| Coverage Policy Manual | |
| Policy #: | 2010030 |
| Category: | Laboratory |
| Initiated: | June 2010 |
| Last Review: | January 2024 |
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| Proteomics, Evaluation of Ovarian (Adnexal) Masses (e.g., OVA1, Overa, ROMA) | |
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| 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 have now been cleared by the U.S. Food and Drug Administration (FDA): Ova1, Overa (the second-generation OVA1 test), and the Risk of Ovarian Malignancy Algorithm (ROMA) Test. The intended use of OVA1 and Overa is as an aid to further assess whether malignancy is present 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 is at a high or low likelihood of finding malignancy on surgery.
Background
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 19,880 women in the U.S. were expected to be diagnosed in 2021 with ovarian cancer, and approximately 12,810 were expected to die of the disease (SEER, 2022). The mortality rate depends on 3 variables: (1) patient characteristics; (2) tumor biology (grade, stage, type); and (3) treatment quality (nature of staging, surgery, and chemotherapy used) (du Bois, 2009). 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 (Matthews, 2022; Zhang, 2020; Joslin, 2014). Patients with ovarian cancer from racial and ethnic minorities are also less likely to be enrolled in clinical trials (Mattei, 2022). These are among the contributing factors to worsened overall survival among these racial and ethnic groups (Zhong, 2022; Zhang, 2020; Ellis, 2018). 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 (Albright, 2021; Bodurtha, 2022; Smick, 2022; Yanaranop, 2016).
Adult women presenting with an adnexal mass have an estimated 68% likelihood of having a benign lesion (Van Holsbeke, 2010). 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 (Eskander, 2016). 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 (see Regulatory Status section). 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; however, these are not yet commercially available (Simmons, 2016; Yanaranop, 2016).
Regulatory Status
In July 2009, the OVA1® test (Aspira Labs [Austin, TX]) was cleared for market 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 the Overa test (also referred 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 (FDA, 2018). 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:
Coding
OVA1 and ROMA tests are combinations of several separate lab tests and involve a proprietary algorithm for determining risk (i.e., they are what the American Medical Association’s CPT calls “Multianalyte Assays with Algorithmic Analyses” [MAAAs]).
Effective 01/01/13, there are specific CPT category I MAAA codes for these tests:
81500 Oncology (ovarian), biochemical assays of two proteins (CA125 and HE4), utilizing serum, with menopausal status, algorithm reported as a risk score – is specific to the ROMA test.
81503 Oncology (ovarian), biochemical assays of five proteins (CA125, apolipoprotein A1, beta-2 microglobulin, transferrin and prealbumin), utilizing serum, algorithm reported as a risk score – is specific to OVA1.
CPT instructs that these codes cannot be reported with the component tests (i.e., codes 86304 and 86305 cannot be reported with 81500, and codes 82172, 82232, 83695, 83700, 84134, 84466, and 86304 cannot be reported with 81503).
Prior to 2013, these tests would most likely be reported using an unlisted CPT code such as 84999 unlisted chemistry procedure or 86849 unlisted immunology procedure.
A new code effective February 1, 2017, is specific to Overa, the new version of OVA1:
0003U - Oncology (ovarian) biochemical assays of five proteins (apolipoprotein A-1, CA 125 II, follicle stimulating hormone, human epididymis protein 4, transferrin), utilizing serum, algorithm reported as a likelihood score.
