Ovarian Cancer Biomarkers

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Medical Experts

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Doyle

Kelly Doyle, PhD, DABCC, FAACC

Associate Professor of Pathology (Clinical), University of Utah

Medical Director, Special Chemistry and Endocrinology, ARUP Laboratories

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Pandya

Vrajesh K. Pandya, PhD, DABCC

Assistant Professor of Pathology (Clinical), University of Utah

Medical Director, Clinical Chemistry and Toxicology

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Rudolf

Joseph Rudolf, MD

Associate Professor of Pathology (Clinical), University of Utah

Medical Director, Automated Core Lab, ARUP Laboratories

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In the United States, ovarian cancer accounts for more deaths than any other gynecologic cancer.^, Screening methods have not been found to reduce mortality, and because early symptoms tend to be nonspecific, most patients present with advanced-stage tumors.^, An evaluation for ovarian cancer may be prompted by symptoms (eg, bloating, pelvic pain, or abdominal pain) or the discovery of an adnexal or pelvic mass. Laboratory testing should include an assessment for serum biomarkers, as well as somatic and germline molecular testing, to assist in treatment decision-making and to determine familial risk.^,

Quick Answers for Clinicians

Is screening for ovarian cancer recommended?

Given currently available therapies and tests, routine screening for ovarian cancer with cancer antigen 125 (CA-125) testing and/or ultrasound is not recommended for the general population because such screening does not reduce mortality.^, Screening may also yield false-positive results, leading to unnecessary stress and surgery.^, Although other biomarkers (eg, B7-H4, human epididymis protein 4 [HE4], and mesothelin) have been studied for their potential value in screening for ovarian cancer, none have been found to be a reliable marker in early-stage disease.

Due to their increased risk, individuals with a personal and/or family history of ovarian cancer and/or pathogenic variants in genes associated with increased risk of ovarian cancer (eg, BRCA1, BRCA2, and others) stand to benefit more than the general population from a reliable method for early detection. Multimodal screening by imaging and CA-125 testing may identify undiagnosed ovarian cancers in patients with BRCA-related breast/ovarian cancer syndrome, potentially at earlier stages, but it is unknown whether this impacts overall survival, and routine screening via this method is not currently recommended.^,

What role do multivariate risk assays and risk algorithms play in ovarian cancer assessment?

The FDA has approved several multivariate index assays (MIAs) that, in conjunction with other factors, may be used “to augment the identification of patients whose gynecologic surgery requires oncology expertise and resources.”^, These tests are recommended for supplemental use only by the FDA and are not indicated for screening.^, Refer to the National Comprehensive Cancer Network’s (NCCN’s) guidelines for more information about the recommended use of MIAs.

Indications for Testing

Laboratory testing for ovarian cancer biomarkers is indicated in patients with an adnexal/pelvic mass, other signs of ovarian cancer (eg, ascites), or symptoms of ovarian cancer (eg, abdominal pain, increased urinary frequency or urgency, feeling full quickly).

Germline genetic testing for hereditary ovarian cancer syndromes should be offered to individuals who are diagnosed with and/or have a family history of ovarian cancer. For more information on when to perform testing for hereditary ovarian cancer syndromes, refer to the Familial Risk Genetic Testing section.

Laboratory Testing

Serum Biomarker Testing in Diagnosis, Prognosis, and Monitoring

Diagnosis, staging, and prognosis of ovarian cancer are largely determined through surgical pathology. However, a preoperative assessment that includes certain biomarkers (described in the following sections), in addition to imaging, physical examination, and some basic laboratory tests such as CBC, chemistry profile, and liver function tests, may provide a gynecologic oncologist with information useful in determining if surgery is the right option for a particular patient. These biomarkers may also have prognostic value and can be used to monitor treatment response and monitor for recurrence. If serial testing is required (eg, for monitoring disease course or for recurrence), all testing should be conducted by the same method at the same laboratory to avoid confounding clinical evaluation and treatment decisions.

Cancer Antigen 125

Testing for cancer antigen 125 (CA-125) concentrations in serum is recommended as part of the preoperative workup for ovarian cancer because CA-125 levels typically correlate with the extent of disease and may be useful in treatment planning.

