| Coverage Policy Manual | |
| Policy #: | 2010039 |
| Category: | Laboratory |
| Initiated: | August 2010 |
| Last Review: | January 2024 |
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| Biomarker, Serum Human Epididymis Protein 4 (HE4) | |
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| Description: |
Human epididymis protein 4 (HE4) is a novel biomarker that has been cleared by the U.S. Food and Drug Administration (FDA) for monitoring patients with epithelial ovarian cancer. HE4 is proposed as a replacement for or a complement to CA-125 for monitoring disease progression and recurrence. HE4 has also been proposed as a test to screen for ovarian cancer in asymptomatic women.
Background
Ovarian cancer is the fifth most common cause of cancer mortality in U.S. women. According to Surveillance Epidemiology and End Results (SEER) data, in 2022, an estimated 19,880 women will be diagnosed with ovarian cancer and 12,810 women will die of the disease (SEER, 2022). The stage at diagnosis is an important predictor of survival; however, most women are not diagnosed until the disease has spread. For the period 2012 to 2018, 57% of women with ovarian cancer were diagnosed when the disease had distant metastases (Stage IV), and this was associated with a 5-year survival rate of 31%. In contrast, the 17% of women diagnosed with localized cancer (Stage 1) had a 5-year survival rate of 93%. Epithelial ovarian tumors account for 85–90% of ovarian cancers (Ledermann, 2013).
Research from the Ovarian Cancer in Women of African Ancestry (OCWAA) consortium reports that Black women with ovarian cancer have worse survival than White women (Harris, 2022). Contributors to this disparity may include education level, nulliparity, smoking status, body mass index, diabetes, and postmenopausal hormone therapy duration.
Treatment
The standard treatment for epithelial ovarian cancer is surgical staging and primary cytoreductive surgery followed by chemotherapy in most cases. There is a lack of consensus about an optimal approach to follow-up patients with ovarian cancer following primary treatment. Patients undergo regular physical examinations and may have imaging studies. In addition, managing patients with serial measurement of the biomarker CA-125 to detect early recurrence of disease is common. A rising CA-125 level has been found to correlate with disease recurrence and has been found to detect recurrent ovarian cancer earlier than clinical detection. However, a survival advantage of initiating treatment based on early detection with CA-125 has not been demonstrated to date. For example, a 2010 randomized controlled trial (RCT) with women in ovarian cancer that was in complete remission did not find a significant difference in overall survival when treatment for remission was initiated when CA-125 concentration exceeded twice the limit of normal compared to delaying treatment initiation until symptom onset (Rustin, 2010).
Human epididymis protein 4 (HE4) is a protein that circulates in the serum and has been found to be overexpressed in epithelial ovarian cancer, lung adenocarcinoma, breast cancer, pancreatic cancer, endometrial cancer, and bladder cancer. HE4 is made up of 2 whey acidic proteins with a 4 disulfide core domain and has been proposed as a biomarker for monitoring patients with epithelial ovarian cancer.
This policy does not address use of the HE4 test for evaluating women with ovarian masses who have not been diagnosed with ovarian cancer. Use of the Risk of Ovarian Malignancy Algorithm (ROMA), which includes HE4, CA-125 and menopausal status, is addressed in policy #2010030 Proteomics-based Testing for the Evaluation of Ovarian (Adnexal) Masses.
Regulatory Status
Multiple HE4 test kits have been cleared by the U.S. Food and Drug Administration (FDA) through the 510(k) process. The FDA determined that this device was substantially equivalent to a CA-125 assay kit for use as an aid in monitoring disease progression or recurrence in patients with epithelial ovarian cancer. The FDA-cleared indication states that serial testing for HE4 should be done in conjunction with other clinical methods used for monitoring ovarian cancer and that the HE4 test is not intended to assess the risk of disease outcomes.