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Policy/ Coverage: |
Effective May 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Proteomics-based tests (e.g., OVA1TM, Overa and ROMA) meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness as an aid to further assess the likelihood that malignancy is present when the physician’s (other than gynecologic oncologist) independent clinical and radiological preoperative evaluations do not indicate malignancy in a patient with an ovarian (adnexal) mass who meets ALL of the following criteria:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Proteomics-based tests for the evaluation of ovarian masses (e.g., OVA1TM, Overa and ROMA) do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any other use including but not limited to:
For members with contracts without primary coverage criteria, proteomics-based tests for the evaluation of ovarian masses (e.g., OVA1TM, Overa and ROMA) are considered investigational for any other use including but not limited to:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective prior to May 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The proteomics-based OVA1TM, Overa and ROMA tests meet primary coverage criteria as an aid to further assess the likelihood that malignancy is present when the physician’s (other than gynecologic oncologist) independent clinical and radiological preoperative evaluations do not indicate malignancy in a patient with an ovarian (adnexal) mass who meets ALL of the following criteria:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The OVA1TM, Overa and ROMA tests do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any other use including but not limited to:
For contracts without primary coverage criteria, the OVA1TM, Overa and ROMA tests are investigational for any other use including but not limited to:
Effective prior to August 2012
The proteomics-based OVA1TM test meets primary coverage criteria as an aid to further assess the likelihood that malignancy is present when the physician’s (other than gynecologic oncologist) independent clinical and radiological preoperative evaluations do not indicate malignancy in a patient with an ovarian (adnexal) mass who meets ALL of the following criteria:
The OVA1TM test does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any other use including but not limited to:
For contracts without primary coverage criteria, the OVA1TM is investigational for any other use including but not limited to:
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| Rationale: |
This policy was originally developed in 2010 with an update in 2011. The policy is now being revised to include information regarding the ROMA test.
Assessment of a diagnostic technology typically focuses on 3 parameters: 1) its technical performance; 2) diagnostic performance (sensitivity, specificity, and positive and negative predictive value) in appropriate populations of patients; and 3) demonstration that the diagnostic information can be used to improve patient outcomes (clinical utility).
Technical performance of a device is typically assessed with 2 types of studies, those that compare test measurements with a gold standard, and those that compare results taken with the same device on different occasions (test-retest.
Diagnostic performance is evaluated by the ability of a test to accurately diagnose a clinical condition in comparison with the gold standard. The sensitivity of a test is the ability to detect a disease when the condition is present (true positive), while specificity indicates the ability to detect patients who are suspected of disease but who do not have the condition (true negative). Evaluation of diagnostic performance, therefore, requires independent assessment by the 2 methods in a population of patients who are suspected of disease but who do not all have the disease.
Evidence related to improvement of clinical outcomes with use of this testing assesses the data linking use of a test to changes in health outcomes (clinical utility). While in some cases, tests can be evaluated adequately using technical and diagnostic performance, when a test identifies a new or different group of patients with a disease; randomized trials are needed to demonstrate impact of the test on the net health outcome.
Literature Review
Detailed information about both of these proteomic tests can be found on the FDA website describing the FDA clearance review process.(U.S. Food and Drug Administration) Descriptions of the developmental process for the OVA1 test were published in a perspective by Fung (Fung, 2010) in 2010. This publication clearly outlines the multiple steps used in test development, including decisions to:
1. improve and lock in analytical performance before initiating the clinical study,
2. separate subsets of samples for training (to establish the multi-marker algorithm) and for validation (to establish performance), and
3. develop and craft claims and labeling to assure the adjunctive use of the test results would be clearly understood.
Of interest, candidate biomarkers were selected based on initial studies using mass spectroscopy but were converted to standard immunoassays to improve analytical performance. Seven final markers were evaluated, none of which individually appeared to be highly specific for malignant ovarian disease. However, the choice of 5 of these (CA 125, prealbumin, apolipoprotein A-1, beta2 microglobulin, and transferrin) produced a composite profile that did appear to have discriminatory ability. The test, as cleared by FDA, is performed on a blood sample, which is to be sent to a reference laboratory for testing using the 5 immunoassays described above. Results of the 5 determinations are entered manually into an Excel® spreadsheet used by the OvaCalc software. This software contains an algorithm which combines the 5 discrete values into a single unitless numerical score from 0.0 to 10.0.
Details of the algorithm appear proprietary, but development is described as an empiric process, based on use of banked samples from academic partners, on a small prospective study of samples from Europe and using a designated subset of samples from the clinical study used to support submission to the FDA. It appears at an undisclosed point in the developmental process as a result of interaction with FDA; separate cut-points were developed for premenopausal and postmenopausal women.
A similar developmental process was described for ROMA by Moore et al (Moore, 2008). They studied 9 biomarkers and chose human epididymis secretory protein 4 (HE4) and CA 125 because these markers in tandem produced the best performance. The algorithm developed was subsequently modified to include menopausal status was and independently validated (Moore, 2011). Separate cut-offs were again used for premenopausal and postmenopausal women.
