Multimarker Serum Testing Related to Ovarian Cancer

POLICY NUMBER

A.2.04.62

DESCRIPTION

A variety of serum biomarkers have been studied for their association with ovarian cancer. Of particular interest have been tests that integrate results from multiple analytes into a risk score to predict the presence of disease. Three tests based on this principle, OVA1, Overa (the second-generation OVA1 test), and the Risk of Ovarian Malignancy Algorithm (ROMA) have been cleared by the U.S. Food and Drug Administration. The intended use of OVA1 and Overa is to use them as an aid to further assess whether malignancy is present in a patient with an ovarian adnexal mass who has not yet been referred to an oncologist, even when the physician's independent clinical and radiologic evaluation does not indicate malignancy. The intended use of ROMA is as an aid, in conjunction with clinical assessment, to assess whether a premenopausal or a postmenopausal woman who presents with an ovarian adnexal mass and has not yet been referred to an oncologist is at a high or low likelihood of finding malignancy on surgery.

Epithelial Ovarian Cancer

The term epithelial ovarian cancer collectively includes high-grade serous epithelial ovarian, fallopian tubal, and peritoneal carcinomas due to their shared pathogenesis, clinical presentation, and treatment. We use epithelial ovarian cancer to refer to this group of malignancies in the discussion that follows. There is currently no serum biomarker that can distinguish between these types of carcinoma. An estimated 19,680 women in the U.S. were estimated to be diagnosed with ovarian cancer in 2024, and approximately 12,740 were expected to die of the disease. The mortality rate depends on three variables:

1. patient characteristics;

2. tumor biology (grade, stage, type); and

3. treatment quality (nature of staging, surgery, and chemotherapy used).

In particular, comprehensive staging and completeness of tumor resection appear to have a positive impact on patient outcomes. Racial, ethnic, and socioeconomic disparities in management and outcomes are prominent in patients with ovarian cancer. Compared to non-Hispanic White and Asian patients, Hispanic and non-Hispanic Black patients are more likely to be diagnosed with advanced disease, and are less likely to undergo optimal primary surgery and adjuvant chemotherapy. Patients with ovarian cancer from racial and ethnic minorities are also less likely to be enrolled in clinical trials. These are among the contributing factors to worsened overall survival among these racial and ethnic groups. Patients with impediments to access healthcare (eg, those living in underserved areas, with low household income, and/or who are underinsured or uninsured), which frequently intersect with racial and ethnic determinants, also experience longer time to diagnosis, suboptimal treatment, and worse outcomes.

Adult women presenting with an adnexal mass have an estimated 68% likelihood of having a benign lesion. About 6% of women with masses have borderline tumors, 22% possess invasive malignant lesions, and 3% have metastatic disease. Surgery is the only way to diagnose ovarian cancer; this is because a biopsy of an ovary with suspected ovarian cancer is usually not performed due to the risk of spreading cancer cells. Most clinicians agree that women with masses that have a high likelihood of malignancy should undergo surgical staging by a gynecologic oncologist. However, women with clearly benign masses do not require a referral to see a specialist. Therefore, criteria and tests that help differentiate benign from malignant pelvic masses are desirable.

In 2016, the American College of Obstetricians and Gynecologists updated a practice bulletin that addressed criteria for referring women with adnexal masses to gynecologic oncologists. Separate criteria were developed for premenopausal and postmenopausal women because the specificity and positive predictive value of cancer antigen 125 (CA 125) are higher in postmenopausal women. Prior guidance, which was based on expert opinion, recommended a CA 125 >200 U/mL for referring premenopausal women with an adnexal mass to a gynecologic oncologist. The current guidance advises using very elevated CA 125 levels with other clinical factors such as ultrasound findings, ascites, a nodular or fixed pelvic mass, or evidence of abdominal or distant metastasis for referral. The referral criteria for postmenopausal women are similar, except that a lower threshold for an elevated CA 125 test is used (35 U/mL). The practice bulletin states that serum biomarker panels are alternatives to CA 125 levels when deciding about a gynecologic oncologist referral.