The serum HE4 tests cleared by the FDA include: HE4 EIA Kit by Fujirebio Diagnostics cleared 6/9/2008 510(k) K072939; ARCHITECT HE4 assay (CMIA) by Fujirebio Diagnostics cleared 3/18/2010 510(k) K093957; ELECSYS HE4 (CMIA) by Roche Diagnostics cleared 9/10/2012 510(k) K112624; and Lumipulse G HE4 Immunoreaction Cartridges by Fujirebio Diagnostics cleared 11/24/2015 510(k) K151378.
Coding
There is a specific CPT code for this test:
86305: Human epididymis protein 4 (HE4).
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Policy/ Coverage: |
Effective August 2012
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Measurement of HE4 does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, measurement of HE4 is considered investigational for all indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective prior to August 2012
Measurement of HE4 does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for all indications including:
For contracts without primary coverage criteria, measurement of HE4 is investigational for all indications including:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
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
This policy was created with a search of the MEDLINE database through June 2010. The literature identified in this search is as follows:
Technical performance
The FDA substantial equivalence determination decision summary documents for the HE4 EIA and ARCHITECT HE4 include data on technical performance. For example, the precision of the ARCHITECT HE4 test was accessed at 3 sites; samples were tested in 2 replicates using 2 lots of 3 controls. Total imprecision of the panels ranged from 3.4% to 5.4%. The upper limit of the 95% confidence interval for total imprecision for all samples was 6.1% or lower; this met the predetermined acceptance criteria for imprecision which was 10% or less. Moreover, the test met acceptance criteria for linearity and stability of samples, as well as observed interference from common endogenous substances (i.e., bilirubin, hemoglobin, and high and low protein concentrations).
Diagnostic performance
Monitoring disease progression and recurrence
The literature on the diagnostic performance of HE4 for monitoring the progression and recurrence of ovarian cancer is limited to material published in FDA documents. A study reported in the 510(k) substantial equivalence determination decision summary for the HE4 EIA assay evaluated whether this test was non-inferior to the CA-125 test. The study included samples from 80 women with epithelial ovarian cancer who were undergoing serial surveillance of cancer progression. Blood samples were obtained from a large cancer center in the United States; they were not drawn specifically for this study. A total of 354 samples were obtained for the 80 women (women had multiple visits over time). Receiver Operating Curve (ROC) analysis was used to compare the two assays and clinical evidence of progression was used as the reference standard. When a positive change in HE4 level (i.e., to indicate disease progression) was defined as a value at least 25% higher than the previous value of the test, the sensitivity of the test was 76/126 (60.3%) and the specificity was 171/228 (75%). (Note that the unit of analysis was the number of samples rather than the number of women). The area under the curve in the ROC curves was found to be similar (0.725 for HE4 and 0.709 for CA-125, respectively) with overlap in the confidence intervals; according to the authors, this indicated that the HE4 assay was not inferior to the CA-125 assay for detecting cancer progression.
Another analysis estimated the cutoff values and specificity for the HE4 and CA-125 assays at a fixed sensitivity. The specificity values for CA-125 and HE4 were not statistically different at the respective cutoffs and sensitivities; for example, using a cutoff of 15.4% above the previous value for the HE4 test, the sensitivity of the HE4 was 64.3% and the specificity was 69.3%. The specificity of CA-125 at a matching sensitivity was 70.2%; this used a cut-off for the CA-125 level of an increase of at least 32.8%. These data were also said to confirm that HE4 EIA test is not inferior to the CA-125 test for detecting ovarian cancer progression.
The 510(k) substantial equivalence determination decision summary for the ARCHITECT HE4 assay reports data from a retrospective study using remnant serial samples from 76 women diagnosed with epithelial ovarian cancer who were being monitored after completion of chemotherapy. The eligibility criteria included availability of at least 3 serial specimens; samples could have been drawn during and/or after treatment. Clinical determination of disease progression was used as the reference standard. A positive test was defined an HE4 level that was 14% higher than the pervious reading. Using this cut-off, the sensitivity of the assay for detecting progressive disease was 53/99 events (53.5%). The specificity of the assay was 260/331 (78.5%). Of note, the sensitivity is lower than that reported above for the HE4 EIA at a similar specificity, when a cutoff of a 25% increase was used (sensitivity=60.3% and specificity=75%).