Technical Performance
Based on the FDA review, analytical performance for the test appears robust. Precision ranges from 1% to 7.4% depending on the sample levels studied and reproducibility from 2.8 to 8.9%. The test appears linear, reagent and samples stable, and there was no observed interference evaluating common endogenous substances (hemoglobin, bilirubin, etc.)
The ROMA test is also a qualitative serum test that combines 2 analytes HE4 EIA and the ARCHITECT CA 125 along with menopausal status into a numerical score. Analytical performance for the ROMA also exhibited good precision with a total CV ranging from 0.49 to 7.72% depending on both sample values and menopausal status. The reproducibility of the test was acceptable, with a CV that ranged from 0.98 to 25.9%, with highest values observed in patients with low scores, as expected. The reagents are variably stable, and users are instructed to follow package inserts for stability on each analyte used. The test was unaffected by interference with hemoglobin, bilirubin, lipids, or human anti-mouse antibodies (HAMA). However, high levels of rheumatoid factor (more than 500 IU/mL) did appear to cause elevations in test values, and testing in patients with elevated rheumatoid factor is not recommended.
Conclusions. Evidence on the technical performance of these tests has been evaluated by the FDA and is available through the FDA website. This information generally indicates acceptable technical performance for use in clinical care.
Diagnostic Performance
Risk scores for both tests are generated using proprietary algorithms. In the absence of a standard for either of the risk score signals, accuracy has been defined in terms of clinical performance.
Diagnostic performance of the OVA1 test was evaluated in a prospective, double-blind clinical study using 27 demographically mixed subject enrollment sites. Patients underwent a complete clinical evaluation prior to surgical intervention and only patients with planned surgical intervention were included in the study. The presurgical process for identifying patients for surgery and for establishing a preliminary diagnosis as benign or malignant were not specifically described but were noted to be “based on a variety of clinical assessments.” The study did require at least one imaging test be performed within 12 weeks of surgery. Presumably use of this somewhat nonstandardized diagnostic methodology provides information on how the test works in conjunction with real-world decision making.
The study enrolled a total of 743 patients with 146 subjects used in the training set and 516 in the testing set. Seventy-four patients were excluded because of missing information or samples.
Diagnostic performance of the ROMA test was evaluated in a prospective, blinded clinical trial using 13 demographically mixed subject enrollment sites. Patients all presented with an adnexal mass and were scheduled to undergo surgery. An Initial Cancer Risk Assessment (ICRA) was performed to determine the detection of benign versus malignant lesions before testing. A total of 461 patients out of 512 enrolled were found to be evaluable. Using pathologic diagnosis as the gold standard in the population of patients studied, all of whom had adnexal masses and were scheduled for surgery (cancer prevalence 15%), the test performance in combination with ICRA was as follows: sensitivity 90.9% (81.6 to 95.7%), specificity 67.2% (62.3 to 71.8%), positive predictive value 32.8% (26.4 to 39.9%), and negative predictive value 97.7% (95 to 98.9%).
While performance in the setting of pre-referral to an oncologist appears promising, several single site reports at cancer centers have demonstrated more inconsistent performance (Molina, 2011; Partheen, 2011; Van Gorp, 2011). The test is recommended for use by non-gynecological oncologists, and performance may differ based on referral setting and physician expertise. One recent European study (Van Gorp, 2012) demonstrated that in the hands of radiologists at a cancer institute, subjective assessment by ultrasound is superior to ROMA in discriminating benign from malignant adnexal masses. No similar study has been performed with the OVA1 test.
Conclusions. Use of the ROMA and OVA proteomic tests in combination with clinical assessment increases the sensitivity for detection of malignancy and also increases the negative predictive value (NPV) for ruling out malignancy. The change in NPV with the addition of these tests to clinical assessment is statistically significant but small.
Evidence related to improvement of clinical outcomes (Clinical Utility)
Although no outcome studies have been performed using the OVA1 test, the test clearly appears to identify a subset of patients with adnexal lesions who would benefit from treatment by a gynecological oncologist.
Identification of these additional true positive cases provides a clear potential to improve patient outcomes through more appropriate treatment choices.
As is the case for false positive cases identified and referred using existing clinical and radiological diagnostic criteria, there is no evidence of harm to patients identified as false positives.
