Coverage Policy Manual
Policy #: 2010030
Category: Laboratory
Initiated: June 2010
Last Review: May 2018
  Proteomics, Evaluation of Ovarian (Adnexal) Masses (e.g., OVA1, Overa, ROMA)

Description:
There are a variety of gene-based biomarkers that 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. Two tests based on this principle have now been cleared by FDA for use in women with adnexal masses (Ova1TM test [Vermillion, Inc. Fremont, CA] and ROMA Test [Fujirebio Diagnostics, Inc. Malvern, PA]) as an aid to further assess the likelihood that malignancy is present. When positive, these tests provide a woman with an opportunity to opt for specialty care.
 
Background
 
In 2009, it was estimated that more than 21,000 women in the U.S. were diagnosed with ovarian cancer and more than 14,000 died of this disease (Bristow, 2009).  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) (du Bois, 2009).   In particular, comprehensive staging and completeness of tumor resection appear to have a positive impact on patient outcome.
 
In 1997, the Society of Surgical Oncology first recommended ovarian cancer surgery and follow-up treatment be performed by physicians with ovarian cancer disease expertise (Hoskins, 1997).  To date dozens of articles and several meta-analyses or systemic reviews have been published relevant to this recommendation looking at long-term outcomes, short-term outcomes and process measures (types of treatment such as complete staging or tumor debulking).
 
At least two meta-analyses have been performed concluding improved outcomes in patients with ovarian cancer when treated by gynecologic oncologists. Data is most convincing for patients with advanced stage disease. Median improvements in survival for patients treated by non-gynecologic oncologists versus gynecologic oncologists have been variable but impressive with increases recently reported to be up to 8 months (12 to 21 months) (Tingulstad, 2003).  In at least some reports, important differences have also been observed showing improved survival in patients with early stage disease as well when treated by gynecologic oncologists (Giede, 2005).
 
A recent systematic review of 198 studies addressing the role of specialty treatment by gynecologic oncologists and evaluation of other practice related factors (type of hospital, surgical volume, etc.) was more guarded in its analysis (duBois, 2009).  This review noted that not all reports confirmed these findings of improved performance based on sub-specialty. It also noted that in some reports only patients presenting with certain stages of disease (in most cases advanced stage although in some cases early stage) were studied and found to exhibit treatment differences. Nevertheless, this review also concluded that the use of sub-specialists and better education of treatment options for both primary care physicians and patients was warranted.
 
The need for proper triage and specialty care for patients with ovarian cancer has recently been re-inforced by a report by Grabowski et al (Grabowski, 2012). They describe 40 patients seen at a tertiary gynecologic oncology unit after primary operation for ovarian cancer. Based on clinical and pathologic information, 35 of these patients were subjected to repeat surgery. Half of the patients were found to require upstaging; 53% of patients had post-operative chemotherapy recommendations modified. These authors suggest that because many patients are not referred for specialty follow-up, results of poor quality staging may be underestimated in their study.
 
In an analysis of predictors of comprehensive surgical treatment (meticulous and extensive disease staging, efforts at debulking of the tumor with removal of all visible lesions, lymphadenectomy) in patients with ovarian cancer, Goff et al. observed that comprehensive treatment was linked not only to physician factors but also to a number of simple demographic factors including age, race, insurance status and geographic location (urban versus rural) (Goff, 2007). Optimization of treatment for ovarian cancer may clearly be complicated by these factors.
 
Adult women presenting with an adnexal mass have an estimated 68% likelihood of having a benign lesion (Van Holsbeke, 2010).  About 6% have borderline tumors, 22% invasive lesions, and 3% metastatic disease.
 
Obviously a majority of patients can be treated without use of surgical oncology expertise. To date no existing diagnostic modalities have been identified to discriminate reliably between benign and malignant lesions. Recent publications have appeared describing the use of CA 125 with a symptom index (Anderson, 2009), the use of an “ovarian crescent sign” on ultrasound (Van Holsbeke, 2010), and the use of three-dimensional ultrasound (Alcazar, 2009) to provide increased diagnostic reliability in this decision-making process, but all of these appear to require further validation before being considered for routine clinical use.
 
The OVA1 is a new proteomic test that has been developed specifically to triage patients thought to have benign adnexal masses with planned treatment by a non-gynecologic-oncologist physician. Patients with positive results should be considered candidates for referral to a gynecologic oncologist for treatment. As described above, this treatment is likely to produce improved patient outcomes.
 
Regulatory Status
 On July 16, 2009, the OVA1TM test (Vermillion, Inc. Fremont, CA) was cleared for market by the U.S. Food and Drug Administration (FDA) as a 510(k) submission. On September 1, 2011, the Risk of Ovarian Malignancy Algorithm (ROMATM test, Fujirebio Diagnostics, Inc., Malvern, PA) was cleared by the U.S. Food and Drug Administration (FDA) as a 510(k) submission. Because the OVA1 test had been found to be a class II medical device by virtue of the July 2009 clearance, ROMA was found to be substantially equivalent to that predicate device.
 
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.
 
In March 2016, the Overa test (Vermillion, Inc. Fremont, CA) received marketing clearance by the U.S. Food and Drug Administration (FDA) as a 510(k) submission.  Overa, a second generation multivariate index assay, is the successor to Vermillion's OVA1® test for determining ovarian cancer risk in conjunction with independent clinical and imaging assessment prior to planned surgery for a women with a pelvic mass.  
 
Coding
OVA1 and ROMA tests are combinations of several separate lab tests and involve a proprietary algorithm for determining risk (ie, 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 (ie, 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.

Policy/
Coverage:
Effective August 2012
 
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:
    • older than 18 years of age;
    •  ovarian adnexal mass present;
    • surgery is planned for treatment of the mass; and
    • the patient has not yet been referred to a gynecologic oncologist.
 