The FDA documents note that there is no clinically accepted cut-off for use in monitoring cancer progression in epithelial ovarian cancer patients using the HE4 assays. As previously mentioned, a study the HE4 EIA assay defined a positive test as a level that was 25% higher than a previous measurement, and a study on the ARCHITECT HE4 test defined a positive test as an increase of at least 14% in the level of HE4. The FDA documents further state that clinicians may which to use the cutoffs in the studies or another cutoff that reflects their own preferences in the tradeoff between sensitivity and specificity.
Evaluating women with a pelvic mass
Several published studies were identified that evaluated the ability of HE4 alone, or in combination with CA-125, to predict ovarian cancer in women with a pelvic mass. Four studies, some with multiple publications, were conducted in the United States; findings of these studies are summarized below.
In 2008, Moore and colleagues published a prospective single-center study including 259 women diagnosed with an ovarian cyst or pelvic mass who were scheduled to undergo surgery in a women’s oncology center (Moore, 2009). Blood samples were collected before surgery and were analyzed for levels of HE4, CA-125, soluble mesothelin-related peptide (SMRP) and CA 72-4, activin A, inhibin, osteopontin, epidermal grown factor (EGFR) and ERBB2 (HER2). Sensitivity and specificity of the markers were determined using histological diagnosis as the reference standard. The gynecologist pathologist and surgeons were blinded to tumor marker analysis results and tumor marker analysis was done by investigators blinded to clinical and pathology findings. The sensitivity and specificity for differentiating between benign and malignant disease was calculated for each individual marker and combinations of two and three markers. The first author of this study and several other authors have served as consultants for and members of the scientific advisory board of Fujirebio Diagnostics.
Samples from 233 of the 259 (90%) women were included in the analysis. Women found to have cancers other than epithelial ovarian cancer (n=24, 9.3% of the sample) were excluded and 2 women did not have preoperative blood samples. Sixty-seven women had invasive epithelial ovarian cancer and 166 had benign ovarian neoplasms. The levels (i.e. mean concentration) of each individual marker other than Her2 differed significantly between patients with benign and malignant disease. At a fixed specificity of 95%, HE4 had the highest sensitivity (72.9%) of any of the single markers. This compares with a sensitivity of 43.3% of CA-125. Only one other marker had a sensitivity higher than CA-125; this was soluble mesothelin-related peptide which had a sensitivity of 53.7%. The combination of HE4 and CA-125 had the highest sensitivity of any 2 markers, 76.4% at a specificity of 95%. The addition of a third marker did not appreciably increase the sensitivity. Excluding women with cancers other than epithelial ovarian cancer limits the ability to generalize the study’s findings to the population of women presenting with an adnexal mass.
This 2008 study served as a pilot for a larger multi-center study by Moore and colleagues, published in 2009 (Moore, 2009). Like the pilot, the study was prospective, included women diagnosed with an ovarian cyst or pelvic mass who were scheduled to undergo surgery, involved pre-surgical collection of blood samples and sought to identify women at high-risk of epithelial ovarian cancer. However, this study only evaluated levels of the 2 biomarkers found to have the highest combined sensitivity in the pilot, HE4 and CA-125. The investigators classified women as high- or low-risk of malignant disease based on their serum values of these 2 markers. The algorithm was designed to achieve a specificity of 75%; that is, having 75% of patients with benign disease correctly classified as low-risk. The investigators then calculated sensitivity; they pre-determined that the minimum performance that would demonstrate a clinically useful test would be a sensitivity greater than 80% at the 75% specificity for the pre- and post-menopausal groups combined.
