Comprehensive Guide to Biomarkers in Ovarian Cancer

If you've ever wondered how doctors interpret blood tests and tumor reports for ovarian cancer, this is your roadmap. Biomarkers are measurable clues from blood, urine, or tumor tissue that help us estimate risk, make a diagnosis, plan treatment, and track response.¹ They are not magic truth serum. But used wisely, they turn scattered data points into a clearer clinical picture.

Why biomarkers matter in ovarian cancer

Most ovarian cancers are diagnosed after they've spread beyond the ovary. That late detection is a big reason survival is so variable: when found early, outcomes are strong; when found late, the path is tougher. Biomarkers help at several decision points. They can raise or lower suspicion when you have an ovarian mass, help choose the right surgeon, refine the treatment plan based on tumor biology, and monitor how well therapy is working.

Equally important is what biomarkers do not do. For people at average risk with no symptoms, major groups like the U.S. Preventive Services Task Force advise against screening with CA‑125 or ultrasound because large trials did not show a mortality benefit and false positives were common. That's frustrating but honest science. Biomarkers are most effective when targeted to the right clinical context.

The landscape at a glance

Ovarian cancer isn't one disease. High-grade serous carcinoma is the most common subtype, but there are also endometrioid, clear cell, mucinous, and low-grade serous tumors, plus sex cord–stromal and germ cell tumors. Each behaves differently and favors different biomarkers. That's why the "right test" depends on who you are, your life stage, and the tumor you might have or already have.

Serum biomarkers: what they are and how they're used

CA‑125

What it is: A protein on the surface of cells lining the ovaries and peritoneum that can spill into blood. Many epithelial ovarian cancers shed CA‑125.

Best uses: Estimating the likelihood a pelvic mass is malignant in combination with imaging and clinical features, and monitoring response and recurrence after a confirmed diagnosis.²

Strengths and limits: CA‑125 is elevated in many high-grade serous and endometrioid cancers, and serial changes during chemotherapy often parallel tumor burden. But it can also rise from benign conditions like menstruation, endometriosis, fibroids, pelvic infection, liver disease, and even recent abdominal surgery. In mucinous tumors, CA‑125 may be normal despite cancer. Different assays can give slightly different numbers, so trend lines are more informative than single values.³

Evidence nuance worth knowing: In a landmark trial, treating recurrence based solely on a rising CA‑125 before symptoms did not improve overall survival compared with waiting for clinical evidence. That's why we interpret CA‑125 in context, not as a solo trigger.

HE4 and the ROMA algorithm

What it is: Human epididymis protein 4 (HE4) is another tumor-associated protein that tends to be elevated in epithelial ovarian cancers. It's less influenced by endometriosis than CA‑125.

Best uses: HE4 is often combined with CA‑125 in the ROMA (Risk of Ovarian Malignancy Algorithm), which also factors in menopausal status to estimate the risk that an adnexal mass is malignant.⁴

Strengths and limits: HE4 can outperform CA‑125 in some settings for distinguishing malignant from benign masses, especially in premenopausal patients.⁴ However, HE4 levels rise with age and can be higher in smokers and in people with reduced kidney function. Laboratories use different HE4 platforms, and reference intervals aren't uniform.

Multivariate blood tests for surgical triage

What they are: FDA-cleared "multivariate index assays" combine several proteins into a single score to help decide whether a person with an ovarian mass should be referred to a gynecologic oncologist for surgery. Examples include OVA1 and its next-generation versions.

Best uses: Preoperative planning and referral. These tests aren't designed to diagnose cancer or screen the general population. Their value is in risk stratification when imaging is indeterminate.

Strengths and limits: They can pick up risk signals even when CA‑125 is normal. But they don't replace imaging, and the algorithms are proprietary, so the weight of each marker isn't transparent. Results are assay-specific, so it's best to follow with the same platform over time if rechecking.