While the ability to triage patients for malignancy with an increased yield of true positive results may be only one of many factors in decision making about where treatment should be delivered, it is a valuable piece of information that will contribute to better health care choices in dealing with a serious disease.
In an editorial on the OVA1 test (Muller, 2010) published in August 2010 in Obstetrics and Gynecology describing the decision-making process for use of the test, 2 important points were re-enforced: 1) that the test should not be used for screening, and 2) that if a careful clinical assessment of risk of malignancy warrants referral to a gynecologic oncologist, the OVA1 test should not be performed. In these cases, a negative test would not negate appropriate referral. These points have been highlighted in a recent FDA action establishing a black box warning for this category of product.
Conclusions: Although direct evidence on the clinical utility of the proteomic tests is lacking, a strong indirect chain of evidence supports the clinical utility of the test. For patients who are considering treatment by a non-gynecologic oncologist, use of proteomic tests will decrease the likelihood that an adnexal mass is categorized as benign when it is actually malignant. As a result, use of these tests will also decrease the likelihood that a patient will require a second follow-up procedure for comprehensive staging, lymphadenectomy and/or tumor debulking.
Black Box Warning
On December 10, 2011, the FDA published an amendment to the regulation for classifying ovarian adnexal mass assessment score test systems to restrict these devices so that a prescribed warning statement that addresses off-label risks be highlighted by 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 or not to proceed with surgery.
Summary
The OVA1 and ROMA tests have both been analytically validated and clinical performance has been established in prospective multi-center clinical trials. Use of these tests improve the diagnostic sensitivity for preoperative detection of ovarian malignancy and also improve the negative predictive value for ruling out malignancy. This improvement in diagnostic performance should result in more appropriate referrals to gynecological oncologists and a reduction in the number of second-look operations, which in turn will improve clinical outcomes.
2013 Update
A literature search conducted through October 2013 did not reveal any new literature that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
Several prospective European studies published in 2012 and 2013 have evaluated the diagnostic accuracy of ROMA compared with other tools for distinguishing between benign and malignant pelvic masses. No similar studies have been published evaluating the diagnostic accuracy of the OVA1 test.
The study with the largest sample size was published by Karlsen and colleagues in 2012 (Karlsen, 2012). The study included 1218 women presenting with pelvic masses. Prior to diagnosis, HE4 and CA125 levels were obtained, and ROMA and the Risk of Malignancy Index (an index consisting of ultrasound findings, menopausal status and CA125 levels) were calculated. At a fixed sensitivity of 94.4%, the specificity of ROMA was 76.5% and the specificity of RMI was 81.5%. At a fixed specificity of 75%, the sensitivity of ROMA was 94.8% and the sensitivity of RMI was 96.0%. Accuracy of ROMA and RMI were not compared statistically, but appeared to be similar. In another study, Kaijser and colleagues evaluated 360 women with pelvic masses who were scheduled for surgery (Kaijser, 2013). The study compared the diagnostic accuracy of ROMA and an ultrasound-based prediction model (LR2) developed by the International Ovarian Tumor Analysis Study (IOTA). Histology was used as the reference standard. The overall performance of LR2 (94% sensitivity and 82% specificity) was significantly better than ROMA (84% sensitivity and 80% specificity).
In May 2013, the Society for Gynecologic Oncology (SGO) issued the following statement on multiplex serum testing for women with pelvic masses: (SGO, 2012)
“Blood levels of five proteins in women with a known ovarian mass have been reported to change when ovarian cancer is present. Tests measuring these proteins may be useful in identifying women who should be referred to a gynecologic oncologist. Recent data have suggested that such tests, along with physician clinical assessment, may improve detection rates of malignancies among women with pelvic masses planning surgery. Results from such tests should not be interpreted independently, nor be used in place of a physician’s clinical assessment. Physicians are strongly encouraged to reference the American Congress of Obstetricians and Gynecologists’ 2011 Committee Opinion “The Role of the Obstetrician-Gynecologist in the Early Detection of Epithelial Ovarian Cancer” to determine an appropriate care plan for their patients. It is important to note that no such test has been evaluated for use as, nor cleared by, the FDA as a screening tool for ovarian cancer. SGO does not formally endorse or promote any specific products or brands.”