Three multimarker serum-based tests specific to ovarian cancer have been cleared by the U.S. Food and Drug Administration (FDA) with the intended use of triaging patients with adnexal masses. These tests are summarized in the table below. The proposed use of the tests is to identify women with a substantial likelihood of malignant disease who may benefit from referral to a gynecologic oncology specialist. Patients with positive results may be considered candidates for referral to a gynecologic oncologist for treatment. The tests have been developed and evaluated only in patients with adnexal masses and planned surgeries. Other potential uses, such as selecting patients to have surgery, screening asymptomatic patients, and monitoring treatment, have not been investigated. Furthermore, the tests are not intended to be used as stand-alone tests, but in conjunction with clinical assessment.

Other multimarker panels and longitudinal screening algorithms are under development, but are not yet commercially available.

Summary of FDA-Cleared Multimarker Serum-Based Tests Specific to Ovarian Cancer

CA 125: cancer antigen 125; FDA: Food and Drug Administration; FSH: follicle-stimulating hormone; HE4: human epididymis secretory protein 4. ROMA: Risk of Ovarian Malignancy Algorithm.

In July 2009, the OVA1® test (Aspira Labs [Austin, TX]) was cleared for marketing by the FDA through the 510(k) process. OVA1® was designed as a tool to further assess the likelihood that malignancy is present when the physician’s independent clinical and radiologic evaluation does not indicate malignancy.

In September 2011, the Risk of Ovarian Malignancy Algorithm (ROMA™ test, Fujirebio Diagnostics [Sequin, TX]) was cleared for marketing by the FDA through the 510(k) process. The intended use of ROMA™ is as an aid, in conjunction with clinical assessment, in assessing whether a premenopausal or postmenopausal woman who presents with an ovarian adnexal mass is at a high or low likelihood of finding malignancy on surgery.

In March 2016, a second-generation test called Overa™ (also referred to as next-generation OVA1®), in which 2 of the 5 biomarkers in OVA1® are replaced with human epididymis secretory protein 4 and follicle-stimulating hormone, was cleared for marketing by the FDA through the 510(k) process. Similar to OVA1®, Overa™ generates a low- or high-risk of malignancy on a scale from 0 to 10.

Black Box Warning

In December 2011, the FDA amended its regulation for classifying ovarian adnexal mass assessment score test systems. The change required that off-label risks be highlighted using a black box warning. The warning is intended to mitigate the risk to health associated with off-label use as a screening test, stand-alone diagnostic test, or as a test to determine whether to proceed with surgery. Considering the history and currently unmet medical needs for ovarian cancer testing, the FDA concluded that there is a risk of off-label use of this device. To address this risk, the FDA requires that manufacturers provide notice concerning the risks of off-label uses in the labeling, advertising, and promotional material of ovarian adnexal mass assessment score test systems. Manufacturers must address the following risks:

• Women without adnexal pelvic masses (ie, for cancer “screening”) are not part of the intended use population for the ovarian adnexal mass assessment score test systems. Public health risks associated with false-positive results for ovarian cancer screening tests are well described in the medical literature and include morbidity or mortality associated with unneeded testing and surgery. The risk from false-negative screening results also includes morbidity and mortality due to failure to detect and treat ovarian malignancy.

• Analogous risks, adjusted for prevalence and types of disease, arise if test results are used to determine the need for surgery in patients who are known to have ovarian adnexal masses.

• If used outside the “OR” rule that is described in this special control guidance, results from ovarian adnexal mass assessment score test systems pose a risk for morbidity and mortality due to nonreferral for oncologic evaluation and treatment.

For additional information regarding proteomic tests for other cancers, refer to the Analysis of Proteomic Patterns for Early Detection of Cancer medical policy.