CEA and CA 19‑9 for mucinous and differential diagnosis

What they are: Carcinoembryonic antigen (CEA) and carbohydrate antigen 19‑9 (CA 19‑9) are markers more commonly used in gastrointestinal cancers. They can be elevated in primary ovarian mucinous tumors and in metastatic mucinous cancers from the GI tract.

Best uses: Helping differentiate a primary ovarian mucinous tumor from a metastasis when pathology and imaging raise that question. Elevated CEA can also push the workup toward the colon, appendix, or pancreas if ovarian findings are atypical.

Strengths and limits: These markers are nonspecific and influenced by smoking, inflammation, and benign GI conditions. They are supportive data points, not definitive answers.

Biomarkers for non-epithelial ovarian tumors

Some ovarian tumors arise from germ cells or stromal cells and have very different marker profiles.

• Germ cell tumors: Alpha-fetoprotein (AFP), beta human chorionic gonadotropin (β‑hCG), and lactate dehydrogenase (LDH) are key. Patterns help distinguish yolk sac tumor (AFP), choriocarcinoma (β‑hCG), and dysgerminoma (LDH).
• Sex cord–stromal tumors (like adult granulosa cell tumor): Inhibin B and anti‑Müllerian hormone (AMH) often rise and can be used for follow-up.

These markers are especially relevant in adolescents and young adults, where germ cell tumors are more common and fertility-sparing approaches are prioritized.

Tissue biomarkers: what the pathology report adds

Immunohistochemical (IHC) markers that confirm origin and subtype

Pathologists use panels of stains to verify the tumor's lineage and subtype. Two workhorses are PAX8 and WT1, which support a Müllerian (ovarian/tubal/primary peritoneal) origin, especially in high-grade serous carcinoma. Estrogen receptor (ER) and progesterone receptor (PR) can help with subtyping in endometrioid and low-grade serous tumors. Aberrant p53 staining patterns are characteristic of high-grade serous carcinoma, reflecting TP53 mutation. These aren't blood tests, but they're foundational for an accurate diagnosis.

Actionable tumor genomics

Modern care includes sequencing the tumor to look for alterations that predict drug sensitivity or resistance. The most clinically impactful in ovarian cancer are in the DNA damage repair pathway.⁵ ⁶

• BRCA1 and BRCA2 (germline and somatic): Tumors with loss of BRCA function often respond better to platinum chemotherapy and may benefit from PARP inhibitors.⁵ ⁶ ⁷ Professional societies recommend germline testing for all people with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma because results affect both therapy and family risk assessment.
• Homologous recombination deficiency (HRD): Genomic "scar" assay integrates loss of heterozygosity and other features to estimate HRD.⁵ HRD-positive tumors tend to be more sensitive to platinum and PARP inhibition.
• Mismatch repair deficiency (dMMR) and microsatellite instability (MSI‑H): Uncommon in ovarian cancer overall but enriched in endometrioid and clear cell subtypes.⁸ ⁹ When present, they identify tumors likely to respond to immune checkpoint blockade.
• HER2 amplification: Seen in a subset of mucinous ovarian carcinomas and rare other subtypes. It may guide targeted therapy in select cases.
• Folate receptor alpha (FOLR1): Overexpressed in many high-grade serous cancers and can be used to select patients for folate receptor–targeted treatments.

Tumor mutational burden (TMB) is generally low in high-grade serous carcinoma, which helps explain why immunotherapy is not a catchall solution here, though MSI‑H and high TMB exceptions exist.

Where biomarkers fit in the clinical pathway

Estimating risk when an ovarian mass is found

When ultrasound finds an adnexal mass, three ingredients shape risk: the ultrasound features, your menopausal status, and blood markers. Tools like the Risk of Malignancy Index (which combines CA‑125, menopausal status, and ultrasound score) and ROMA (which uses HE4, CA‑125, and menopausal status) put numbers around that risk.⁴ ¹⁰ The goal is to identify who should have surgery with a gynecologic oncologist, because complete staging and cytoreduction by a specialist improves outcomes.

