Latest Review Date: December 2024

Category:  Laboratory

POLICY:

All uses of the OVA1®, Ova1Plus®, Overa™, OvaWatch ℠, and ROMA™ tests are considered 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.

DESCRIPTION OF PROCEDURE OR SERVICE:

A variety of serum biomarkers have been studied in 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-generationOVA1 test), and the Risk of Ovarian Malignancy Algorithm (ROMA) have been cleared by the U.S. Food and Drug Administration (FDA). The intended use of OVA1 and Overa is 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. The OvaWatch ℠ serum blood test combines seven tumor biomarkers along with age and menopausal status to make a prediction of ovarian malignancy in individuals with adnexal masses who have been considered indeterminate or benign on clinical assessment. This is used for both premenopausal and postmenopausal individuals. Ova1Plus is a proprietary reflex process combining two FDA-cleared tests, Ova1, leveraging high sensitivity, and Overa.

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 expected 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) characteristics of the patient; 2) the biology of the tumor (grade, stage, and type); and 3) the quality of treatment (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 (e.g., 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% have borderline tumors, 22%, invasive malignant lesions, and 3%, metastatic disease. Surgery is the only way to diagnose ovarian cancer; this is because biopsy of an ovary with suspected ovarian cancer is usually not performed due to the risk of spreading cancer cells. Clinicians generally agree that women with masses that have a high likelihood of malignancy should undergo surgical staging by gynecologic oncologists. However, women with clearly benign masses do not require referral to a specialist. Criteria and tests that help differentiate benign from malignant pelvic masses are thus desirable.

In 2016, the American College of Obstetricians and Gynecologists (ACOG) 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 in 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 now been cleared by the U.S. Food and Drug Administration (FDA) with the intended use of triaging patients with adnexal masses. They are summarized in Table 1. 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 surgical removal. 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 to be used in conjunction with clinical assessment.

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

Table 1. 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.

KEY POINTS:

The most recent review incorporates literature through October 30, 2024.

Summary of Evidence

For individuals who have adnexal mass(es) undergoing surgery for possible ovarian cancer who receive multimarker serum testing with clinical assessment preoperatively to assess ovarian cancer risk, the evidence includes studies assessing technical performance and diagnostic accuracy. Relevant outcomes are overall survival and test accuracy. OVA1 and Overa are intended for use in patients for whom clinical assessment does not clearly indicate cancer. When used in this manner, sensitivity for ovarian malignancy was 92% and specificity was 42% with OVA1; with Overa, sensitivity was 94% and specificity was 65%. ROMA is intended for use with clinical assessment, but no specific method has been defined. One study, which used clinical assessment and ROMA results, showed a sensitivity of 90% and specificity of 67%. One prospective was conducted of women with adnexal masses identified on clinical examination and indeterminate or asymptomatic by imaging for OvaWatch. A prospective data set had 501 patients where 106 patients with adnexal mass underwent surgery. However, the National Comprehensive Cancer Network NCCN guidelines recommend (category 2A) that all patients with suspected ovarian cancer should be evaluated by an experienced gynecologic oncologist.  Given the National Comprehensive Cancer Network recommendation, direct evidence will be required to demonstrate that the use of FDA-cleared multimarker serum testing to inform decisions regarding referral to a gynecologic oncology specialist for surgery has clinical usefulness. Direct evidence of clinical usefulness is provided by studies that have compared health outcomes for patients managed with and without the FDA-cleared multimarker serum testing. Because these are intervention studies, the preferred evidence would be from randomized controlled trials. No trials were identified that have evaluated whether referral based on FDA-cleared multimarker serum testing improves health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

American College of Obstetricians and Gynecologists

In 2017, with reaffirmation in 2024, the American College of Obstetricians and Gynecologists (ACOG) opinion on the role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer addressed using multimarker serum testing. The opinion states that multimarker panels lack strong evidence for use in asymptomatic women without adnexal masses and do not improve early detection and survival rates in average-risk women. The Society for Gynecologic Oncology endorsed this ACOG opinion.

In 2016, an ACOG Practice Bulletin addressing the evaluation and management of adnexal masses made a level B recommendation (based on limited or inconsistent scientific evidence) that consultation with or referral to a gynecologic oncologist is recommended for premenopausal or postmenopausal with an elevated score on a formal risk assessment test such as the multivariate index assay, risk of malignancy index, or the Risk of Ovarian Malignancy Algorithm, or one of the ultrasound-based scoring systems from the International Ovarian Tumor Analysis group. A level C recommendation (based on consensus and expert opinion) was given to using serum biomarker panels as an alternative to cancer antigen 125 (CA 125) level to decide about the referral to a gynecologic oncologist for an adnexal mass requiring surgery.

National Institute for Health and Care Excellence

In 2011, the National Institute for Health and Care Excellence issued guidance on the identification and management of ovarian cancer. The guideline does not provide any recommendations regarding additional serum marker testing besides testing for serum CA 125 levels in women with symptoms suggestive of ovarian cancer.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) guideline on ovarian cancer (v. 3.2024) includes the following statement:

The FDA has approved the use of ROMA, OVA1, and OVERA for estimating the risk for ovarian cancer in women with an adnexal mass for which surgery is planned and have not been referred to an oncologist. Although the American College of Obstetricians and Gynecologists (ACOG) has suggested that ROMA and OVA1 may be useful for deciding which patients to refer to a gynecologic oncologist, other professional organizations have been non-committal. Not all studies have found that multi-biomarker assays improve all metrics (i.e. sensitivity, specificity, positive predictive value, negative predictive value) for prediction of malignancy compared with other methods (e.g. imaging, single-biomarker tests, symptom index/clinical assessment). Currently, the NCCN Panel does not recommend the use of these biomarker tests for determining the status of an undiagnosed adnexal/pelvic mass.

