What is CA (Cancer Antigen) 125?

What is CA-125?

CA-125 (Cancer Antigen 125) is a high-molecular-weight glycoprotein tumor marker primarily used to aid in the diagnosis and monitoring of epithelial ovarian cancer, elevated in approximately 85% of patients with advanced disease but only 50% of early-stage cases. 1

Biochemical Nature and Origin

• CA-125 is a large membrane glycoprotein (also known as mucin 16 or MUC16) that belongs to the mucin family and is expressed on the cell surface of derivatives of embryonic coelomic epithelium 2
• The antigen is expressed by epithelial ovarian tumors and various pathological and normal tissues of Müllerian origin, including the endometrium 3
• The exact physiological function of CA-125 remains unclear, though its distribution suggests it may have a normal physiological role 3

Clinical Applications in Ovarian Cancer

Diagnostic Use

• CA-125 should be measured before surgery and before starting chemotherapy in all patients with suspected ovarian cancer 4
• The marker has a specificity of 98.5% in women over 50 years old when using a threshold of 35 U/mL 4
• CA-125 is elevated in approximately 80-90% of serous carcinomas (both low and high grade) 4

Critical Diagnostic Limitations

• CA-125 only detects 50% of stage I ovarian cancers, so a normal level does not exclude early-stage disease 1, 4
• Elevated CA-125 is not specific to ovarian cancer and may be elevated in non-gynecological malignancies (colorectal cancer, breast cancer) and numerous benign conditions 1, 5
• False-positive elevations occur with endometriosis, adenomyosis, pelvic inflammatory disease, benign ovarian cysts, menstruation, pregnancy, peritonitis, pleural effusion, ascites, and cirrhosis 5, 6

Monitoring Treatment Response

• CA-125 should be measured before each of the six cycles of chemotherapy and one month after the last cycle to monitor response to treatment 4
• The marker is FDA-recommended to monitor response to therapy in patients with epithelial ovarian cancer and to detect residual or recurrent disease 2
• CA-125 has a sensitivity of 62-74% for detecting ovarian cancer recurrence 5

Reference Ranges and Interpretation

Standard Thresholds

• The generally accepted upper limit of normal is 35 U/mL 7
• The specificity is nearly 100% when using thresholds of 30-35 U/mL 8

Physiologic Variations

• Premenopausal women have higher baseline levels (mean 19.3 U/mL) compared to postmenopausal women (mean 11.7 U/mL) 7
• Among premenopausal women, CA-125 levels vary significantly by menstrual phase: 62 U/mL during menses, 51 U/mL during proliferative phase, and 32 U/mL during luteal phase 7
• For postmenopausal women, the upper limit should be 35 U/mL for those with vaginal bleeding and 20 U/mL for those without bleeding 7

Clinical Interpretation Caveats

• CA-125 results must be interpreted in conjunction with clinical, imaging, and histological findings, never in isolation 4
• Marked elevations greater than 1,000 U/mL (and even up to 5,000 U/mL) can occur in benign conditions, limiting its ability to differentiate benign from malignant disease 6
• A progressively elevated CA-125 level over time, even within the normal range, should prompt further evaluation as it may indicate malignancy 4
• Previous radiotherapy may cause elevated CA-125 levels 5

Use in Other Tumor Types

Mucinous Ovarian Tumors

• When CA-125 is not elevated, particularly in mucinous or endometrioid tumors, other markers should be measured 4
• Measuring CEA and CA 19-9 in addition to CA-125 helps distinguish primary mucinous ovarian tumors from gastrointestinal metastases 1, 5
• A CA-125/CEA ratio greater than 25:1 favors ovarian origin over gastrointestinal origin 5

Endometrial Cancer

• CA-125 should be considered in select endometrial cancer patients with advanced disease, serous histology, or elevated pretreatment levels 5
• More than half of patients with advanced-stage or high-grade endometrial cancer have elevated pretreatment CA-125 levels 5
• CA-125 accounts for 15% of asymptomatic recurrence detection in endometrial cancer 5

Germ Cell Tumors

• In young women (particularly under 35 years), alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (beta-hCG) should be measured instead to exclude germ cell tumors 4

Why CA-125 is NOT Used for Screening

• No effective and sensitive screening test for ovarian cancer is currently available, and CA-125 screening is not recommended by any major organization 4
• The PLCO trial demonstrated that screening with transvaginal ultrasonography and CA-125 did not decrease mortality from ovarian cancer 4
• The positive predictive value of CA-125 screening is only about 2% in average-risk women, meaning 98% of positive tests are false positives 8
• False-positive screening results led to serious complications in some women undergoing unnecessary interventions 4

Emerging Alternatives and Combinations

• Ultrasound-based diagnostic models (IOTA Simple Rules or IOTA ADNEX model) are superior to CA-125 alone in distinguishing between benign and malignant ovarian tumors 1, 5
• Combined use of CA-125 with HE4 (human epididymis protein 4) provides better sensitivity and specificity in identifying epithelial ovarian cancer relapse 2
• The OVA1 test (using 5 markers: transthyretin, apolipoprotein A1, transferrin, beta-2 microglobulin, and CA-125) should NOT be used as a screening tool according to the Society of Gynecologic Oncologists and FDA 4
• Other emerging markers (mesothelin, B7-H4, DcR3, spondin-2) do not increase early enough to be useful in detecting early-stage ovarian cancer 4