The National Comprehensive Cancer Network (NCCN) guideline on ovarian cancer includes the following statement: (NCCN, 2013)
“It has been suggested that specific biomarkers (serum HE4 and CA-125) along with an algorithm (Risk of Ovarian Malignancy Algorithm [ROMA]) may be useful for determining whether a pelvic mass is malignant or benign. The FDA has approved the use of HE4 and CA-125 for estimating the risk of ovarian cancer in women with a pelvic mass. Currently, the NCCN Panel does not recommend the use of these biomarkers for determining the status of an undiagnosed pelvic mass.”
2014 Update
A literature search conducted using the MEDLINE database through October 2014 did not reveal any new information that would prompt a change in the coverage statement.
There are no randomized controlled trials published that assess the clinical utility of proteomics-based testing in the evaluation of ovarian cancer. In 2014, Kaijser et al published a study that did not directly evaluate clinical utility but that provides relevant information (Kaijser, 2014). It was a retrospective cohort study that included 101 newly diagnosed cases of biopsy-proven invasive ovarian cancer. Blood samples obtained before treatment were analyzed; HE4 and CA125 levels were measured and the ROMA algorithm was calculated. Median overall survival in the study cohort was 3.7 years. In a multivariate analysis controlling for confounding variables, neither HE4 levels nor ROMA were independently associated with progression-free survival (PFS) or disease-specific survival (DSS). For example, for ROMA and the outcome of PFS, the adjusted hazard ratio (HR) for each 10% increase in risk was 0.98, 95% confidence interval (CI), 0.88 to 1.11. Patients were not prospectively managed according to their HE4 levels or ROMA score and thus the actual impact of these tests on PFS and DSS cannot be determined from this study.
2015 Update
A literature search was conducted using the MEDLINE database through October 2015. There were no new studies identified assessing the clinical utility of the OVA1 or ROMA tests. Two studies assessing the diagnostic performance of the tests were identified (Grenache, 2015; Moore, 2014). Results of these studies did not prompt a change in the coverage statement.
Moore and colleagues (Moore, 2014) evaluated ROMA in conjunction with clinical assessment, using either positive clinical assessment or positive ROMA as a positive test (similar to the recommended usage for OVA1). Using this method of combining tests guarantees a higher sensitivity and lower specificity for the combined test than for either test alone. Used in this way, ROMA would only need to be evaluated in patients with a negative clinical assessment. In this study, 461 women were enrolled, of whom a total of 86 (19%) had a malignancy. Combined assessment improved sensitivity from 77.9% to 89.7%, but worsened specificity from 84.3% to 67.2%.
2018 Update
This policy is being updated with a literature conducted using the MEDLINE database through April 2018. The update is primarily focused on the Overa test. The following is a summary of the key identified literature.
Overa Test
In March 2016, a second-generation test called Overa™ (also referred 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.
Overa is a qualitative serum test that combines immunoassay results for 5 analytes (CA 125, apo AI, transferrin, follicular stimulating hormone, human epididymis protein 4 [HE4]) into a single numeric score. Analytic performance for the test demonstrated good test precision (CV range, 1.54%) and good reproducibility (overall percent CV, 1.63%). The test appears linear, reagent and samples stable, and there was no observed interference evaluating common endogenous substances (eg, hemoglobin, bilirubin) (FDA, 2017).
Descriptions of the developmental process for the Overa test have been published in FDA documents.12 The FDA documents do not provide details on how biomarkers were selected. The test, as cleared by the FDA, is performed on a blood sample, which is to be sent to a reference laboratory for testing using the 5 immunoassays previously described. Results of the 5 determinations are entered into a proprietary algorithm, called OvaCalc software (v4.0.0), which combines the 5 discrete values into a single unitless numeric score from 0.0 to 10.0.
Clinical validity was evaluated in a nonconcurrent prospective study of 493 preoperatively collected serum specimens from premenopausal and postmenopausal women presenting with an adnexal mass requiring surgical intervention.12 Overa test scores were determined based on the analysis of archived serum specimens from a previous study,16 and the patient was stratified into a low- or high-risk group for finding malignancy on surgery. The analysis examined whether patient referral to a gynecologic oncologist was supported when dual assessment was determined to be positive (either Overa or clinical assessment was positive, or both were positive). A dual assessment was considered negative when both Overa and clinical assessment were negative.
