CA 125: a Predictor in Ovarian Carcinoma, Endometrial Cancer and other Carcinomas
Jian Q. Wang, M.D.*
CA 125, a high molecular weight (>200 kD) glycoprotein, is expressed on the surface of coelomic epithelium and recognized by the murine monoclonal antibody OC125.1 The second generation CA 125 II assay which uses two monoclonal antibodies, OC125 and M11, correlates well with CA 125 but does not demonstrate interference with human antimouse antibodies (HAMA).2
CA125 measurement is used clinically for prognosis, early diagnosis of recurrence and follow-up in patients with carcinomas. Measuring the serum level of CA-125 antigen is a less expensive method to detect recurrent cancers than radioimmunoscintigraphy.33 Combined with CEA, CA19-9, and breast cancer antigen 225 (BCA225), CA125 can be used for the differential diagnosis of a metastatic adenocarcinoma.32
Serum CA 125 concentration is >35 U/mL in about 80% of women with carcinoma of the ovary,3-5 26% of women with benign ovarian tumors3,5,6 and 66% of patients with non-neoplastic conditions including the first trimester of pregnancy, menstruation, endometriosis, adenomyosis, uterine fibroids, acute salpingitis, hepatic diseases (e.g., cirrhosis) and inflammation of the peritoneum, pericardium and pleura. Only 3% and 0.8% of normal healthy control women have a serum CA 125 concentration over 35 and 65 U/mL, respectively.7-10 Pelvic-peritoneal tuberculosis is associated with elevated serum CA 125.3 In patients with carcinoma that has disseminated beyond the ovary (FIGO stages II, III and IV), 90% have serum concentrations >35 U/mL; however, only 50% of cancer patients whose disease is confined to the ovary (stage I) are positive.1
Combined serum CA 125 (>30 U/mL) and pelvic examination as a screening test for ovarian cancer has a specificity of 99.6% and a positive predictive value of 6-25%.7,8 Transvaginal ultrasound (TVUS) has superior sensitivity and specificity to CA 125 alone, and should be done before interpretation of a CA 125.11-13 Serial determinations of CA 125 with investigation of patients with persistently elevated values increases the positive predictive value in ovarian cancer screening.7 However, low prevalence of the disease in patients without a family history of ovarian cancer results in only one case discovered for every 30 false-positives using ultrasound and CA 125.14-18
The higher the CA 125, the more likely an elevated CA 125 is due to gynecologic cancer. In women with a pelvic mass, a serum CA 125 concentration >35 U/mL, 65 U/mL and 95 U/mL can distinguish malignancy from benign disease with 82%, 93% and 96% accuracy, respectively. When less care is taken in patient selection, the predictive values are much lower.5,6,19,20 In patients with a CA 125 >65 U/mL, gynecologic, non-gynecologic cancers and non-gynecologic conditions constitute 74%, 10% and 13% of diagnosis, respectively. In patients with a CA 125 >1000 U/mL, these same conditions are responsible for 89%, 7% and 3% of diagnosis, respectively.21 Endometriosis and metastatic breast carcinoma are the most common benign and nongynecologic conditions that cause an elevated CA 125. The absence of a pelvic mass makes malignant disease very unlikely.