These tools help with triage; they don't replace expert ultrasound interpretation. Sophisticated imaging models such as IOTA (International Ovarian Tumor Analysis) rely on detailed sonographic patterns and often outperform any single blood test. In practice, we combine them.

Planning treatment based on tumor biology

After tissue diagnosis, genomic markers shape the plan. BRCA status and broader HRD status inform the expected sensitivity to platinum chemotherapy and eligibility for PARP inhibitors.⁵ ⁶ dMMR/MSI‑H status opens doors to immunotherapy in the right setting. HER2 amplification in mucinous carcinoma may direct targeted therapy. These are evidence-based pivots backed by randomized trials and guideline consensus.

Monitoring response and surveillance

For epithelial ovarian cancer with elevated CA‑125 at baseline, a falling CA‑125 during chemotherapy correlates with tumor shrinkage on scans.³ The depth of the CA‑125 "nadir" after treatment has prognostic value in some studies. HE4 can also drop with treatment, and there is research suggesting it may rise earlier than CA‑125 with recurrence, though practices vary by center.

After remission, many clinicians follow CA‑125 periodically if it was elevated at diagnosis. The key nuance: starting treatment just because CA‑125 creeps up has not been shown to extend life, so decisions typically hinge on symptoms, imaging, and the full clinical picture.

Life stage and special situations

Premenopausal vs postmenopausal

In premenopausal people, benign conditions like endometriosis and fibroids are more common and can elevate CA‑125. That lowers the specificity of CA‑125 as a malignancy signal. ROMA was built to account for this by using different cutoffs by menopausal status.⁴ In postmenopausal people, a new complex ovarian mass with a high CA‑125 is more concerning and often triggers referral.

Pregnancy

Pregnancy can alter several biomarkers and physiology. CA‑125 can be higher in the first trimester and around delivery. β‑hCG is naturally elevated throughout pregnancy, complicating interpretation if a germ cell tumor is suspected. When pregnancy and an adnexal mass overlap, we lean more on imaging patterns, multidisciplinary input, and careful selection of markers with known pregnancy behavior. Interpretation requires caution and specialist input.

Adolescents and young adults

Germ cell tumors are more common in this group, and the triad of AFP, β‑hCG, and LDH is central. Many of these tumors are highly chemosensitive, and markers often fall dramatically with treatment, providing a reliable, real-time indicator of response.

Mechanisms: why these markers move

It helps to know what's behind the numbers. CA‑125 is a glycoprotein shed from irritated or malignant peritoneal surfaces, so anything inflaming the pelvis can nudge it up. HE4 is produced by the reproductive tract and some tumors but is cleared partly by the kidneys, so renal function affects levels. DNA repair defects like BRCA mutations create reliance on backup repair pathways, which is why platinum chemotherapy and PARP inhibition exploit a tumor's "Achilles' heel." Mismatch repair deficiency leaves a fingerprint of errors across the genome, which immune therapies can recognize more easily.

What biomarkers cannot do

They can't confirm or exclude ovarian cancer on their own. They can't tell you whether a mass is surgically resectable without imaging and exam. And they can't predict the future perfectly. Results must be interpreted alongside symptoms, imaging, operative findings, and pathology.

Assay realities: getting reliable numbers

• Assay variability: CA‑125 and HE4 come in multiple platforms with different calibrators. Staying with the same lab improves trend reliability.
• Physiologic confounders: Menstruation, endometriosis, pelvic infection, liver disease, and recent surgery can raise CA‑125. Age, smoking, and reduced kidney function can raise HE4.
• Interferences: High-dose biotin supplements can distort some immunoassays that use biotin–streptavidin capture. Heterophile antibodies in the blood can rarely cause false results. If numbers don't fit the clinical story, labs can use blocking reagents or alternative methods.
• Reference ranges: "Normal" cutoffs differ by lab and menopausal status. A value just over the line may be noise in one context and meaningful in another.

