Gynecological Cancer

European Group of Tumor Markers (EGTM) Guidelines for Use of Biomarkers in Gynecological Cancer: 2012

Söletormos G, Duffy MJ, Bonfrer H, Othman S, Tholander B, Hyltoft Petersen P, Troonen H, Molina R, Torre GC, Kulpa J, Zwirner M, Tuxen MK

Established Tumor Markers for Ovarian Cancer

  • In women with epithelial ovarian cancer, approximately 80% have CA 125 levels > 35kU/L, with elevations in 50%-60% in clinical stage I disease, 80%-90% in stage II, and > 90% in stage III-IV.
  • CA 125 is not recommended as a screening test in asymptomatic women without a hereditary risk outside the context of a clinical trial because CA 125 lacks diagnostic sensitivity for stage I disease and those with mucinous-type tumors and additionally lacks disease specificity, especially for premenopausal women.
  • CA 125 is advised annually in women with a hereditary ovarian cancer syndrome in addition to pelvic and ultrasound examination. However, there is no evidence that screening these high-risk women reduces morbidity or mortality.
  • CA 125 combined with Ultrasound is recommended in distinguishing benign from malignant disease in women with a pelvic mass, particularly in postmenopausal women. An algorithm to calculate the risk of malignancy index (RMI) has been developed, where CA 125 is incorporated with transvaginal ultrasound and menopausal status to estimate the probability of malignant potential for a pelvic mass in premenopausal and postmenopausal women with reported sensitivities of 71%-78 % and specificities of 75%-94 %.
  • Concentrations of CA 125 > 95kU/L in postmenopausal women can discriminate malignant from benign pelvis masses with a positive predictive value of 95%.
  • Benign conditions resulting in increased CA 125 levels are a confounding factor in premenopausal women e.g. (pregnancy, endometriosis, cysts and uterine leiomyoma).
  • CA 125 may be considered for monitoring treatment of ovarian cancer, but there is no consensus on how to define a CA 125-based response. It is recommended that the marker response should be based on a decrement of 50% in concentrations or alternatively be based on a statistical estimation of decrements adjusted to both analytical and biological variation of the marker.
  • CA 125 may be of prognostic significance preoperatively, postoperatively and during the first three courses of primary chemotherapy.
  • CA 125 measurements are recommended during follow-up. Continuously elevated concentrations during follow-up are predictive for tumor growth. To indicate progression either a confirmed doubling of CA 125 levels or an approach based on analytical and biological variation may be used.
  • Alpha-fetoprotein (AFP) and human choriongonadotropin (HCG) are established markers for germ cell tumors both for diagnosis and monitoring. Elevated AFP and HCG concentrations > 100 IU/L indicate the presence of nondysgerminotous elements.

Potential Tumor Markers for Epithelial Ovarian Cancer

  • Human Epididymis protein (HE4) has been proposed as a new tumor marker especially for non-mucinous subtypes of epithelial ovarian cancer. Initial studies have suggested an increased diagnostic specificity of HE4 compared to CA 125, mainly in premenopausal women. The sensitivity of CA 125 and HE4 is suggested to be similar.
  • Data indicate that HE4 measurement in healthy premenopausal women as well as in women with endometriosis may be carried out at any phase of the menstrual cycle, and irrespective of hormonal medication.
  • An algorithm, the "Risk of Ovarian Malignancy Algorithm" (ROMA) has been suggested to evaluate the performance of utilizing the combination of HE4 and CA 125 to predict the risk of serous epithelial ovarian cancer in women with pelvic mass. However, the ROMA algorithm should undergo further clinical evaluation before recommending the algorithm in clinical use.
  • The utility of combing HE4 and CA 125 is unclear due to small and selected study populations. Further prospective studies are needed to investigate HE4 before implementing the marker into routine clinical practice.
  • CEA and CA 19.9 measurements may be considered in determining treatment response in monitoring of patients with mucinous tumors.

Additional Reading

  1. Bast, R. C., Jr. "Early detection of ovarian cancer: new technologies in pursuit of a disease that is neither common nor rare." Trans.Am.Clin.Climatol.Assoc. 115 (2004): 233-47.
  2. Duffy, M. J., et al. "CA125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use." Int.J.Gynecol.Cancer 15.5 (2005): 679-91.
  3. Guppy, A. E. and G. J. Rustin. "CA125 response: can it replace the traditional response criteria in ovarian cancer?" Oncologist. 7.5 (2002): 437-43.
  4. Lu, R., et al. "Human epididymis protein 4 (HE4) plays a key role in ovarian cancer cell adhesion and motility." Biochem.Biophys.Res.Commun. 419.2 (2012): 274-80.
  5. Lutz, A. M., et al. "Early diagnosis of ovarian carcinoma: is a solution in sight?" Radiology 259.2 (2011): 329-45.
  6. Molina, R., et al. "HE4 a novel tumour marker for ovarian cancer: comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases." Tumour.Biol. 32.6 (2011): 1087-95.
  7. Neesham, D. "Ovarian cancer screening." Aust.Fam.Physician 36.3 (2007): 126-28.
  8. Sturgeon, C. M., et al. "National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers." Clin.Chem. 54.12 (2008): e11-e79.
  9. Van, Gorp T., et al. "HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm." Br.J.Cancer 104.5 (2011): 863-70.

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