CA-125 is useful in monitoring treatment response in patients with ovarian cancer.^, In patients with initially elevated CA-125, concentrations generally correlate with disease activity, decreasing during treatment response and increasing in cases of disease progression and drug resistance. However, CA-125 concentrations may return to normal even in the presence of persistent disease.

If initially elevated, CA-125 may be useful in monitoring for recurrence. The National Comprehensive Cancer Network (NCCN) recommends that for patients with epithelial tumors, a CA-125 measurement should be considered every 2-4 months for 2 years, every 3-6 months for years 3-5, and then annually thereafter. In borderline tumors, a CA-125 measurement should be considered every 3-6 months for up to 5 years and then annually thereafter.

Human Epididymis Protein 4

Some evidence suggests that human epididymis protein 4 (HE4) concentrations may have prognostic value for epithelial ovarian cancer,^, and some studies have indicated that high HE4 levels may be a stronger marker of worse prognosis than high CA-125 levels. However, results are not consistent across studies, and HE4 testing is not recommended as a routine element of the workup for ovarian cancer.

Serum HE4 concentrations decrease in patients who respond to treatment and may be useful for monitoring treatment, either in conjunction with CA-125 or in patients without elevated CA-125.^, Additionally, HE4 concentrations may be useful in monitoring for recurrence in individuals without elevated CA-125 at initial diagnosis.

Other Biomarkers

Testing for other biomarkers may be useful in certain clinical scenarios, specifically in the assessment of certain nonepithelial ovarian cancers. Carcinoembryonic antigen (CEA) and CA 19-9 are used to support diagnosis and monitor recurrence in mucinous ovarian cancer. Testing for alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (β- hCG), and lactate dehydrogenase (LDH) is recommended in malignant germ cell tumors (eg, germinomas and dysgerminomas) to support diagnosis, serve as prognostic markers, and monitor treatment response and recurrence. Inhibin A and B can be used to support diagnosis and monitor recurrence in malignant sex cord-stromal tumors of the ovary. Estradiol, testosterone, and Müllerian inhibitory substance can similarly be used to monitor recurrence in malignant sex cord-stromal tumors of the ovary.

Tumor Tissue Testing for Treatment Decision-Making

Somatic BRCA1 and BRCA2 Variants

Although assessment for germline pathogenic variants in BRCA1 and BRCA2 can be used to determine cancer susceptibility (refer to the Familial Risk Genetic Testing section), detection of somatic variants in these genes may also assist in treatment decision-making.^, If no germline variants in BRCA1 and BRCA2 are detected, then somatic tumor testing for BRCA1 and BRCA2 variants should be performed. Certain variants have implications for which treatments are likely to be effective. Refer to the NCCN’s guidelines for more information.^,

An assessment for variants in other genes (eg, RAD51C/D, PALB2, and BRIP1) may be considered.^,

Mismatch Repair Deficiency/Microsatellite Instability

Mismatch repair (MMR) deficiency or microsatellite instability (MSI) testing can be used to assist in treatment decisions and test for Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC). Treatment options (eg, PD-L1 inhibitors) may be informed by MMR deficiency and MSI status.^, Somatic testing for MMR deficiency should be offered to patients with clear cell, mucinous, or endometrioid ovarian cancer, and may be offered to patients diagnosed with other subtypes of epithelial ovarian cancer.

Familial Risk Genetic Testing

Germline Genetic Testing in Ovarian Cancer Workup

When a diagnosis of ovarian cancer is confirmed, the patient should undergo a genetic risk evaluation, including germline testing for hereditary ovarian cancer syndromes.^, Approximately 25% of ovarian cancers are the result of a heritable condition.^,

Although BRCA1 and BRCA2 are the best characterized and most prevalent ovarian cancer susceptibility genes, other genes (eg, ATM, BRIP1, PALB2, RAD51C, and RAD51D, and Lynch syndrome genes MLH1, MSH2, MSH6, and EPCAM) are also associated with an increased susceptibility to ovarian cancer.

Germline Genetic Testing in Other Situations

Individuals considered to be at risk for hereditary ovarian cancer should be offered genetic counseling, even if they are not currently being assessed for ovarian cancer.^,

Refer to the Hereditary Cancer Testing Criteria in the NCCN guidelines for the complete criteria.