LCD L38371: Multimarker Serum Tests Related to Ovarian Cancer Testing

This is a non-coverage policy for all multi marker serum tests related to ovarian cancer testing.

History/Background and/or General Information

Ovarian cancer accounts for 2.5% of all malignancies in women and 5% of all cancer deaths due to the disease’s relatively high fatality rate. 1 The most common histologic subtype of ovarian cancer is epithelial ovarian cancer which is most commonly detected in advanced stage (65% of cases are stage II or IV) when the cure rate is only 18%. 2 The incidence rate of ovarian cancer has dropped 29%, from 16.6 (per 100,000) in 1985 to 11.8 in 2014 and the mortality rate for ovarian cancer has declined 33% from 1976 (10.0 per 100,000) to 2015 (6.7 per 100,000) due to reductions in incidence and improvements in treatment. 3 Nevertheless, improving early detection and prevention is a research priority because local-stage disease (confined to the ovary) has a 5-year relative survival rate of 93%. 1 Currently, there is no strategy for early detection of ovarian cancer that reduces ovarian cancer mortality. 2

Ovarian cancer is staged surgically and the prognosis of ovarian cancer is closely related to the stage of the tumor at the time of diagnosis. The early involvement of the gynecologic oncologist is associated with improved survival and outcomes due to increased adherence to guidelines including optimal cytoreductive surgery and chemotherapy. 4-8 As a result, NCCN guidelines recommend that all patients with suspected ovarian malignancies undergo primary assessment and debulking by a gynecologic oncologist as this results in a survival advantage. 9 The proportion of women with ovarian cancer who undergo this surgery by a gynecologic oncologist can be as low as 33%. 10,11

Per the American College of Obstetrics and Gynecology (ACOG), the evaluation of an adnexal mass should consider individual patient characteristics, physical examination findings, imaging results, and serum marker levels to help separate masses into the categories of probably benign, uncertain, and likely malignant, which can then guide appropriate management. 12 Per ACOG, the most extensively studied serum marker is cancer antigen 125 (CA 125), which is a protein associated with epithelial ovarian malignancies, but it is also frequently expressed at lower levels by nonmalignant conditions. In evaluating adnexal masses, CA 125 measurement is most useful in postmenopausal women and in identifying nonmucinous epithelial cancer. The CA 125 level is elevated in 80% of patients with epithelial ovarian cancer but in only 50% of patients with stage I disease. 12 Therefore, CA 125 is not considered to be an appropriate screening test for ovarian cancer.

Current NCCN guidelines recommend that patients with a suspicious pelvic mass and/or symptoms (bloating, pelvic/abdominal pain, difficult eating) have a CA 125 or other tumor markers as clinically indicated as part of the workup. 9 ACOG guidelines (Level B evidence) state “the combination of an elevated CA 125 level and a pelvic mass in a postmenopausal woman is highly suspicious for malignancy, and patients with these findings should be referred to or treated in consultation with a gynecologic oncologist”. 12

Various serum based tests have been proposed to triage patients with adnexal masses. A suggested use of the tests is to identify women who have a higher likelihood of malignant disease and may benefit from referral to a gynecologic oncologist. These tests are combinations of several individual serum laboratory tests known as multi-analyte assays with algorithmic analyses (MAAA) and are performed on a blood sample by a reference laboratory using a proprietary algorithm.

There are currently three FDA cleared tests: Ova1 ® , Overa ® , and ROMA TM .

Ova 1 ®

The OVA1 ® test uses proprietary OvaCalc Software to incorporate the values for five analytes from separately run immunoassays into a single numerical score between 0.0 and 10.0. The five analytes are Cancer Antigen 125 (CA 125), Transferrin (TRF), Apolipoprotein A-1 (APO A-1), Beta-2 Microglobulin (B2M), and Prealbumin (TT). This score is then interpreted in the context of menopausal or premenopausal status.

According to the FDA 510K decision summary, the Ova1 ® test is intended for women greater than or equal to 18 years of age who present with an ovarian adnexal mass for which surgery is planned and who are not yet referred to an oncologist . 13 The assay is intended for use as a prognostic indicator of a woman’s likelihood that malignancy is present when the physician’s independent clinical and radiological evaluation does not indicate malignancy. The test is not intended to be used as a screen or standalone diagnostic assay and is intended for use in conjunction with imaging studies and clinical assessments in women for whom surgical intervention is planned.

Overa ®

This is an assay that uses 5 protein biomarkers: Cancer Antigen 125 (CA 125), Transferrin (TRF), Apolipoprotein A-1 (APO A-1), Follicle-Stimulating Hormone (FSH),and Human Epididymis Protein 4 (HE4) the results of which are combined to calculate a single cancer risk score using proprietary software – OvaCALC. This score is then interpreted using menopausal or premenopausal status. According to the FDA 510K decision summary document, Overa ® (referred to as OVA1 Next Generation or Multivariate Index Assay (MIA2G)) is intended for women greater than or equal to 18 years of age who present with an ovarian adnexal mass for which surgery is planned and who are not yet referred to an oncologist. The assay is intended for use as a prognostic indicator of a woman’s likelihood that malignancy is present when the physician’s independent clinical and radiological evaluation does not indicate malignancy. 14

Risk of Ovarian Malignancy Algorithm (ROMA TM )

This is an assay that combines HE4, CA 125 and menopausal status into a numerical score. According to the initial FDA 510K clearance received, ROMA TM is intended to aid in assessing whether a premenopausal or post-menopausal woman who presents with an ovarian adnexal mass is at high or low likelihood of finding malignancy on surgery. It is indicated for women who meet the following criteria: over age 18; ovarian adnexal mass present for which surgery is planned, and not yet referred to an oncologist. ROMA TM must be interpreted in conjunction with an independent clinical and radiological assessment. 15,16

Each of the above tests have black box warnings stating “PRECAUTION: Test should not be used without an independent clinical and imaging evaluation and is not intended to be a screening test or to determine whether a patient should proceed to surgery. Incorrect use of this test carries a risk of unnecessary testing, surgery, and/or delayed diagnosis."

A literature search was performed in PubMed. Studies identified for potential inclusion were obtained from searches in PubMed with no date limits. Search terms included "OVA1", "multivariate index assay", "adnexal mass", “Overa”, “OVA1 next generation”, “second generation multivariate index”, “Risk of Ovarian Malignancy Algorithm”, “ovarian mass assessment” or “adnexal mass assessment”. Studies had to have been published in peer reviewed journals and include a patient population that met the FDA clearance criteria which includes over age 18, ovarian adnexal mass present for which surgery is planned, and not yet referred to an oncologist.

OVA1 ®

Fifteen studies were identified for OVA1 ® . Nine were excluded due to a variety of reasons including: OVA1 ® was not the index test, OVA1 ® performance assessed as an individual test; test not performed with the intended FDA-cleared intended usage as an adjunct test, the primary endpoint of the study was to examine how pelvic imaging influenced the OVA1 ® score, not the performance of the OVA1 ® test, cost-evaluation studies, and use of OVA1 ® for indications other than adnexal mass assessment. 17-25

Five of the six studies had limitations such as including patients who had been evaluated by a gynecologic oncologist prior to being tested and the studies contained overlapping patient populations. 26-30 Therefore, the results may not be generalizable or broadly applicable. All the studies were funded by the test manufacturer.