CA 125

Cancer antigen 125 (CA 125) is the only tumor marker recommended for clinical use in the diagnosis and management of ovarian cancer.

The reference range of CA 125 is 0-35 units/mL (0-35 kU/L).

The cutoff of 35 kU/L for CA 125 was determined from the distribution of values in healthy individuals to include 99% of the normal population. ^[1] The lack of an international standard for CA 125 hampers comparability among laboratories, and values derived from different methods are not interchangeable. As such, baseline levels in patients who undergo serial CA 125 monitoring should be redetermined if the methodology in the assay is changed. ^[2]

Serum CA 125 values tend to decline with age and the onset of menopause. Levels also vary by race; concentrations tend to be lower in postmenopausal Asian and African women than in their white counterparts. ^[1]

Up to 80% of women with ovarian carcinoma of epithelial origin have elevated serum CA 125 levels, with the frequency of elevation correlating with the clinically detected stage. ^[3] The degree of elevation has also been shown to correlate with tumor burden and International Federation of Obstetrics and Gynecologic (FIGO) pathologic stage. However, owing to the lack of sensitivity and specificity, elevations in single or sequential CA 125 levels alone are not recommended for ovarian cancer screening or in the initial diagnosis of ovarian cancer. ^{[4, 5]} CA 125 levels may also be elevated in other malignancies, as well as in benign and physiologic conditions.

Malignant conditions associated with elevated CA 125 levels include the following:

• Epithelial ovarian carcinoma (including fallopian tube and primary serous peritoneal carcinoma): 75%-85%

• Endometrial carcinoma: 25%-48% of cases

• Endocervical adenocarcinoma: 83% of cases

• Pancreatic carcinoma: 59% of cases

• Breast carcinoma: 12%-40% of cases

• Lymphoma: 35% of cases ^[6]

• Lung carcinoma: 32% of cases

• Colorectal carcinoma: 20% of cases

• Squamous cervical/vaginal carcinoma: 7%-14% of cases

Benign conditions associated with elevated CA 125 levels include the following:

• Endometriosis: 88% of cases

• Cirrhosis: 40%-80% of cases

• Acute peritonitis: 75% of cases

• Acute pancreatitis: 38% of cases

• Acute pelvic inflammatory disease: 33% of cases

• First trimester of pregnancy: 2%-24% of cases

• Nondisease state: 0.6%-1.4% of healthy individuals

Owing to the heterogeneity of its distribution, an elevated CA 125 value must be interpreted in the context of the clinical scenario and indication for which it is being tested.

There are 5 major scenarios in which testing CA 125 is useful, discussed below.

Adjunct in the discrimination of pelvic masses

Elevations in CA 125 levels are used as an adjunct to aid in differentiation of malignant from benign pelvic masses detected with clinical examination or imaging. ^[4] This is particularly useful in postmenopausal women, in whom confounding variables from benign and physiologic conditions are absent or infrequent. CA 125 can be used to calculate a risk of malignancy index (RMI), which is used to form the basis of algorithms in the management of pelvic masses in the United Kingdom. ^[7]

Monitoring response to therapy

Declining CA 125 levels have been shown to correlate with treatment response, even when disease is not detectable with physical examination or imaging. In this setting, serial CA 125 testing has more clinical utility than a single determination.

The Gynecologic Cancer Intergroup (GCIG) defines a response to treatment as a reduction of 50% or more in pretreatment CA 125 levels maintained for at least 28 days. ^[8] The pretreatment value must be at least twice the upper limit of the reference range and taken 2 weeks prior to treatment. Subsequent samples are taken at weeks 2 and 4 of treatment and at intervals of 2-3 weeks thereafter. However, tumor recurrence may occur in the setting of normal CA 125 levels, and serum measurements do not replace imaging and physical examination of the patient. ^[8]

A study by Potenza et al indicated that in patients with epithelial ovarian cancer, combined analysis of CA 125 and human epididymis protein 4 (HE4) is an effective indicator of success in chemotherapy. Negativization of CA 125 and HE4 following the third cycle of chemotherapy correlated with long progression-free survival (the odds ratios [ORs] being 9.1 and 5.5, respectively), as did “biomarker serum levels lower than the mean value in the affected population at the time of diagnosis” (ORs = 3.7 and 3.4, respectively). ^[9]

Detection of recurrence

Rising levels of CA 125 in the absence of clinical or radiographic findings indicate what is termed as a biochemical relapse, which precedes a clinically detected relapse by 2-6 months. ^[4] Although increasing CA 125 levels correlate with tumor recurrence after primary treatment, management of biochemical relapses remain controversial. A recent study concluded that positron emission tomography (PET/CT) scanning is useful in diagnosing relapses in patients with a CA 125 value of at least 17.6 U/mL. ^[10]