A total of 566 patients were enrolled; of these, 531 (94%) were evaluable, 248 pre-menopausal women and 283 post-menopausal women. After surgery, 352 (66%) of women were diagnosed with benign disease, 129 (24%) with epithelial ovarian cancer and 50 (9%) with other types of malignant disease. The median CA-125 levels were 20.5 IU/mL for benign disease and 210.9 IU/mL for malignant disease.
The corresponding median HE4 levels were 58.6 picomolar (pM) and 274.4 pM, respectively. Based on the values of CA-125 and HE4, 280 (56%) women were classified as low-risk and 223 (44%) as high-risk (28 women appear to be missing from this analysis). This resulted in a specificity of 74.7% and a sensitivity of 88.7% (lower limit of the 95% confidence interval was 82.6%). Thus, the test met the investigators criteria for clinical usefulness. The algorithm incorrectly classified 9 patients with low-malignant potential tumors and 8 patients with epithelial ovarian cancer into the low-risk group. When data for pre-menopausal and post-menopausal women were examined separately, at the 75% specificity level, the algorithm had 92.3% sensitivity for predicting risk status in post-menopausal women but only 76.5% sensitivity for pre-menopausal women. Thus, like CA-125 alone, the combination of CA-125 and HE4 appears to perform less well in pre-menopausal women.
A retrospective study published in 2010 by Nolen and colleagues aimed to identify a biomarker panel that surpassed the combination of CA-125 and HE4 for distinguishing between benign and malignant disease in women with pelvic masses (Nolen, 2010). They used a training set of blood samples from 405 women (141 with benign disease and 264 with ovarian cancer) and a validation set of samples from 309 women (140 with benign disease and 169 with ovarian cancer). Both sets consisted of samples from post-menopausal women. Women in the benign group had a range of benign adnexal lesions; those with pelvic inflammatory disease were not included. Sixty-five markers were tested in the training set (this included 2 of the 5 markers in the OVA1 test, CA-125 and apolipoprotein A-1). In the training set, the best performing 2-marker combination was CA-125 and HE4 and several multimarker combinations showed promise. However, in the validation set, none of the 3- or 4-marker panels performed better than the CA-125 plus HE4 combination. At a set specificity of 85%, the sensitivity of the CA-125 and HE4 combination in the validation set was 83%. At a specificity of 77.9%, the sensitivity of this combination was 89.4%.
Also in 2010, Andresen and colleagues published a study evaluating the ability of CA-125, HE4 and a symptom index to predict ovarian cancer in symptomatic women (Anderson, 2010). The symptom index was developed by the study investigators and evaluated in previous publications. It was considered positive if patients had at least one of the following: symptoms for less than one year but more than 12 times per month; bloating or increased abdominal size; abdominal or pelvic pain; and difficulty eating or feeling full quickly. The study used a case-control design and included 74 women with ovarian cancer and 137 healthy women; in the analysis, cases and controls were frequency matched by age. All women completed surveys asking about symptoms and donated blood samples; cases had blood samples taken prior to surgery for pelvic masses. The 3-marker decision rule defining the test as positive if any single test was positive yielded a high sensitivity (94.6%) but a relatively low specificity (79.6%). The 2-marker combination of CA-125 and HE4 had a higher specificity than the 3-marker combination (89.8%) with 89.2% sensitivity. As a single marker, CA-125 had the highest overall sensitivity (81%) at 95% specificity. In high-risk cases only, at 95% specificity, HE4 had the highest sensitivity, identifying 100% of 14 cases compared to 78.6% (11 of 14) using CA-125 test results. The criteria for considering patients to be high-risk were not clearly defined in the study.
Note that the above studies did not use attempt to categorize women as likely or not likely to have malignant disease based on their level of HE4; that is, they did not select a specific cutoff for a positive test. Instead, in the analyses, they examined whether the mean level of HE4 was significantly different in women with benign and malignant disease.
Screening asymptomatic women
No published studies were identified that evaluated the diagnostic performance of the HE4 biomarker for screening asymptomatic women for ovarian cancer.
