Home Ovarian and Gynecologic Cancer Biomarkers ROMA Test for Ovarian Cancer Risk: CA-125, HE4, Menopause Status, and Risk...

ROMA Test for Ovarian Cancer Risk: CA-125, HE4, Menopause Status, and Risk Score

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Learn how the ROMA ovarian cancer risk test combines CA-125, HE4, and menopause status, why cutoffs vary by assay, and what high or low risk scores mean before surgery.

The ROMA test, short for Risk of Ovarian Malignancy Algorithm, combines two blood biomarkers—CA-125 and HE4—with menopause status to estimate whether an adnexal mass has a higher or lower risk of epithelial ovarian cancer before surgery. ROMA is not a screening test for people without a known pelvic mass, and it cannot diagnose ovarian cancer on its own. Its purpose is to support preoperative risk assessment so clinicians can decide whether gynecologic oncology involvement is appropriate. The exact score format and cutoff depend on the laboratory platform. Some reports show a percentage, while others use a platform-specific index; premenopausal and postmenopausal thresholds also differ. This means a ROMA value should always be interpreted using the cutoff printed on the same laboratory report. A high-risk result increases concern but can occur with benign disease. A low-risk result lowers concern but cannot override suspicious imaging, symptoms, examination findings, or other evidence.

  • ROMA combines CA-125, HE4, and menopause status: the calculation is designed for women with an adnexal mass who are being evaluated before surgery.
  • There is no single universal ROMA cutoff: thresholds vary by assay and report format, so use the laboratory-specific premenopausal or postmenopausal reference.
  • A high ROMA result means higher estimated malignancy risk, not a cancer diagnosis: pathology is still required to determine what the mass is.
  • A low ROMA result does not rule out ovarian cancer: some tumors produce little CA-125 or HE4, especially at lower disease volume.
  • Kidney function can strongly affect HE4: reduced renal function may raise HE4 and can increase a ROMA score even without ovarian malignancy.

Table of Contents

What the ROMA Test Is and When It Is Used

ROMA is a preoperative risk-stratification tool. It was developed to help classify women with an ovarian or adnexal mass into lower- and higher-risk groups for epithelial ovarian malignancy. Its intended role is to add objective biomarker information to the clinician’s assessment before surgery.

The setting matters more than many patients realize. ROMA is intended for a person who already has an adnexal mass and is being evaluated for surgical management. It is not intended to screen average-risk women with no mass, and it should not be ordered as a general cancer check because of nonspecific symptoms alone.

The test does not directly examine the mass. It uses a blood sample to measure CA-125 and HE4, then combines those values with whether the patient is considered premenopausal or postmenopausal. The algorithm produces a risk score that is compared with a validated cutoff.

A high-risk result can support referral to a gynecologic oncologist before the operation. This can be important because when ovarian cancer is present, the initial operation may need formal staging and maximal safe cytoreduction. Planning that expertise in advance is preferable to discovering malignancy unexpectedly during or after surgery.

ROMA is only one part of the assessment. Ultrasound morphology, mass size, solid components, papillary projections, blood flow, ascites, bilateral disease, age, symptoms, examination, and family history can all affect risk. A low score cannot turn a clearly suspicious mass into a benign one.

ROMA also has a different purpose from the broader ovarian cancer biomarker panel used after diagnosis for BRCA, HRD, and tumor treatment profiling. ROMA is mainly about preoperative triage, not precision treatment selection.

How CA-125, HE4, and Menopause Status Affect ROMA

ROMA combines three pieces of information because no single serum marker is reliable enough to diagnose ovarian cancer.

CA-125 is a protein that can be elevated in epithelial ovarian cancer, especially high-grade serous disease. It is also produced or released in many benign conditions. Endometriosis, menstruation, pregnancy, fibroids, pelvic infection, liver disease, and inflammation of the abdominal or chest lining can all raise CA-125. Some early-stage ovarian cancers have normal levels. These limits explain why a CA-125 ovarian cancer result cannot be interpreted as a simple positive or negative cancer test.

HE4, or human epididymis protein 4, is another serum protein associated with epithelial ovarian cancer. In some studies it provides better specificity than CA-125 for distinguishing malignant from certain benign gynecologic masses. However, it is not cancer-specific. Reduced kidney function can cause substantial HE4 elevations, and age and smoking can influence levels. The laboratory method also matters. A detailed HE4 test interpretation should therefore include renal function and the assay’s reference range.

Menopause status changes the algorithm because the baseline likelihood of ovarian malignancy and the typical distributions of CA-125 and HE4 differ before and after menopause. Commercial ROMA implementations define premenopausal and postmenopausal status according to their validated instructions. In women with uncertain status because of hysterectomy, hormonal therapy, ovarian suppression, or perimenopause, the clinician and laboratory may need to clarify which category applies.