POLICY

All uses of the OVA1, Overa, and ROMA tests are investigational, including but not limited to:

• preoperative evaluation of adnexal masses to triage for malignancy, or

• screening for ovarian cancer, or

• selecting individuals for surgery for an adnexal mass, or

• evaluation of individuals with clinical or radiologic evidence of malignancy, or

• evaluation of individuals with nonspecific signs or symptoms suggesting possible malignancy, or

• postoperative testing and monitoring to assess surgical outcome and/or to detect recurrent malignant disease following treatment.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

OVA1, Overa, and ROMA tests are combinations of several separate lab tests and involve proprietary algorithms for determining risk (ie, what CPT calls Multianalyte Assays with Algorithmic Analyses [MAAAs]). Ova1Plus is a proprietary reflex process combining two FDA-cleared tests, Ova1, leveraging high sensitivity, and Overa. No separate evidence was identified for Ova1Plus and as both of the individual tests are included within the policy no additional evidence review provided at this time. OvaWatch is a multivariate index assay that provides a single risk assessment score; currently, an FDA submission is in process and evidence review will be considered if it is cleared.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting. 

POLICY HISTORY

07/22/2010: Approved by Medical Policy Advisory Committee

06/21/2011: Policy reviewed; no changes.

02/20/2013: Policy description updated to add information regarding the ROMA test. Policy statement revised to delete the following medically necessary policy statement: The proteomics-based OVA1TM test may be considered medically necessary as an aid to further assess the likelihood that malignancy is present when the physician’s (other than gynecological oncologist) independent clinical and radiological pre-operative evaluations do not indicate malignancy in a patient with an ovarian (adnexal) mass. This testing is now considered investigational for all indications. The Code Reference section changed from Covered to Non-Covered. Added CPT codes 81500 and 81503 to the Code Reference section as non-covered. Deleted 84999, 220, 236.2, 239.5, and 620.2 from the Code Reference section.

03/25/2014: Policy title changed from "Proteomics-based Testing for the Evaluation of Ovarian (Adnexal) Masses" to "Proteomics-Based Testing Related to Ovarian Cancer." No changes to policy statement.

01/09/2015: Policy description revised and updated regarding devices. Policy statement unchanged.

08/14/2015: Code Reference section updated for ICD-10.

12/21/2015: Policy description updated regarding proteomic tests. Policy statement unchanged. Investigative definition updated in policy guidelines section.

06/06/2016: Policy number A.2.04.62 added.

01/18/2017: Policy title changed from "Proteomics-Based Testing Related to Ovarian Cancer" to "Multimarker Serum Testing Related to Ovarian Cancer." Policy description updated to add information regarding the Overa™ test. Policy statement unchanged. Policy Guidelines updated regarding the OVA1 and ROMA tests.

01/17/2018: Policy description updated regarding epithelial ovarian cancer and multimarker serum-based tests. Policy statement updated to add the Overa test as investigational. Policy Guidelines updated to include the Overa test. Code Reference section updated to add CPT code 0003U.

04/04/2018: Policy description updated regarding multimarker serum-based tests specific to ovarian cancer. Policy statement unchanged.

01/15/2019: Policy reviewed; no changes.

01/16/2020: Policy reviewed; no changes.

02/02/2021: Policy description updated. Policy statement unchanged.

02/04/2022: Policy description updated regarding epithelial ovarian cancer. Policy statement unchanged.

01/26/2023: Policy description updated regarding estimated cases of ovarian cancer and racial, ethnic, and socioeconomic disparities. Policy statement updated to change "patients" to "individuals."

03/30/2023: Code Reference section updated to add new CPT code 0375U, effective 04/01/2023.

09/01/2023: Policy description and Policy Guidelines updated regarding the OvaWatch test. Policy statement updated to include the OvaWatch test as investigational. Sources updated. Code Reference section updated to add CPT code 81599.

01/16/2024: Policy description updated regarding new data for women with epithelial ovarian cancer. Policy statement unchanged.

10/01/2024: Code Reference section updated to add new CPT code 0507U.

02/10/2025: Policy description updated regarding new data for ovarian cancer. Policy updated to remove the OvaWatch test from the Policy Description and policy statement. Policy Guidelines updated regarding lab tests.

SOURCE(S)

1. Blue Cross Blue Shield Association policy # 2.04.62

2. https://aspirawh.com/ovawatch/ . Accessed June 2023. 

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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