I. Jacobs,et al.  Results of annual screening in phase I of the United Kingdom familial ovarian cancer screening study highlight the need for strict adherence to screening schedule. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  Tore Halvorsen,et al.  Evaluation of a risk of malignancy index based on serum CA125, ultrasound findings and menopausal status in the pre‐operative diagnosis of pelvic masses , 1996, British journal of obstetrics and gynaecology.

[34]  J. Gohagan,et al.  Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. , 2011, JAMA.

[35]  Steven J Skates,et al.  A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. , 2009, Gynecologic oncology.

[36]  T. Bourne,et al.  Logistic regression model to distinguish between the benign and malignant adnexal mass before surgery: a multicenter study by the International Ovarian Tumor Analysis Group. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  M. Parmar,et al.  Definitions for Response and Progression in Ovarian Cancer Clinical Trials Incorporating RECIST 1.1 and CA 125 Agreed by the Gynecological Cancer Intergroup (GCIG) , 2010, International Journal of Gynecologic Cancer.

[38]  P. H. Petersen,et al.  Biological variation of total prostate-specific antigen: a survey of published estimates and consequences for clinical practice. , 2005, Clinical chemistry.

[39]  Richard G. Moore,et al.  A 2‐stage ovarian cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies early‐stage incident cancers and demonstrates high positive predictive value , 2013, Cancer.

[40]  Robert C. Bast,et al.  Combined use of biomarkers for detection of ovarian cancer in high-risk women , 2010, Tumor Biology.

[41]  R. Bast,et al.  Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. , 1996, Journal of the National Cancer Institute.

[42]  T. Bourne,et al.  Multicentre external validation of IOTA prediction models and RMI by operators with varied training , 2013, British Journal of Cancer.

[43]  Xiaoxiang Chen,et al.  Nadir CA-125 level as prognosis indicator of high-grade serous ovarian cancer , 2013, Journal of Ovarian Research.

[44]  K. Lu,et al.  Endometrial and ovarian cancer in women with Lynch syndrome: update in screening and prevention , 2013, Familial Cancer.

[45]  J. Hendriks,et al.  CA125 nadir concentration is an independent predictor of tumor recurrence in patients with ovarian cancer: a population-based study. , 2010, Gynecologic oncology.

[46]  J. Riedinger,et al.  Prognostic value of serum CA 125 bi-exponential decrease during first line paclitaxel/platinum chemotherapy: a French multicentric study. , 2008, Gynecologic oncology.

[47]  I. Jacobs,et al.  Protein expression levels of carcinoembryonic antigen (CEA) in Danish ovarian cancer patients: from the Danish ‘MALOVA’ovarian cancer study , 2008, Pathology.

[48]  NIH consensus conference. Ovarian cancer. Screening, treatment, and follow-up. NIH Consensus Development Panel on Ovarian Cancer. , 1995, JAMA.

[49]  D Timmerman,et al.  HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm , 2011, British Journal of Cancer.

[50]  K. Baggerly,et al.  The emerging role of HE4 in the evaluation of epithelial ovarian and endometrial carcinomas. , 2013, Oncology.

[51]  J. H. Price,et al.  Serum CA19.9 levels are commonly elevated in primary ovarian mucinous tumours but cannot be used to predict the histological subtype , 2010, Journal of Clinical Pathology.

[52]  M. Duffy,et al.  Design of tumor biomarker-monitoring trials: a proposal by the European Group on Tumor Markers. , 2013, Clinical chemistry.

[53]  M. Duffy,et al.  CA125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use , 2004, International Journal of Gynecologic Cancer.

[54]  Robert C. Bast,et al.  Ovarian cancer: screening, treatment, and followup. , 1995, NIH consensus statement.

[55]  J. Baselga,et al.  Nadir CA-125 concentration in the normal range as an independent prognostic factor for optimally treated advanced epithelial ovarian cancer. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[56]  N. Viñolas,et al.  Mucins CA 125, CA 19.9, CA 15.3 and TAG-72.3 as Tumor Markers in Patients with Lung Cancer: Comparison with CYFRA 21-1, CEA, SCC and NSE , 2008, Tumor Biology.

[57]  G. Rustin,et al.  Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study. , 1996, Annals of oncology : official journal of the European Society for Medical Oncology.

[58]  D. Oram,et al.  A risk of malignancy index incorporating CA 125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer , 1991, British journal of obstetrics and gynaecology.

[59]  H E Lambert,et al.  Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[60]  A. Berchuck,et al.  Large Prospective Study of Ovarian Cancer Screening in High-Risk Women: CA125 Cut-Point Defined by Menopausal Status , 2011, Cancer Prevention Research.

[61]  S. Doniņa,et al.  An ovarian cancer malignancy risk index composed of HE4, CA125, ultrasonographic score, and menopausal status: use in differentiation of ovarian cancers and benign lesions , 2012, Tumor Biology.

[62]  J. Oosterwijk,et al.  Time to stop ovarian cancer screening in BRCA1/2 mutation carriers? , 2009, International journal of cancer.

[63]  A. Gadducci,et al.  Serum and tissue biomarkers as predictive and prognostic variables in epithelial ovarian cancer. , 2009, Critical reviews in oncology/hematology.

[64]  G. Rustin,et al.  Use of CA-125 to assess response to new agents in ovarian cancer trials. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  P. Dombernowsky,et al.  Tumor markers cancer antigen 15.3, carcinoembryonic antigen, and tissue polypeptide antigen for monitoring metastatic breast cancer during first-line chemotherapy and follow-up. , 1996, Clinical chemistry.

[66]  R. Molina,et al.  HE4 a novel tumour marker for ovarian cancer: comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases , 2011, Tumor Biology.

[67]  R. Kryscio,et al.  Long-Term Survival of Women With Epithelial Ovarian Cancer Detected by Ultrasonographic Screening , 2011, Obstetrics and gynecology.

[68]  A. Tailor,et al.  Risk of malignancy index for referral of ovarian cancer cases to a tertiary center: does it identify the correct cases? , 2005, International Journal of Gynecologic Cancer.

[69]  S. Pignata,et al.  Follow-up with CA125 after primary therapy of advanced ovarian cancer: in favor of continuing to prescribe CA125 during follow-up. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[70]  L. Frati,et al.  HE4 combined with MDCT imaging is a good marker in the evaluation of disease extension in advanced epithelial ovarian carcinoma , 2012, Tumor Biology.

[71]  H. Nielsen,et al.  National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. , 2008, Clinical chemistry.

[72]  G. Guyatt,et al.  Grading quality of evidence and strength of recommendations , 2004, BMJ : British Medical Journal.

[73]  C. Sturgeon Practice guidelines for tumor marker use in the clinic. , 2002, Clinical chemistry.

[74]  M. Duffy,et al.  The National Institute for Health and Clinical Excellence (NICE) guidelines for early detection of ovarian cancer: the pivotal role of the clinical laboratory , 2011, Annals of clinical biochemistry.