ROMA’s strength is not that each component is perfect. It is that the algorithm uses their combined pattern. A modest CA-125 with a high HE4 may still produce a high-risk score. Likewise, a high CA-125 from endometriosis with a relatively low HE4 may produce a different risk classification than CA-125 alone would suggest.

ROMA Formula, Score Formats, and Cutoffs

ROMA is calculated from logarithmic transformations of HE4 and CA-125. In the original published model, separate predictive-index equations were used for premenopausal and postmenopausal women. That predictive index was then converted into a probability-like percentage.

The commonly published equations are:

  • Premenopausal predictive index: −12.0 + 2.38 × ln(HE4) + 0.0626 × ln(CA-125)
  • Postmenopausal predictive index: −8.09 + 1.04 × ln(HE4) + 0.732 × ln(CA-125)
  • ROMA percentage: e^(PI) ÷ [1 + e^(PI)] × 100

These formulas are useful for understanding how the algorithm works, but patients should not calculate ROMA themselves from separate laboratory tests. Commercial assays are validated with specific analyzers, reagents, units, quality controls, and thresholds. Using values from a different HE4 or CA-125 platform can produce a number that has not been clinically validated.

Cutoffs are also platform-dependent. In one FDA-cleared implementation using a 0-to-10 ROMA score, values of 1.31 or higher in premenopausal women and 2.77 or higher in postmenopausal women were categorized as higher risk. These correspond conceptually to the classic percentage thresholds of about 13.1% and 27.7%, but other commercial methods have used different percentage cutoffs, such as approximately 7.4% and 25.3%.

That variation is why there is no safe universal statement such as “ROMA above 13% is always high.” The correct interpretation is the one validated for the exact assay on the report.

A ROMA result is also not a literal personalized probability in every clinical context. The chance that a high-risk classification actually represents cancer depends on the population being tested, including the prevalence of malignancy. A risk algorithm validated in women already selected for surgery will not have the same predictive value in a low-risk screening population.

What High, Low, and Borderline ROMA Results Mean

A high-risk ROMA result means the combination of CA-125, HE4, and menopause status crosses the assay’s threshold associated with a greater likelihood of epithelial ovarian malignancy in the intended-use population. It should increase attention to surgical planning and specialist referral, but it is not proof of cancer.

Benign masses can still produce high scores. Kidney impairment may elevate HE4; endometriosis or inflammation may elevate CA-125; and both markers can vary with non-cancer conditions. The clinical team should look at the components when a result seems inconsistent with imaging.

A low-risk ROMA result means the biomarker pattern falls below the validated threshold. This lowers estimated risk but does not guarantee that the mass is benign. Some ovarian cancers, particularly small or biologically low-marker tumors, may not produce enough CA-125 or HE4 to cross the threshold.

Some reports may show a value very close to the cutoff. There is no universal “borderline ROMA” category unless the laboratory defines one. A score just below and just above a cutoff should not be treated as biologically opposite states. Analytical variation and biologic fluctuation exist, so the entire preoperative picture matters.

A useful framework is:

  • High ROMA + suspicious ultrasound: concern is reinforced; gynecologic oncology involvement is often appropriate.
  • High ROMA + reassuring ultrasound: review kidney function, benign causes, imaging quality, age, and symptoms rather than assuming cancer.
  • Low ROMA + reassuring ultrasound: supports lower risk in the validated population.
  • Low ROMA + highly suspicious ultrasound or metastatic signs: the clinical concern takes priority; further specialist evaluation remains warranted.

ROMA does not determine tumor stage, grade, BRCA status, HRD status, or prognosis. If pathology confirms ovarian cancer, those questions require separate testing.

ROMA Accuracy and Comparison With Other Risk Tools

ROMA has been studied extensively, and meta-analyses generally find useful discrimination between benign and malignant adnexal masses. A 2025 comparative meta-analysis reported that ROMA, HE4, CA-125, and the Risk of Malignancy Index all have clinically useful but imperfect diagnostic performance. Results vary by menopausal status, tumor histology, disease prevalence, assay, and study design.

Sensitivity answers, “Among people who truly have malignancy, how many does the test identify as high risk?” Specificity answers, “Among people without malignancy, how many does it correctly classify as lower risk?” Raising sensitivity usually lowers specificity, so no cutoff can eliminate both missed cancers and false-positive referrals.

ROMA is often compared with:

  • CA-125 alone: simpler and widely available but less specific in some benign gynecologic conditions.
  • HE4 alone: sometimes more specific but strongly influenced by renal function and age.
  • Risk of Malignancy Index (RMI): combines CA-125, ultrasound findings, and menopausal status rather than HE4.
  • OVA1: a five-protein multivariate index assay with its own score and cutoffs.
  • Overa: a later five-biomarker assay using CA-125, HE4, apolipoprotein A1, FSH, and transferrin.