The method used for combining clinical assessment and Overa test result was to consider the test positive if either clinical assessment or Overa test was positive. Thus, in practice, Overa testing would not be necessary if clinical assessment alone indicated cancer. Using Overa testing in this manner guarantees that Overa testing will be more sensitive and less specific than clinical assessment alone, even if it has no better than chance capability of detecting ovarian cancer. Sensitivity improved from 74% to 94%, and specificity decreased from 93% to 65%.
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Practice Guidelines and Position Statements
American Congress of Obstetricians and Gynecologists
The American Congress of Obstetricians and Gynecologists (ACOG) addressed the use of the OVA1 test in its 2011 guidelines on the role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer, and these guidelines were confirmed in 2017 (ACOG, 2017.) In 2013, the Society for Gynecologic Oncology endorsed these ACOG guidelines (Society for Gynecologic Oncology, 2013). This ACOG document included the following comments, which were not specific guidelines about the use of the test:
· The OVA1 test “appears to improve the predictability of ovarian cancer in women with pelvic masses.”
· “This is not a screening test, but it may be useful for evaluating women with a pelvic mass.”
· “Clinical utility is not yet established.”
Further, in 2016, an ACOG Practice Bulletin addressed the evaluation and management of adnexal masses makes 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 (Society for Gynecologic Oncology, 2013).
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
ROMA compared with HE4 and CA 125
Since the Wang et al (2014) and Dayyani et al (2016) meta-analyses, multiple studies have compared the use of the ROMA test to HE4 and CA 125 in various subgroups based on menopausal status, the cutoff value used, and different racial/ethnic background (Cho et al, 2015; Terlikowska et al, 2016; Shen et al, 2019; Shin et al, 2019; Dunton et al, 2019; Han et al, 2019). These studies demonstrate that ROMA's sensitivity (range, 54.5% to 93%) and specificity (range, 75% to 96%) can vary importantly depending on variation in these factors. For example, in a few recent studies of racial/ethnic subpopulations, ROMA's sensitivity dramatically declined and was lowest when used in a sample of 274 African American women (54.5%; 95% CI 33.7-75.3) (Dunton et al, 2019), and when distinguishing between malignant/borderline vs benign or between malignant and borderline/benign in a sample of 177 premenopausal Korean women (46.4% and 52.6%, respectively) (Shin et al, 2019). On the other hand, specificity was highest (95.9%) in a subgroup of 104 postmenopausal women when using a "new optimal cutoff value" of 33.4% instead of 29.9% (Terlikowska et al, 2016).
ROMA compared with Risk Malignancy Index-I
Chacon et al (2019) conducted a meta-analysis comparing ROMA with RMI for detecting ovarian cancer. Among the 2662 women included in the meta-analysis, 50 percent were premenopausal and 50 percent were postmenopausal. Mean ovarian cancer prevalence was 29% in premenopausal women and 51% in postmenopausal women. The majority of studies were conducted at a single-center. Although pooled sensitivities for ROMA were similar to those reported in previous systematic reviews that compared ROMA to HE4 and CA 125, specificities for ROMA were somewhat lower in this meta-analysis (range of 82-85% in Wang et al 2014 and Dayyani et al 2016 meta-analyses compared with 75-78%). However, findings from this meta-analysis by Chacon et al (2019) should be interpreted with caution due to important limitations including a high-risk of selection bias in most studies and significant unexplained statistical heterogeneity in the meta-analyses.
National Comprehensive Cancer Network
The NCCN (2019) guidelines on ovarian cancer (v.2.2019) include the following statement:
Regarding the OVA1 test, the NCCN guidelines state:
U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force (2012) recommended against screening women for ovarian cancer (D recommendation). This recommendation was confirmed in their 2018 update (Grossman et al, 2018). The Task Force has not addressed multimarker serum testing related to ovarian cancer.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2020, the NCCN guideline on ovarian cancer (v.1.2020 ) includes the following statement (NCCN, 2020):
“It has been suggested that specific biomarkers (serum HE4 and CA 125) along with an algorithm (Risk of Ovarian Malignancy Algorithm [ROMA]) may be useful for determining whether a pelvic mass is malignant or benign. The FDA has approved the use of HE4 and CA-125 for estimating the risk of ovarian cancer in women with a pelvic mass. Currently, the NCCN Panel does not recommend the use of these biomarkers for determining the status of an undiagnosed pelvic mass.”
