CA-125 is a cell surface glycoprotein associated with ovarian carcinoma cells, but not normal adult ovarian cells.  It is expressed on the surface of serous, endometrioid, clear cell, mucinous, and undifferentiated tumors of the ovary, but less often by Brenner, sex cord, and germ cell ovarian tumors. It is a normal constituent of fallopian tube, endocervix, and endometrium.  CA-125 also occurs in mesothelial cells lining the adult pleura, pericardium, and peritoneum. CA-125 is not specific for ovarian cancer, but can also be elevated in patients with pancreas, breast, colon and lung cancer.

Elevated CA-125 levels have been observed in many different conditions.  CA-125 levels are higher in healthy women less than 49 years old than in healthy women over 49 years and in healthy men, presumably due to the effect of menstruation.  The expression of CA-125 in normal endometrium and decidual endometrium accounts for the elevations in serum levels during menstruation and pregnancy.  CA-125 is highest during the first trimester of pregnancy, where levels up to 1250 U/mL have been reported.  Serum levels become elevated between 30 and 40 days after the last menstrual period, peak between 35 and 60 days, and fall by the end of the first trimester.  Women in in vitro fertilization programs also have elevated CA-125 levels of 80 to 500 U/mL due to ovarian hyperstimulation. Smoking does not appear to affect serum CA-125.  Benign diseases affecting mesothelial tissues are associated with elevated serum CA-125 levels, particularly those associated with ascites and pleural and pericardial effusion.

The elevation of CA-125 levels in a number of benign conditions precludes its use as a screening test in the general population.  However, the majority of these benign conditions occur in pre-menopausal women, while ovarian cancer occurs most commonly in postmenopausal women. The best target group for an ovarian cancer-screening program is women more than 45 years of age, where the annual incidence is 40 cases per 100,000 women. In order to achieve a positive predictive value of 10%, the screening test needs a specificity of at least 99.6%.  The specificity of a single serum CA 125 measurement for ovarian cancer in postmenopausal women is 97%.  Although this specificity appears high, there are 75 false positive results for each ovarian cancer identified.  Since the most likely consequence of a positive screening test would be laparoscopy or laparotomy, this type of screening program is not clinically acceptable.  Combining CA-125 measurements with vaginal examination or ultrasound scanning significantly increases the specificity for cancer to >99.6%, but also increases the complexity and expense of the screening program. 

Most recently, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) randomized, controlled trial demonstrated that CA125 screening did not reduce ovarian cancer mortality rates but did increase the risk of harm due to unnecessary surgeries and associated complications (JAMA 2011;305:2295-303).

In contrast to its poor utility as a screening test, CA125 is useful in the differential diagnosis of adult women who present with an adnexal mass. More than 50% of patients with malignant ovarian tumors have levels greater than 65 U/mL, compared with only 5% of patients with benign tumors.  CA125 levels >95 U/mL in postmenopausal women are particularly helpful in distinguishing benign from malignant disease

CA125 can also be combined with sonography to calculate a risk of malignancy index (RMI). The RMI calculation involves multiplication of CA125 concentration by menopausal status and ultrasound score. Clinicians frequently use cutoffs of 200 to 250 to distinguish benign from malignant masses.

Postoperative CA-125 levels correlate with residual tumor volume, but the data is not clear whether they independently affect subsequent survival.  Postoperative serum CA-125 should be determined at least 3 weeks after surgery, because serum levels can be increased when the abdominal cavity is opened.CA125 levels >35 U/mL detect residual disease with 95% accuracy.

The rate of fall of serum CA-125 postoperatively has some prognostic value.  The serum half-life of CA-125 is 5 to 10 days. Theoretically, levels should decrease about 50% each week following successful therapy. Patients with responsive disease have CA-125 half-lives of 9 +/- 5 days, while patients with static or progressive disease have half-lives greater than 20 +/- 2 days.  

Oncologists commonly use CA125 to monitor patient’s response to chemotherapy. Patients are typically tested 2 weeks prior to initiation of therapy and every 2 to 4 weeks afterward.  Current guidelines for long-term followup suggest measuring CA125 every 2 to 4 months for 2 years.

The half-life of CA-125 during induction chemotherapy has some prognostic value.  In patients with stage 1 or 2 disease and complete tumor removal, the CA-125 half-life averages less than 2 weeks.  Patients with a CA-125 half-life greater than 40 days have a poor prognosis. 

CA-125 levels can be used to monitor patients for tumor progression or recurrence.  A persistently rising serum CA-125 level is consistently associated with progression of disease and frequently occurs several months prior to clinical symptoms.  A doubling of CA-125 levels is a reliable indicator of recurrent disease.  In patients undergoing second look surgery, elevated levels almost always correlate with tumor recurrence.  However, a serum CA-125 level within the reference range does not exclude the presence of cancer.  False negative CA-125 results are usually due to small tumor volumes, but may also be due to ovarian tumors not expressing the antigen.  CA-125 serum levels are elevated in 20% of patients with microsopic size tumors, 40% with tumors less than 1 cm, and 70% with tumors between one and two cm.

CA-125 is present in normal endometrium.  Serum levels are elevated in some patients with endometriosis and endometrial cancer.  Elevated CA-125 levels are found in approximately 10% of patients with stage I and II endometriosis levels and 50% of stage III and IV patients. Approximately 30% of all patients with endometrial cancer have elevated CA-125 levels, but the incidence of CA-125 elevation varies with clinical stage.  Twenty percent of patients with stages I and II cancer have elevated values, compared to 80% of patients with stages III and IV.  CA-125 levels may have prognostic value.  Patients with elevated pre-operative CA-125 levels are more likely to have extra-uterine cancer during staging laparotomy and are more likely to have recurrent disease.

Serum CA-125 measurement may be useful in distinguishing pancreatic cancer and chronic pancreatitis.  CA 19.9, the most commonly used tumor marker for pancreatic cancer, is elevated in both conditions, while CA-125 is elevated only in pancreatic cancer.

The CA 125 reference range is 0-35 units/mL.  A difference of more than 15% between two measurements is considered to be medically significant.

Specimen requirement is one SST tube of blood.

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