There may be some utility in pre-screening women with a family history of ovarian cancer with CA 125 prior to referral for ultrasound. Using a cut-off of 20 U/mL as the criterion for ultrasound referral would decrease costs because only 25% would be referred. However, 29% of the true-positive cases detected by a strategy in which all patients are initially screened by ultrasound would be missed by CA 125 pre-screening22,23
CA 125 is useful as a prognostic marker and confirms the clinical impression of the patient. Patients with CA 125 concentrations >450 U/mL have a very poor median survival of 7 months; whereas, patients with a CA 125 concentration <55 U/mL have a better median survival of 23 months.24 Post-operative serum CA 125 predicts 2-year overall survival (>35 U/mL 87%; > 65 U/mL 30%).25 The rate and magnitude of decrease in the CA 125 after the first course of chemotherapy is predictive of prognosis. Patients with a >50% decrease in the CA 125 concentration have a 2-year survival of 45% compared to 22% in patients with a decrease in CA 125 that is <50%.26 An increase to more than 60 U/mL after the first coarse of chemotherapy accurately predicts tumor relapse.1
The most important use of CA 125 is in the assessment of patients for recurrent disease post-oophorectomy. Residual disease is detected in 95% of patients with serum CA 125 concentrations >35 U/mL who are monitored for recurrent ovarian carcinoma. However, a negative result does not exclude the presence of the disease; half of the patients with such negative results have microscopic residual carcinoma. Post surgical monitoring of patients for recurrent ovarian carcinoma is best achieved by combining second-look operations and CA 125 monitoring. 28-29 If the cut-off is lowered to 16 U/mL, 57% of patients considered to be in remission using a cut-off of 35 U/mL are now considered to have recurrent disease.30
CA125 elevation in post-treatment patients of endometrial cancer is also a predictor of recurrence and poor prognosis. Among 23 patients, seven of the 12 (58%) with post-treatment elevation of CA125 developed tumor recurrence. But none of the 11patients (0%) without post-treatment elevation of CA125 developed a recurrence.31
Algorithm 5: Ovarian Cancer Monitoring
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- Rustin GJ. The clinical value of tumour markers in the management of ovarian cancer. Ann Clin Biochem 1996;33:284-9.
- Eltabbakh GH, Gupta MK, Belinson JL, Kennedy AW, Webster K, Paraiso MFR. Comparison between Centacor CA 125 and CA 125 II assays. Eur J Gynaec Oncol 1996;17:504-6
- Gadducci A, Ferdeghini M, Rispoli G, Pontera C, Bianchi R, Fioretti P. Comparison of tumor-associated trypsin inhibitor (TATI) with CA 125 as a marker for diagnosis and monitoring of epithelial ovarian cancer. Scand J Clin Lab Invest 1991;51(Suppl 207):19-24.
- Nistal de Paz F, Herrero-Fernandez B, Perez-Simon R, Fernandez-Perez E, et al. Pelvic-peritoneal tuberculosis simulating ovarian carcinoma: report of three cases with elevation of the CA 125. Am J Gastroenterol 1996;91:1660-1.
- Gadducci A, Ferdeghini M, Prontera C, et al. The concomitant determination of different tumor markers in patients with epithelial ovarian cancer and benign ovarian masses: relevance for differential diagnosis. Gynecol Oncol 1992;44:147-54.
- Vasilev SA, Schlaerth JB, Campeau J, Morrow CP. Serum CA 125 levels in preoperative evaluation of pelvic masses. Obstet Gynecol 1988;71:751.
- Zurawski VR, Sjovall K, Schoenfeld DA, et al. Prospective evaluation of serum CA 125 levels in a normal population, phase I: the specificities of single and serial determinations in testing for ovarian cancer. Gynecol Oncol 1990;36:299-305.
- Jacobs IJ, Skates S, Davies AP, Woolas RP, et al. Risk of diagnosis of ovarian cancer after raised serum CA 125 concentration: a prospective cohort study. Br Med J 1996;313:1355-8
- Kenemans P, Yedema CA, Bon GG, von Mensdorff-Pouilly S. CA 125 in gynecological pathology - a review. Eur J Obstet Gynecol Reprod Biol 1993;49:115-24.
- Alagoz T, Buller RE, Berman M, Anderson B, Manetta A, DiSaia P. What is a normal CA 125 level? Gynecol Oncol 1994;53:93-7.
- Troiano RN, Quedens-Case C, Taylor KJW. Correlation of findings on transvaginal sonography with serum CA 125 levels. Am J Roent 1997;168:1587-90.
- Botsis D, Kassanos D, Kalogirou D, Karakitsos P, Liapis A, Antoniou G. Transvaginal color Doppler and CA 125 as tools in the differential diagnosis of postmenopausal ovarian masses. Maturitas 1997;26:203-9.
- Dorum A, Kristensen GB, Abeler VM, Trope CG, Moller P. Early detection of familial ovarian cancer. Eur J Cancer 1996;32A:1645-51.