A retrospective study published in 2010 by Anderson and colleagues aimed to determine the potential value of using HE4 and other biomarkers in early identification of ovarian cancer in asymptomatic women (Anderson, 2010). The study included 34 women with ovarian cancer and 70 matched controls, all of whom were participating in an unrelated randomized controlled trial including smokers at increased risk of lung cancer. Blood samples were available for the women between 0 and 18 years before ovarian cancer diagnosis. In descriptive analyses, individual serum markers, including HE4, CA-125, and mesothelin, showed increasing accuracy over time approaching the diagnosis of ovarian cancer. Mean concentrations of these markers, which were measured by visually-read immunoassays, began to increase approximately 3 years before diagnosis but attained detectable levels only within the final year before diagnosis. The study had a small sample size, limiting the ability to conduct quantitative analysis, and included only heavy smokers and therefore may not be representative of the population of women at risk of ovarian cancer.
In 2011, Urban and colleagues retrospectively reviewed preclinical samples to evaluate the potential utility of HE4 and other markers as a secondary screening test in women found to have epithelial ovarian cancer (Urban, 2011). There were samples from 112 ovarian cancer patients and 706 matched controls. Individuals participated in the Prostate, Lung, Colorectal and Ovarian (PLCO) trial and had been screened annually for 6 years with CA-125. Serum samples to evaluate potential markers were taken from the year proximate to the one in which women were diagnosed with ovarian cancer. (Serum samples were not available for the 4th screen so they were taken from the 3rd year for the women diagnosed with ovarian cancer between the 3rd and 4th screens.) The investigators evaluated the associations between CA-125, HE4, and levels of 5 other markers with malignancy, accounting for increasing CA-125 levels and adjusting for demographic characteristics. Increase in CA-125 levels was associated with statistically significant increases in all of the markers. Levels of HE4 were most elevated, compared to controls i.e. the highest average HE4 level was 4.26 standard deviations above the mean HE4 level in control samples. The utility of HE4 as a biomarker to screen for ovarian cancer along with CA-125 needs to be further evaluated in prospective studies and confirmed in RCTs that evaluate the impact of screening on health outcomes.
Clinical utility
No prospective studies were identified that compared health outcomes in patients managed with and without HE4 testing, alone or in combination with CA-125 or other disease markers. In addition, no randomized controlled trials evaluating the clinical utility of screening asymptomatic women with HE4 were identified.
Ongoing Clinical Trials
A Trial Using Novel Markers to Predict Malignancy in Elevated-Risk Women (NCT01121640): This is a randomized controlled trial comparing 2 epithelial ovarian cancer screening protocols. One strategy involves assessment of CA-125 at every screen and HE4 at a confirmatory screen and the other involves CA-125 and HE4 assessment at every screen. The primary study outcome is the positive predictive value of the 2 screening protocols. The expected date of study completion is June 2014.
Practice Guidelines and Position Statements
The 2012 National Comprehensive Cancer Network (NCCN) ovarian cancer guideline states that, for monitoring/follow-up of patients with stage I-IV ovarian cancer with a complete response to initial treatment, “CA-125 or other tumor marker” should be used at every visit if initially elevated (NCCN, 2012). The guideline does not specify any marker other than CA-125 for monitoring patients after treatment.
The NCCN guideline states the following on screening for ovarian cancer:
“Randomized data do not yet support routine screening for ovarian cancer in the general population, and routine screening is not currently recommended by any professional society. Some physicians follow women with high-risk factors (e.g. those with BRCA mutations, those with a family history) using CA-125 monitoring and endovaginal ultrasound; however, prospective validation of these tests remains elusive.”
Scottish Intercollegiate Guidelines Network (SIGN) reaffirmed its national clinical guideline on epithelial ovarian cancer in 2007 (SIGN, 2012).
