Which blood markers (CA‑125 (cancer antigen 125), HE4 (human epididymis protein 4)) and the ROMA (Risk of Ovarian Malignancy Algorithm) are used to evaluate ovarian cancer?

Blood Markers for Ovarian Cancer Evaluation

Primary Marker: CA-125

CA-125 should be measured in all patients with suspected ovarian cancer before surgery and chemotherapy, serving as the foundational tumor marker despite its limitations. 1, 2

Diagnostic Performance

• CA-125 has a specificity of 98.5% in women over 50 years old when using a threshold of 35 U/mL, making it highly reliable in postmenopausal women 1
• The marker is elevated in approximately 80-90% of serous carcinomas (both low and high grade) 1
• Critical limitation: CA-125 detects only 50% of stage I ovarian cancers, so a normal level does not exclude early malignancy 1, 3
• CA-125 should be measured before each of the six chemotherapy cycles and one month after the last cycle to monitor treatment response 1

Clinical Context and False Positives

• CA-125 results must be interpreted alongside clinical, imaging, and histological findings because false positives occur in multiple benign conditions including endometriosis, adenomyosis, pelvic inflammatory disease, and benign ovarian cysts 1, 3
• A progressively elevated CA-125 level over time, even within the normal range, should prompt further evaluation as it may indicate malignancy 1

Secondary Marker: HE4 (Human Epididymis Protein 4)

HE4 demonstrates superior specificity compared to CA-125, particularly in premenopausal women, making it valuable when high specificity is needed. 4

Diagnostic Advantages

• HE4 achieves a specificity of 93.6% overall, significantly higher than CA-125's 82.1% 4
• In premenopausal women specifically, HE4 shows even better performance with 93.8% specificity compared to CA-125's 76.3% 4
• HE4 appears more efficient than CA-125 in ruling in epithelial ovarian cancer patients, including early-stage tumors, in both pre- and postmenopausal women 5
• HE4 has significantly higher concentrations in ovarian cancer compared to other gynecological malignancies (p < 0.001), providing better cancer-type specificity 6

Limitations

• HE4 and other markers (mesothelin, B7-H4, DcR3, spondin-2) do not increase early enough to be useful in detecting early-stage ovarian cancer 7, 1
• Both HE4 and CA-125 show lowest concentrations in mucinous tumors 6

ROMA (Risk of Ovarian Malignancy Algorithm)

ROMA provides the best overall diagnostic efficiency by combining HE4 and CA-125 with menopausal status, achieving superior balanced performance across both sensitivity and specificity. 5, 8

Diagnostic Performance

• ROMA demonstrates the highest area under the ROC curve (0.91) compared to HE4 (0.89) and CA-125 (0.87) 4
• Using routine cut-off thresholds, ROMA shows well-balanced values: premenopausal women (sensitivity 87%, specificity 86.1%); postmenopausal women (sensitivity 90%, specificity 94.3%) 5
• ROMA cut-offs are 13.1 for premenopausal women and 27.7 for postmenopausal women 6

Performance by Menopausal Status

• In postmenopausal women, ROMA performs significantly better (AUC 0.93) than in premenopausal women (AUC 0.86) 4
• When specificity is fixed at 98%, ROMA achieves: premenopausal (sensitivity 69.6%, positive predictive value 80%, positive likelihood ratio 35.1); postmenopausal (sensitivity 88%, positive predictive value 97.8%, positive likelihood ratio 77.4) 5

Optimal Clinical Application

• ROMA algorithm might be most efficiently used in patients with normal HE4 but abnormal CA-125 serum levels, where cancer risk is 44.4% 6
• Regular detection of HE4, CA-125, and ROMA index can help predict postoperative recurrence of ovarian cancer 8

Alternative Markers When CA-125 is Not Elevated

When CA-125 is not elevated, particularly in mucinous or endometrioid tumors, measure CA 19-9 as an alternative marker. 1

• CA 19-9 should be measured when CA-125 is normal, especially in clear cell tumors, teratomas, and mucinous tumors 1
• In young women (particularly under 35 years), measure alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (beta-hCG) to exclude germ cell tumors 1

Tests NOT Recommended

The OVA1 test should NOT be used as a screening tool for ovarian cancer according to the Society of Gynecologic Oncologists and FDA. 7, 1

• OVA1 uses 5 markers (transthyretin, apolipoprotein A1, transferrin, beta-2 microglobulin, and CA-125) but lacks validation for screening 7, 1
• The OvaSure test requires additional validation before use outside clinical trials 1

Critical Clinical Algorithm

For evaluating a patient with suspected ovarian cancer:

1. Measure CA-125 in all patients initially 1, 2
2. Add HE4 measurement, particularly in premenopausal women or when high specificity is needed 4
3. Calculate ROMA score using both markers and menopausal status for optimal diagnostic efficiency 5, 8
4. If CA-125 is normal, measure CA 19-9 (especially for mucinous/clear cell/teratomas) 1
5. In women under 35, add AFP and beta-hCG to exclude germ cell tumors 1
6. Monitor CA-125 before each chemotherapy cycle and one month post-treatment 1
7. During surveillance, serial monitoring can detect recurrence before clinical symptoms 2