The OVA1 test and Overa test were developed for similar preoperative triage purposes but use more biomarkers than ROMA. Head-to-head performance can differ depending on the case mix, and no single assay should be declared universally superior based on one study.

In real practice, the best tool is one that has been validated for the patient population, is available locally, and changes a meaningful clinical decision. High-quality ultrasound assessment can also be very powerful, especially in experienced hands. Biomarker algorithms are most useful as complements to imaging and expert evaluation.

Factors That Can Affect a ROMA Result

Because ROMA is built from CA-125 and HE4, anything that changes either marker can affect the final score.

Kidney dysfunction is one of the most important confounders. HE4 is cleared in part through the kidneys, and concentrations can rise markedly as renal function declines. A high HE4 and ROMA result in a person with reduced estimated glomerular filtration rate may therefore overstate ovarian malignancy risk.

Benign gynecologic conditions can affect CA-125. Endometriosis, adenomyosis, fibroids, menstruation, pelvic inflammatory disease, and benign cysts can increase the marker. This is especially relevant in premenopausal women, in whom benign causes of CA-125 elevation are common.

Other factors include:

  • pregnancy, which can alter reproductive and serum-marker physiology;
  • age, which is associated with higher HE4 even without cancer;
  • smoking, which can raise HE4;
  • liver or serosal inflammation, which can raise CA-125;
  • other cancers, which can elevate either marker;
  • assay differences, because CA-125 and HE4 methods are not perfectly interchangeable.

Timing relative to treatment matters too. ROMA is designed for preoperative risk assessment of an adnexal mass, not for monitoring chemotherapy response or recurrence. After ovarian cancer is diagnosed, serial CA-125, imaging, clinical assessment, and tumor molecular biomarkers have more established roles. Repeating ROMA as a surveillance score is not the same as using the assay for its cleared indication.

A result that seems surprising should be reviewed component by component. If HE4 is disproportionately high, kidney function deserves attention. If CA-125 is high in a younger patient with known endometriosis, that benign explanation may contribute. These clues do not prove a benign cause, but they prevent a single algorithmic score from being interpreted without context.

Next Steps After a ROMA Test

No special diet or fasting is usually required for the CA-125 and HE4 measurements used in ROMA, unless other blood tests ordered at the same time require it. The more important preparation is making sure the ordering team knows the patient’s menopause status, kidney disease, smoking history, pregnancy status, and relevant gynecologic conditions.

After the result, the clinician should first verify the assay-specific risk category printed by the laboratory. Do not apply a cutoff copied from another website or another commercial platform.

Then the result is integrated with the preoperative assessment. Depending on the full risk picture, next steps may include:

  1. referral to a gynecologic oncologist before surgery;
  2. repeat or expert pelvic ultrasound if imaging is indeterminate;
  3. CT or other imaging when there are signs of more extensive disease;
  4. review of kidney function if HE4 is unexpectedly high;
  5. proceeding with the already planned operation in the most appropriate surgical setting.

ROMA does not replace pathology. The definitive diagnosis of an adnexal mass usually comes from tissue obtained during surgery or biopsy. If epithelial ovarian cancer is confirmed, the care plan may then include stage determination, histologic classification, germline hereditary testing, tumor BRCA testing, and HRD testing for ovarian cancer when relevant to treatment.

Patients can ask several practical questions: Which ROMA assay did the laboratory use? Is my result high or low for my menopause category? How suspicious is my ultrasound independent of the blood test? Could kidney disease or another condition be affecting HE4 or CA-125? Would a gynecologic oncologist change the surgical plan?

The most important principle is that ROMA is a decision-support test. It is most useful when it helps put a patient with an adnexal mass in the right hands before surgery, while avoiding the false certainty that any serum algorithm could provide a final diagnosis.

When a mass is being followed over several weeks or months, clinicians should also avoid treating ROMA as a surveillance trend. The algorithm was validated to classify preoperative risk at a point in time, not to prove that a mass is growing, shrinking, or responding to treatment. If the clinical plan changes because a cyst resolves, enlarges, develops solid components, or new symptoms appear, updated imaging and clinical assessment usually provide more direct information. A repeated ROMA value may be obtained in some settings, but a percentage change has no universally validated meaning comparable with a serial tumor-marker response criterion. This distinction helps prevent overinterpreting small laboratory fluctuations near a cutoff.

References

Disclaimer

This article is for general education and does not diagnose an ovarian mass or determine whether surgery or specialist referral is needed. ROMA should be interpreted using the exact laboratory assay and cutoff together with imaging, kidney function, menopause status, symptoms, and clinical findings. Pathology is required to establish the diagnosis of ovarian cancer.

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