The guideline has the following recommendation on screening for ovarian cancer:
“Screening for ovarian cancer in high risk groups should only be offered in the context of a research study designed to gather data on:
Summary
There are limited data on the diagnostic test performance of the HE4 test used to monitor disease progression and recurrence in women after initial treatment for epithelial ovarian cancer. The available data on diagnostic test performance are in FDA documents; the reported studies were small, retrospective, may have included duplicate data on the same women, and used different cut-offs for identifying a recurrence. In general, there is no established cut-off for determining when an HE4 test is positive, when used for identifying disease progression or recurrence. Moreover, a survival advantage of early detection of ovarian cancer recurrence using HE4 levels or other biomarkers has not been established. No published studies were identified evaluating use of the HE4 test to screen asymptomatic women for ovarian cancer.
2013 Update
A literature search conducted using the MEDLINE database through July 2013. There was no new information identified that would prompt a change in the coverage statement. No prospective studies were identified that compared health outcomes in patients managed with and without HE4 testing, alone or in combination with CA-125 or other disease markers. In addition, no randomized controlled trials evaluating the clinical utility of screening asymptomatic women with HE4 were identified.
In December 2012, the U.S. Preventive Services Task Force (USPSTF) published an updated recommendation statement on screening for ovarian cancer (USPSTF, 2013). The USPSTF recommended against screening for ovarian cancer in asymptomatic women (D recommendation). HE4 was not specifically discussed.
2014 Update
A literature search conducted through July 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
A 2013 study by Braicu et al evaluated 275 patients with advanced primary ovarian cancer who underwent cytoreductive surgery and adjuvant platinum-based chemotherapy at a specialized clinic (Braicu, 2013). In 221 of 275 (80.4%), preoperative HE4 and CA-125 values, as well as data on residual tumor mass after debulking were available. For HE4 levels, the AUC for residual tumor mass was 0.634. At an HE4 cutoff value of 235 pM, the sensitivity was 76.6% and specificity was 47.4%. When the cutoff for HE4 was 500 pM, the sensitivity was 51.9% and the specificity was 70.4%. For CA-125, the AUC for residual tumor mass was 0.643, nearly the same as for HE4. At a cutoff of 500 IU/mL, the sensitivity of CA-125 for predicting complete tumor resection was 69.4% and the specificity was 52.3%. Using the most accurate cutoffs for HE4 (235 pM) and CA-125 (500 IU/mL), the combined combination of the 2 markers had sensitivity of 64.8% and specificity of 73.5%. Median follow-up was 25 months (range, 1-49 months) In multivariate analysis, neither HE4 nor CA-125 levels significantly predicted overall survival or progression-free survival.
Several meta-analyses of studies on the accuracy of HE4 for diagnosing ovarian cancer were published in 2012 and 2013. Table 1 presents the pooled sensitivities and specificities of HE4 from meta-analyses that conducted quality assessments of individual studies and that limited their reviews to studies using pathologic findings as the reference standard for ovarian cancer diagnosis (Ferraro, 2013; Wu, 2012; Yang, 2013; Yu, 2012).
Table 1. Meta-Analyses of Studies on HE4 for Diagnosing Ovarian Cancer
Yang et al (2013) No. of Studies 31; Sensitivity (95% Cl) 0.73 (0.71 to 0.75) Specificity (95% CI) 0.89 (0.88 to 0.90)
Ferraro et al (2013) No. of Studies 14; Sensitivity (95% Cl) 0.79 (0.71 to 0.75) Specificity (95% CI) 0.93 (0.88 to 0.90)
Yu et al (2012) No. of Studies 12; Sensitivity (95% Cl) 0.80 (0.71 to 0.75) Specificity (95% CI) 0.92 (0.88 to 0.90)
Wu et al (2012) a No. of Studies 7; Sensitivity (95% Cl) 0.74 (0.71 to 0.75) Specificity (95% CI)) 0.90 (0.88 to 0.90)
CI: confidence interval.
a Studies using HE4 to distinguish between ovarian cancer and benign disease.