In addition, the guideline states "based on data documenting increased survival, the NCCN Guidelines Panel recommends that all patients with suspected ovarian malignancies (especially those with an adnexal mass) should undergo evaluation by an experienced gynecologic oncologist prior to surgery."

U.S. Preventive Services Task Force Recommendations

In 2018, the U.S. Preventive Services Task Force recommended against screening asymptomatic women for ovarian cancer (D recommendation). The Task Force has not addressed multimarker serum testing related to ovarian cancer.

KEY WORDS:

OVA1, proteomics-based testing, ovarian mass, ovarian cancer, ROMA, risk of ovarian malignancy algorithm, Overa, Ova1Plus®, OvaWatch ℠.

APPROVED BY GOVERNING BODIES:

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.

The Ova1Plus® test combines FDA-cleared tests, Ova1® and Overa®, into a reflex test.

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 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 two of the five 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 zero to ten.

In December 2022, the OvaWatch ℠ test was introduced by Aspira Women’s Health. It is intended for use in assessing the risk of ovarian cancer for women with adnexal masses that have been considered indeterminate or benign by initial clinical assessment. The OvaWatchSM test has not been FDA approved.

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 (i.e., 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.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP:  Special benefit consideration may apply. Refer to member’s benefit plan. 

CURRENT CODING:

CPT Codes:

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POLICY HISTORY:

Medical Policy Panel, April 2010

Medical Policy Group, April 2010 (2)

Medical Policy Administration Committee, June 2010

Available for comment June 18-August 2, 2010

Medical Policy Group, April 2011 (1): Update to Key Points and References; no change in policy statement

Medical Policy Group, November 2012: 2013 Coding Updates; Added Codes 81500 and 81503

Medical Policy Panel, November 2012

Medical Policy Group, January 2013 (1): Update to Descriptions, Policy, Key Points, Key Words, Governing Bodies, Coding and References related to reversal of coverage for OVA1 to investigational and addition of ROMA testing to this policy as investigational

Medical Policy Administration Committee, January 2013

Available for comment January 10, 2013 through February 23, 2013

Medical Policy Panel, November 2013

Medical Policy Group, January 2014 (1): Update to Key Points and References; change in title to remove “for the evaluation of ovarian (adnexal) masses” and add “related to ovarian cancer”; no change to policy statement.

Medical Policy Panel, November 2014

Medical Policy Group, November 2014 (1): Updates to Description, Key Points, and References.  No change to policy statement.

Medical Policy Panel, November 2015

Medical Policy Group, November 2015 (3):  Updates to Key Points and References; no change to policy statement.

Medical Policy Panel, December 2016

Medical Policy Group, December 2016 (3): 2016 Updates to Title, Description, Key Points, Approved by Governing Bodies, Key Words & References; no change to policy statement; removed policy statements for dates of service prior to February 24, 2014; removed previous coding section for codes no longer applicable effective prior to 01/01/13.

Medical Policy Group, January 2017: Coding update for 02/01/17.  Added new code 0003U to the Coding section.

Medical Policy Group, March 2017 (3):  ad hoc review of ACOG Practice Bulletin Number 174; updated information under “Practice Guidelines and Position Statements” for ACOG & References; no change in policy statement

Medical Policy Panel, December 2017

Medical Policy Group, January 2018 (3):  2017 Updates to Description, Key Points & References; policy statement updated to include Overa testing; no change in policy statement intent.

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (9): 2018 Updates to Description, Key Points, and References; no change to policy statement.

Medical Policy Panel, December 2019

Medical Policy Group, December 2019 (9): 2019 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Panel, December 2020

Medical Policy Group, December 2020 (9): 2020 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Panel, December 2021

Medical Policy Group, December 2021 (9): 2021 Updates to Description, Key Points, References. Policy statement updated to remove “not medically necessary,” no change to policy intent.

Medical Policy Panel, December 2022

Medical Policy Group, December 2022 (9): 2022 Updates to Description, Key Points, References. Word "patients" replaced with "individuals" in policy statement; no change to policy intent.

Medical Policy Panel, December 2023

Medical Policy Group, January 2024 (5): Updates to Description, Key Points; Practice Guidelines and Position Statements, and References. No change to Policy Statement.

Medical Policy Group, July 2024 (5): Updates to Description, Key Points, Key Words; Ova1Plus®, OvaWatch ℠, Approved by Governing Bodies, Current Coding section: 0375U, and References. Policy Statement updated to include: Ova1Plus®, and OvaWatch®, as investigational. These were previously considered investigational per our medical policy #495- Investigational Criteria Policy. No change to Policy intent.

Medical Policy Panel, December 2024

Medical Policy Group, December 2024 (5):  Updates to Description, Key Points, and References.  No change to policy statements.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.