CA 125: Reference Range, Interpretation, Collection And Panels

Up to 80% of females with ovarian carcinoma of epithelial origin have elevated serum CA 125 levels, with the frequency of elevation correlating with the clinically detected stage. [5] The degree of elevation has also been shown to correlate with tumor burden and International Federation of Gynecology and Obstetrics 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. [6, 7] CA 125 levels may also be elevated in other malignancies, as well as in benign and physiological 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 [8]
• 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.

CA 125 values must be interpreted in the context of clinical presentation, imaging, and other laboratory results. Isolated elevation is not diagnostic of malignancy and may reflect a wide range of benign or physiological conditions. CA 125 is most useful for monitoring response to therapy, detecting recurrence, and guiding management decisions in ovarian and endometrial cancers. [9] Routine CA 125 screening is not recommended for average-risk populations due to high false-positive and false-negative rates. [10]

Long-term follow-up from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) confirmed that longitudinal CA 125–based screening detects more early-stage ovarian cancers but does not reduce mortality. As such, professional societies continue to advise against CA 125–based screening in average-risk women, even when using algorithms such as the Risk of Ovarian Cancer Algorithm. [11]

CA 125 and HE4 are currently the only approved biomarkers for epithelial ovarian cancer; multimarker indices such as the Risk of Malignancy Algorithm (ROMA) that incorporate CA 125, HE4, and menopausal status improve presurgical evaluation of adnexal masses. [9]

There are five major scenarios in which testing CA 125 is useful, as 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. [6] This is particularly useful in postmenopausal females, in whom confounding variables from benign and physiological conditions are absent or infrequent. CA 125 can be used to calculate a risk for malignancy index, which is used to form the basis of algorithms in the management of pelvic masses in the United Kingdom. [12]

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 defines a response to treatment as a reduction of 50% or more in pretreatment CA 125 levels maintained for at least 28 days. [13] 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. [13]

A study by Potenza et al indicated that in patients with epithelial ovarian cancer (EOC), 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 (PFS) (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). [14]

Biomarker studies in advanced ovarian cancer trials, such as the NIRVANA-R trial, highlight that achieving normal CA 125 levels (0-35 U/mL) after chemotherapy is a strong prognostic factor for PFS. In this trial, patients with normal CA 125 after chemotherapy had a 6-month PFS rate of 72% vs 25% in those with elevated CA 125 (> 35 U/mL). [15]

Meta-analyses demonstrate that combining CA 125 with HE4 significantly increases diagnostic performance — sensitivity up to 93.6% and specificity up to 88.3% — compared to CA 125 alone; these findings support using such combined biomarker strategies where available. [16]

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. [6] Although increasing CA 125 levels correlate with tumor recurrence after primary treatment, management of biochemical relapses remain controversial. A recent study concluded that a combination of positron emission tomography and computed tomography scanning is useful in diagnosing relapses in patients with a CA 125 value of at least 17.6 U/mL. [17]

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. [18] 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 vs 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. [6]

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. [19, 20] 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. [21] 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 for death compared with levels lower than 65 kU/L. [22]

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. [23]

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. [22]

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. [24]

Individuals with a deleterious mutation in the genes BRCA1 or BRCA2 are qualified as having hereditary breast and ovarian cancer syndrome (HBOCS). In these females, the lifetime risk for developing ovarian cancer ranges from 11% to as high as 62% in some series. [25, 26]

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 or 5-10 years before the earliest age of first diagnosis of ovarian cancer in the family. [22]

A National Institutes of Health consensus panel also recommends annual CA 125 measurements in addition to pelvic examinations and TVUS among females with HBCOS, who have an estimated lifetime risk for 40% of developing ovarian cancer. [27]

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. [28]

Meta-analyses studies confirm that elevated CA 125 is associated with increased risk for mortality and heart failure readmission in patients undergoing transcatheter aortic valve replacement. Higher preprocedural CA 125 levels are linked to a 2.17- to 3.27-fold increased risk for mortality (adjusted hazard ratio, high certainty evidence). [29]

In rheumatoid arthritis–associated interstitial lung disease, CA 125 levels trend higher in patients with usual interstitial pneumonia pattern, though this did not reach statistical significance in a recent cross-sectional study. CA 125 may help assess disease severity and pattern, but its clinical application remains investigational. [30]