Meta-analyses differed somewhat in their study inclusion criteria, search dates and other factors but, as shown in Table 1, had similar results in terms of diagnostic value of HE4; pooled sensitivities ranged from 0.73 to 0.80, and pooled specificities ranged from 0.89 to 0.93.
Two of the meta-analyses also pooled studies on the diagnostic accuracy of CA-125. In the Ferraro et al meta-analysis (13 studies), pooled sensitivity was 0.79 (95% CI, 0.77 to 0.82) and pooled specificity was 0.78 (95% CI, 0.76 to 0.80). In an additional analysis by Ferraro et al, a meta-analysis of 4 studies on the combination of HE4 and CA-125 found a sensitivity of 0.82 (95% CI, 0.78 to 0.86) and specificity of 0.76 (95% CI, 0.72 to 0.80). The overall diagnostic performance of HE4 alone, or in combination with CA-125 was not statistically significantly better than CA-125 alone.
Yu et al conducted a meta-analysis of 10 studies on CA-125 and found a pooled sensitivity of 0.66 (95% CI, 0.62 to 0.70) and a pooled specificity of 0.87 (95% CI, 0.85 to 0.89) (Yu, 2012) the diagnostic performance did not differ significantly from the performance of HE4 (as shown in Table 1). However, in a subanalysis of the studies in which the control groups consisted of women with benign disease, the specificity but not sensitivity of HE4 was significantly higher than CA-125. In this subgroup, the pooled sensitivity was 0.77 (95% CI, 0.74 to 0.81) for HE4 and 0.73 (95% CI, 0.68 to 0.77) for CA-125, and the pooled specificity was 0.91 (95% CI, 0.89 to 0.92) for HE4 and 0.79 (95% CI, 0.77 to 0.82).
Studies published on 2013 evaluated the diagnostic performance of HE4 as a second-line test after subjective assessment of transvaginal ultrasound. Final histologic diagnosis was used as the reference standard. Kaijser et al enrolled 389 patients with a suspicious pelvic mass who were scheduled for surgery (Kaijser, 2013). Data on 360 (93%) patients were available for analysis. Experienced ultrasonographers categorized each mass as benign, borderline or invasive malignant. Serum samples were obtained before surgery and HE4 levels were measured, using a cutoff of at least 70 pmol/L to indicate malignancy. Overall, subjective ultrasound evaluation by an experienced examiner had higher sensitivity and specificity than serum HE4. Sensitivity was 97% with subjective assessment ultrasound and 74% with HE4, and specificity was 90% and 85%, respectively. The additional consideration of HE4 values after sonographers categorized a mass as benign resulted in a slight increase in sensitivity and a large increase in the number of false-positives. Moreover, sequential use of serum HE4 after sonographers categorized a mass as malignant resulted in lower sensitivity and an increase in specificity.
Moszynski et al retrospectively reviewed records on 253 women with adnexal masses (Moszynski, 2013). Women were examined with transvaginal ultrasound by an experienced examiner before surgery. The sonographer categorized masses as certainly benign, probably benign, uncertain, probably malignant and certainly malignant. Tumors in the certainly benign and certainly malignant categories were excluded from further analysis, and the remainder (n=145) were considered suspicious tumors. HE4 and CA-125 levels were measured in serum, a cutoff of 65 pmol/L was used for HE4. The sensitivity and specificity of ultrasound evaluation for diagnosing the suspicious tumors was 93.3% and 90.6%, respectively. Neither HE4 nor CA-125 improved diagnostic accuracy for suspicious tumors. Sensitivity and specificity of HE4 was 80.0% and 91.7%, respectively, and the sensitivity and specificity of CA-125 was 85.8% and 74.7%, respectively. A logistic regression analysis confirmed that neither HE4 nor CA-125 improved diagnostic accuracy beyond that of subjective assessment of ultrasonography.