Genetic risk markers: protecting families and guiding therapy

About one in five people with epithelial ovarian cancer carry a germline pathogenic variant, most commonly in BRCA1 or BRCA2 but also in genes like RAD51C, RAD51D, BRIP1, and the mismatch repair genes associated with Lynch syndrome.⁷ ¹¹ That's why guidelines from NCCN and ASCO recommend offering germline testing to all with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. The results affect treatment options today and allow relatives to pursue preventive strategies. For those without cancer but with a strong family history or certain ancestries (for example, Ashkenazi Jewish), risk assessment using validated tools and genetics expertise is appropriate.

Imaging and biomarkers: better together

Transvaginal ultrasound is the first-line imaging for an adnexal mass, with CT or MRI used for staging or problem-solving. Biomarkers complement imaging by quantifying risk and tracking change over time. A multilocular solid mass with papillary projections and ascites on ultrasound plus elevated CA‑125 leans malignant. A simple cyst with normal markers and no symptoms is more likely benign. It's the pattern that matters.

Emerging and future biomarkers

Research is moving fast, and a few areas look promising, though most are not yet standard of care.

• Circulating tumor DNA (ctDNA): Tumor-specific DNA fragments in blood can identify mutations like BRCA and track them over time.¹² ¹³ Rising ctDNA after therapy may signal molecular relapse earlier than scans, but trials are ongoing to show how acting on that information changes outcomes.
• DNA methylation signatures and multi-omic panels: Blood-based patterns that reflect tumor-specific epigenetic changes are under study for earlier detection. Large cohorts are being followed, and more research is needed before routine use.
• Exosomes and microRNAs: Tumor-derived vesicles and small RNAs circulate in blood and may provide sensitive signals. Assays are improving, but clinical utility remains to be proven.
• Resistance markers: Reversion mutations that restore BRCA function can emerge under therapy. Detecting them in tumor or ctDNA may explain a loss of drug sensitivity and steer the next choice.

Putting it all together: examples

Scenario 1: A 62‑year‑old with bloating and an adnexal mass has CA‑125 of 480 U/mL, HE4 elevated, and ultrasound features highly suggestive of malignancy. ROMA and RMI indicate high risk. Referral to a gynecologic oncologist is warranted. Tumor sequencing later shows BRCA1 loss and HRD positivity, informing the chemotherapy plan and maintenance strategy.

Scenario 2: A 32‑year‑old with endometriosis has a 6 cm ovarian cyst and CA‑125 of 90 U/mL. HE4 is normal, and ultrasound shows classic endometrioma features. The elevated CA‑125 is likely from benign inflammation rather than cancer. Management focuses on imaging follow-up and symptoms, not the number alone.

Scenario 3: A 24‑year‑old with a rapidly growing mass has AFP of 2,500 ng/mL and elevated LDH. Imaging suggests a germ cell tumor. After fertility-sparing surgery and chemotherapy, AFP falls to normal. AFP then becomes the most informative marker for surveillance.

What to ask your care team about biomarkers

• Which biomarkers fit my tumor type and life stage, and why?
• How will we use these results with imaging and symptoms to make decisions?
• Are my tests being run on the same platform each time so we can compare trends?
• Do my kidney function, menstrual cycle, or supplements affect these results?
• Should I have germline genetic testing, and what would the results mean for my family?

Key takeaways

Biomarkers don't diagnose ovarian cancer by themselves. They sharpen the picture when combined with expert imaging, pathology, and clinical judgment. CA‑125 and HE4 help stratify risk and follow response; multivariate panels assist with surgical triage; tumor genomics like BRCA and HRD guide therapy; and germline testing protects families while informing care.¹ ⁶ Results are assay-dependent and context-sensitive, so trends and patterns matter more than single numbers. And while research on liquid biopsies and methylation signatures is exciting, practice today remains grounded in tried-and-true markers used thoughtfully.

If you remember one thing, let it be this: biomarkers are tools. In the right hands, and in the right context, they make ovarian cancer care more precise and more personal.