A recent European collaborative study suggests that early treatment of biochemical relapse does not provide survival benefit and is associated with a decreased quality of life. ^[11] However, limitations of the study include the lack of a standardized second or third line of chemotherapy, since agents evolved over the 10-year accrual period. Furthermore, there were no surgical considerations in terms of optimal versus suboptimal primary or secondary cytoreductive surgeries or whether the tumors were platinum sensitive or resistant. As such, the National Comprehensive Cancer Network (NCCN) recommends that physicians discuss the pros and cons of monitoring CA 125 levels with their patients. If rising CA 125 levels are detected, enrollment in a clinical trial or observation until onset of symptoms or clinically detected disease arises is recommended. ^[4]

Increased levels of CA 125 also correlate with the presence of tumor in a second-look operation after primary treatment with debulking surgery and chemotherapy. CA 125 levels above 35 units/mL predict the presence on second-look operation with 95% accuracy. ^{[12, 13]} However, the false-negative rate is high, with a range of 50%-60% in some studies; as such, the necessity of a second-look cannot be judged based solely on CA 125 levels. ^[14] Moreover, second-look laparotomy is currently considered controversial and is offered only in patients enrolled in clinical trials or when surgical findings alter subsequent management.

Prognosis determination

Increased levels of CA 125 have been shown to be independent prognostic factors for survival in ovarian carcinoma. One study showed that patients with a preoperative CA 125 level above 65 kU/L had a statistically significant lower 5-year survival likelihood, conferring a 6.37-fold risk of death compared with levels lower than 65 kU/L. ^[15]

Similarly, a study by Nasioudis et al found that in patients with stage-1 ovarian sex cord-stromal tumors, those with an elevated serum CA 125 level prior to cancer surgery had a worse 5-year overall survival rate (86.8%) than did patients in whom serum CA 125 was not elevated (94.8%). Worse survival in association with elevated CA 125 was further supported after the investigators controlled for patient age, comorbidities, tumor histology, tumor size, and the performance of lymphadenectomy. ^[16]

In addition to the absolute level, the half-life of CA 125 is also a prognosticator for survival, with one study showing a half-life of less than 20 days correlating with improved survival. The same study also showed that the postoperative nadir of CA 125 was also a powerful predictor of survival. ^[15]

Early detection of hereditary syndromes

At present, no randomized data support routine screening in the general population for ovarian cancer, and no professional society recommends using CA 125 for routine screening. However, several societies suggest using CA 125 for early detection in high-risk patients, such as those with a genetic predisposition for hereditary ovarian cancer syndromes. ^[17]

Individuals with a deleterious mutation in the genes BRCA1 or BRCA2 are qualified as having hereditary breast and ovarian cancer syndrome (HBOCS). In these women, the lifetime risk of developing ovarian cancer ranges from 11% to as high as 62% in some series. ^{[18, 19]}

In patients with HBCOS who have not elected to undergo salpingo-oophorectomy as primary prevention, the NCCN recommends considering concurrent transvaginal ultrasonography (TVUS) and CA 125 measurements every 6 months starting at age 30 years or 5-10 years before the earliest age of first diagnosis of ovarian cancer in the family. ^[15]

A National Institutes of Health (NIH) consensus panel also recommends annual CA 125 measurements in addition to pelvic examinations and TVUS among women with HBCOS, who have an estimated lifetime risk of 40% of developing ovarian cancer. ^[20]

Lastly, the NCCN also recognizes that concurrent CA 125 and TVUS may also be helpful in early detection in patients with hereditary nonpolyposis colorectal cancer or Lynch syndrome, at the clinician’s discretion. ^[21]

Specimen: Blood or serum

Collection method: Routine venipuncture

Patient preparation: No patient preparation is needed prior to the collection of the sample

Container: Blood is collected into a purple-top tube with ethylenediaminetetraacetic acid (EDTA)

Interactions: Heparin and oxalate may interfere with testing; these should be avoided

Storage: The American Association for Clinical Chemistry (AACC) recommends analyzing serum shortly after centrifugation of the obtained blood specimen. The serum specimen can then be stored at either 4°C (1-5 days) or -20°C (2 weeks to 3 months) in the short term or -70°C in the long term to ensure stability. ^[22]

Panels: Although CA 125 has been used with other tumor markers in the clinical trial and research, it is typically not part of a panel as it is the only tumor marker recommended by the National Academy for Clinical Biochemistry for clinical use in patients with ovarian cancer. ^[23]

Description

CA 125 is an antigenic determinant on a high–molecular-weight glycoprotein recognized by a monoclonal antibody (OC 125). The full-length CA 125 glycoprotein contains more than 11,000 amino acids in its proteinaceous core and has been termed Muc16 to reflect the mucinlike nature of the antigen and is now identified as a new member of the protein family of mucins. ^[24]

The precise function of the antigenic determinant is unknown but can be found in both benign and malignant tissue.