Regarding the OVA1 test, the NCCN guideline states:
“The OVA1 test uses 5 markers (including transthyretin, apolipoprotein A1, transferrin, beta-2 microglobulin, and CA 125) to assess who should undergo surgery by an experienced gynecologic oncologist and who can have surgery in the community, Based on data documenting an increased survival, NCCN Guidelines Panel Members recommend that all patients should undergo surgery by an experienced gynecologic oncologist (category 1).”
In 2018, the U.S. Preventive Services Task Force recommended against screening asymptomatic women for ovarian cancer (D recommendation) (Grossman, 2018). The Task Force has not addressed multimarker serum testing related to ovarian cancer.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A systematic review by Suri et al assessed the diagnostic accuracy of ROMA in comparison with CA 125 and HE4 through meta-analysis (Suri, 2021). This sensitivity analysis found ROMA had better diagnostic accuracy in postmenopausal women (sensitivity 88%, specificity 83%) than premenopausal women (sensitivity 80%, specificity 80%), and better discrimination (AUROC 0.94 [SE 0.01) and 0.88 [SE 0.01], respectively). The review found no evidence of publication bias, nor did it find differential results when analyses were limited to blinded studies.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
The clinical validity was evaluated in a prospective, double-blind, clinical study using 27 enrollment sites (FDA, 2022). The study was supported by the commercial sponsor of the test. Patients underwent a complete clinical evaluation before surgical intervention, and only patients with adnexal masses who had a planned surgical intervention were included. The study enrolled 743 patients, with 146 subjects used in the training set and 516 in the testing set. Seventy-four patients were excluded because of missing information or samples. The final prevalence of cancer in the population was 27%.
Clinical validity was evaluated in a nonconcurrent prospective study of 493 preoperatively collected serum specimens from premenopausal and postmenopausal women presenting with an adnexal mass requiring surgical intervention (FDA, 2022). Overa test scores were determined based on the analysis of archived serum specimens from a previous study, and the patient was stratified into a low- or high-risk group for finding malignancy on surgery (Bristow, 2013). The analysis examined whether patient referral to a gynecologic oncologist was supported when a dual assessment was determined to be positive (either Overa or clinical assessment was positive, or both were positive). A dual assessment was considered negative when both Overa and clinical assessment were negative.
Multiple individual studies have compared the use of the ROMA test to HE4 and CA 125 in various subgroups based on menopausal status, the cutoff value used, and different racial/ethnic backgrounds (Al Musalhi, 2016; Cho, 2015; Terlikowska, 2016; Shen, 2020; Shin, 2020; Dunton, 2019; Han, 2019; Carreras-Dieguez, 2022). These studies demonstrate that ROMA's sensitivity (range, 54.5% to 93%) and specificity (range, 75% to 96%) can vary importantly depending on variation in these factors.
Davenport et al conducted a meta-analysis comparing commonly-used tests, including ROMA, RMI, International Ovarian Tumor Analysis Logistic Regression Model 2 (LR2, a model incorporating menopausal status and ultrasound findings), and Assessment of Different NEoplasias in the adneXa (ADNEX), a model incorporating menopausal status, CA 125, type of center (referral center for gynecologic oncology vs. other), and ultrasound findings) (Davenport, 2022). The analysis included 59 studies, 42 of which evaluated ROMA; 32,059 patients (9545 cases of ovarian cancer) were included. Mean ovarian cancer prevalence ranged from 16% to 27% in premenopausal patients and 38% to 55% in postmenopausal women. In general, ROMA and other tests had higher sensitivity than RMI, but carried lower specificity, particularly in premenopausal women. This analysis carries important limitations, including high risk of selection bias, index test- and reference standard-related biases, and heterogeneity.
In 2011, the National Institute for Health and Care Excellence issued guidance on the identification and management of ovarian cancer (NICE, 2011). 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.
In 2022, the National Comprehensive Cancer Network (NCCN) guideline on ovarian cancer (v. 5.2022) includes the following statement (NCCN, 2022):
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 Congress 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 malignancies (especially those with an adnexal mass) should undergo evaluation by an experienced gynecologic oncologist prior to surgery."
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement.
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