- Carlson KJ, Skates SJ, Singer DE. Screening for ovarian cancer. Ann Intern Med 1994;121:124-32.
- Bourne TH, Campbell S, Reynolds K, et al. The potential role of serum CA 125 in an ultrasound-based screening program for familial ovarian cancer. Gynecol Oncol 1994;52:379-85.
- Muto MG, Cramer DW, Brown DL, et al. Screening for ovarian cancer: the preliminary experience of a familial ovarian cancer center. Gynecol Oncol 1993;51:12-20.
- Helzlsouer KJ, Bosh TL, Alberg AJ, et al. Prospective study of serum CA-125 levels as markers of ovarian cancer. JAMA 1993;269:1123-6.
- Vuento MH, Stenman UH, Pirhonen JP, Makinen JI, Laippala PJ, Salmi TA. Significance of a single CA 125 assay combined with ultrasound in the early detection of ovarian and endometrial cancer. Gynecol Oncol 1997;64:141-6.
- Finkler NJ. Clinical utility of CA 125 in preoperative diagnosis of patients with pelvic masses. Eur J Obstet Gynecol Reprod Biol 1993;49:105-7.
- Jacobs IJ, Rivera H, Oram DH, Bast RC Jr. Differential diagnosis of ovarian cancer with tumour markers CA 125, CA 15-3 and TAG 72-3. Br J Obstet Gynecol 1993;100:1120-4.
- Eltabbakh GH, Belinson JL, Kennedy AW, Gupta M, Webster K, Blumenson LE. Serum CA-125 measurements U/mL. Clinical value. J Reprod Med 1997;42:617-24.
- Bourne TH, Campbell S, Reynolds K, et al. The potential role of serum CA 125 in an ultrasound-based screening program for familial ovarian cancer. Gynecol Oncol. 1994;52:379-85.
- Antoni J, Rakar S. Colour and pulsed Doppler US and tumour marker CA125 in differentiation between benign and malignant ovarian masses. Anticancer Res. 1995;15:1527-32.
- Fisken J, Leonard RCF, Stewart M, et al. The prognostic value of early CA 125 serum assays in epithelial ovarian carcinoma. Br J Cancer 1993;68:140-5.
- Makar APH, Kristensen GB, Kern J, Bormer OP, Abeler VM, Trope CG. Prognostic value of pre- and postoperative serum CA 125 levels in ovarian cancer: new aspects and multivariate analysis. Obstet Gynecol 1992;79:1002-10.
- Munstedt K, Krisch M, Sachsse S, Vahrson H. Serum CA 125 levels and survival in advanced ovarian cancer. Arch Gynecol Obstet 1997;259:117-123.
- Rustin GJ, Nelstrop AE, Tuxen MK, Lambert HE. Defining progression of ovarian carinoma during follow-up according to CA 125: a North Thames group study. Ann Oncol 1996;7:361-4.
- Tomas C, Kauppila A. Tumor markers of epithelial and stromal cell origin at second-look laparotomy in ovarian carcinoma. Br J Cancer 1993;45:279-83.
- Gallion HH, Hunter JE, van Nagell JR, et al. The prognostic implications of low serum CA 125 levels prior to the second-look operation for stage III and IV epithelial ovarian cancer. Gynecol Oncol 1992;46:29-32.
- Sugiyama T, Nishida T, Komai K, Nishimura H, Yakushiji M, Nishimura H. Comparison of CA 125 assays with abdominopelvic computed tomography and transvaginal ultrasound in monitoring of ovarian cancer. International J Gynecol Obstet 1996;54:251-6.
- Lo S, Khoo US, Cheng DKL, et al. Role of serial tumor markers in the surveillance for recurrence in endometrial cancer. Cancer Detect Prev. 1999; 23:397-400.
- Brown RW, Campagna LB, Dunn JK, Cagle PT, Immunohistochemical identification of tumor markers in metastatic adenocarcinoma: A diagnostic adjunct in the determination of primary site. Am J Cln Pathol 1997; 12-19.
- Markman M. Radioimmunoscintigraphy in the management of colorectal and ovarian cancer: does identification improve outcome? Cancer Investigation. 2000; 18:289-290.