CA 125 is expressed by more than 80% of nonmucinous epithelial ovarian carcinomas and is found in most carcinomas of Müllerian origin, including fallopian tube and primary serous peritoneal carcinoma. ^[12] In addition, it can be expressed by several benign and physiologic conditions, as detailed in Interpretation.

The first-generation immunoassay for CA 125 was commercialized in 1983 (CA-125 I) and used the OC 125 antibody for both capture and detection. ^[25] In 1991, a second-generation assay was developed (CA-125 II), using M11 mouse monoclonal antibody as capture and OC 125 as a tracer. Incorporation of these two distinct and nonoverlapping epitopes improved sensitivity and decreased variability. ^[26] As such, the type of immunoassay used should be considered, as results are not interchangeable.

The first-generation assay is no longer manufactured in the United States.

Indications/Applications

CA 125 is the only tumor marker recommended for clinical use in the diagnosis and management of ovarian cancer. There are 5 main indications in which the determination of CA 125 levels is recommended.

Table 1 summarizes the recommendations from different societies in both Europe and the United States. ^[23]

Table 1. Recommendations for CA 125 Testing in Ovarian Cancer by Different Expert Groups (Open Table in a new window)

Considerations

Ovarian cancer is only one of several conditions, benign and malignant, that can cause elevations in CA 125. As such, one must consider the presence of these conditions (see Interpretation) when interpreting levels of CA 125 in a patient with or suspected of having ovarian cancer. Postmenopausal patients are the particular age group in whom testing for CA 125 is particularly useful, as many of the benign conditions that can confound interpretation are absent.

Serial determinations of CA 125 provide more useful data than single determinations in determining response to treatment. Moreover, the half-life and nadir determined through such can provide powerful prognostic information for the clinician.

Although no data support using CA 125 for early detection of ovarian cancer in the general population, a patient’s family history and proven deleterious mutations in genes predisposing to hereditary ovarian cancer syndromes should be taken into consideration, as early detection and intervention may be of benefit.

No evidence supports the use of CA 125 with or without TVUS to screen the general population for ovarian cancer. Single determinations of CA 125 in asymptomatic women without a family history of ovarian cancer lack sensitivity and specificity and are not recommended by any expert group. Moreover, several studies have found no mortality benefit.

A large randomized trial involving more than 78,000 women found that concurrent screening with TVUS and CA 125 did not decrease mortality in patients found to have ovarian cancer. In addition, false-positive results led to serious consequences in some women. ^[31]

A multicenter, prospective study involving 1149 patients with an adnexal mass showed adding CA 125 to ultrasonography did not improve diagnostic performance. ^[32] However, an ongoing trial involving 202,638 postmenopausal women is assessing screening for ovarian cancer (UK Collaborative Trial of Ovarian Cancer Screening) using multimodality screening with ultrasonography and CA 125 versus either ultrasonography alone or no screening. Preliminary results suggest that multimodal screening is more effective at detecting early-stage cancer. ^{[33, 34]}

A multicenter study by Choi et al indicated that when using reference cutoff values in premenopausal women, the specificity and accuracy of the Risk of Ovarian Malignancy Algorithm (ROMA; 0.926 and 0.875, respectively) are better than those of CA 125 alone (0.787 and 0.777, respectively) in the differentiation of epithelial ovarian cancer (EOC) from a benign adnexal mass. Sensitivity, however, was comparable in the study (0.707 vs 0.747, respectively). When optimum cutoff values were used, the specificity and accuracy of CA 125 (0.922 and 0.871, respectively) were comparable to those of ROMA (0.947 and 0.868, respectively), but the sensitivity was lower (0.613 vs 0.707, respectively). In postmenopausal women, ROMA demonstrated no better diagnostic performance than CA 125 alone. ^[35]

Similarly, a retrospective study by Han et al, looking at sensitivity, specificity, and receiver operating characteristic curve analysis, found that in postmenopausal women, ROMA was not better than CA 125 alone in predicting the presence of ovarian malignancy. ^[36]