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:
    • screening for ovarian cancer, or
    • selecting patients for surgery for an adnexal mass, or
    • evaluation of patients with clinical or radiologic evidence of malignancy, or
    • evaluation of patients with nonspecific signs or symptoms suggesting possible malignancy, or
    • post-operative testing and monitoring to assess surgical outcome and/or to detect recurrent malignant disease following treatment.
 
For contracts without primary coverage criteria, the OVA1TM, Overa and ROMA tests are investigational for any other use including but not limited to:
    • screening for ovarian cancer, or
    • selecting patients for surgery for an adnexal mass, or
    • evaluation of patients with clinical or radiologic evidence of malignancy, or
    • evaluation of patients with nonspecific signs or symptoms suggesting possible malignancy, or post-operative testing and monitoring to assess surgical outcome and/or to detect recurrent malignant disease following treatment.
 
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:
    • older than 18 years of age;
    •  ovarian adnexal mass present;
    • surgery is planned for treatment of the mass; and
    •  the patient has not yet been referred to a gynecologic oncologist.
 
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:
    • screening for ovarian cancer, or
    • selecting patients for surgery for an adnexal mass, or
    • evaluation of patients with clinical or radiologic evidence of malignancy, or
    • evaluation of patients with nonspecific signs or symptoms suggesting possible malignancy, or
    • post-operative testing and monitoring to assess surgical outcome and/or to detect recurrent malignant disease following treatment.
 
For contracts without primary coverage criteria, the OVA1TM  is investigational for any other use including but not limited to:
    • screening for ovarian cancer, or
    • selecting patients for surgery for an adnexal mass, or
    • evaluation of patients with clinical or radiologic evidence of malignancy, or
    • evaluation of patients with nonspecific signs or symptoms suggesting possible malignancy, or
    • post-operative testing and monitoring to assess surgical outcome and/or to detect recurrent malignant disease following treatment.

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%.

CPT/HCPCS:
0003UOncology (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
81500Oncology (ovarian), biochemical assays of two proteins (CA-125 and HE4), utilizing serum, with menopausal status, algorithm reported as a risk score
81503Oncology (ovarian), biochemical assays of five proteins (CA-125, apolipoprotein A1, beta-2 microglobulin, transferrin, and pre-albumin), utilizing serum, algorithm reported as a risk score
84999Unlisted chemistry procedure
86849Unlisted immunology procedure

References: A recipe for proteomics diagnostic test development: the OVA1 test from biomarker discovery to FDA clearance. Clin Chem 2010; 56(2):327-9.

ACOG Committee Opinion: number 280, December 2002.(2002) The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer. Obstet Gynecol 2002; 100(6):1413-6.

Alcazar JL, Rodriguez D.(2009) Three-dimensional power Doppler vascular sonographic sampling for predicting ovarian cancer in cystic-solid and solid vascularized masses. J Ultrasound Med 2009; 28(3):275-81.

American College of Obstetrics, Gynecologists' Committee on Practice B-G. Practice Bulletin No. 174: Evaluation and Management of Adnexal Masses. Obstet Gynecol. Nov 2016;128(5):e210-e226. PMID 27776072

Andersen MR, Goff BA, Lowe KA et al.(2009) Combining a symptom index with CA 125 to improve detection of ovarian cancer. Cancer 2009; 113(3):484-9.

Andersen MR, Goff BA, Lowe KA et al.(2010) Use of a Symptom Index, CA125, and HE4 to predict ovarian cancer. Gynecol Oncol 2010; 116(3):378-83.

Bristow RE, Smith A, Zhang Z, et al.(2013) Ovarian malignancy risk stratification of the adnexal mass using a multivariate index assay. Gynecol Oncol. Feb 2013;128(2):252-259. PMID 23178277

Bristow RE, Zahurak ML, Diaz-Montes TP et al.(2009) Impact of surgeon and hospital ovarian cancer surgical case volume on in-hospital mortality and related short-term outcomes. Gynecol Oncol 2009; 115(3):334-8.

Dearking AC, Aletti GD, McGree ME et al.(2007) How relevant are ACOG and SGO guidelines for referral of adnexal mass? Obstet Gynecol 2007; 110(4):841-8.

du Bois A, Rochon J, Pfisterer J et al.(2009) Variation in institutional infrastructure, physician specialization and experience, and outcome in ovarian cancer: a systematic review. Gynecol Oncol 2009; 112(2):422-36.

Giede KC, Kieser K, Dodge J et al.(2005) Who should operate on patients with ovarian cancer? An evidence-based review. Gynecol Oncol 2005; 99(2):447-61.

Goff BA, Matthews BJ, Larson EH et al.(2007) Predictors of comprehensive surgical treatment in patients with ovarian cancer. Cancer 2007; 109(10):2031-42.

Grenache DG, Heichman KA, Werner TL, et al.(2015) Clinical performance of two multi-marker blood tests for predicting malignancy in women with an adnexal mass. Clin Chim Acta. Jan 1 2015;438:358-363. PMID 25283731

Guidance for Industry and FDA Staff - Class II Special Controls Guidance Document: Ovarian Adnexal Mass Assessment Score Test System. https://www.fda.gov/RegulatoryInformation/Guidances/ucm237299.htm. Accessed October 17, 2017.

Hoskins W, Rice L, Rubin S.(1997) Ovarian cancer surgical practice guidelines. Oncology 1997; 11(6):896-904.

Kaijser J, Van Belle V, Van Gorp T, et al.(2014) Prognostic Value of Serum HE4 Levels and Risk of Ovarian Malignancy Algorithm Scores at the Time of Ovarian Cancer Diagnosis. Int J Gynecol Cancer. Sep 2014;24(7):1173-1180.

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