Section summary
A number of studies evaluating the diagnostic accuracy of HE4 for evaluating adnexal masses have been published and there are several meta-analyses of these studies. Two meta-analyses compared the diagnostic accuracy of HE4 and CA-125. One of these did not find a statistically significant difference in diagnostic performance, and the other did not find a significant difference overall and found a significantly higher specificity but not sensitivity in the subgroup of studies in which women with benign disease were included in the control group. In addition, studies have not found that HE4 improves diagnostic accuracy beyond that of subjective assessment of transvaginal ultrasound. The evidence is insufficient to conclude that HE4 alone or in combination with CA-125 has significantly better diagnostic performance than CA-125 alone.
The National Institute for Health and Clinical Excellence (NICE) issued guidance in 2011 on the recognition and initial management of ovarian cancer (NICE, 2011). The guideline includes the following recommendations:
The NICE guidance does not mention HE4.
2015 Update
A literature search conducted through February 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
A number of meta-analyses of studies on the accuracy of HE4 for diagnosing ovarian cancer have been published. Table 1 presents the pooled sensitivities and specificities of HE4 from meta-analyses that conducted quality assessments of individual studies and that limited their reviews to studies using pathologic findings as the reference standard for ovarian cancer diagnosis. (Macedo, 2014; Ferraro, 2013; Yang, 2013; Yu. 2013; Wang, 2014).
Table 1. Meta-Analyses of Studies on HE4 for Diagnosing Ovarian Cancer
Maceda et al (2014) No. of Studies 45; Sensitivity (95% Cl) 0.78 (0.77 to 0.79); Specificity 0.86 (0.85 to 0.87)
Wang et al (2014) No. of Studies 28; Sensitivity (95% Cl) 0.76 (0.72 to 0.80); Specificity 0.93 (0.90 to 0.96)
Zhen et al (2014 No. of Studies 25; Sensitivity (95% Cl) 0.74 (0.72 to 0.76); Specificity 0.90 (0.89 to 0.91)
Yang et al (2013) No. of Studies 31; Sensitivity (95% Cl) 0.73 (0.71 to 0.75) Specificity (95% CI) 0.89 (0.88 to 0.90)
Ferraro et al (2013) No. of Studies 14; Sensitivity (95% Cl) 0.79 (0.71 to 0.75) Specificity (95% CI) 0.93 (0.88 to 0.90)
Yu et al (2012) No. of Studies 12; Sensitivity (95% Cl) 0.80 (0.71 to 0.75) Specificity (95% CI) 0.92 (0.88 to 0.90)
Wu et al (2012) No. of Studies 7; Sensitivity (95% Cl) 0.74 (0.71 to 0.75) Specificity (95% CI)) 0.90 (0.88 to 0.90)
CI: confidence interval.
a Studies using HE4 to distinguish between ovarian cancer and benign disease.
Several of the above meta-analyses also pooled data from studies on the diagnostic accuracy of CA-125, alone and/or in combination with HE4 and findings are shown in Table 2.
Table 2. Meta-Analyses of Studies on CA-125 and the Combination of HE4 and CA-125 for
Diagnosing Ovarian Cancer
CA-125
Wang et al (2014) No. of Studies 28; Sensitivity (95% CI) 0.79 (0.74 to 0.84); Specificity (95% CI) 0.82 (0.77 to 0.87)
Zhen et al (2014) No. of Studies 25; Sensitivity (95% CI) 0.74 (0.72 to 0.76); Specificity (95% CI) 0.83 (0.81 to 0.84)
Ferraro et al (2013) No. of Studies 13; Sensitivity (95%CI) 0.79 (0.77 to 0.82); Specificity (95% CI) 0.78 (0.76 to 0.80)
Yu et al (2012) No. of Studies 10; Sensitivity (95% CI) 0.66 (0.62 to 0.70); Specificity (95% CI) 0.87 (0.85 to 0.89)
HE4 and CA-125
Zhen et al (2014) No. of Studies 9; Sensitivity (95% CI) 0.90 (0.87 to 0.92); Specificity (95% CI) 0.85 (0.82 to 0.87)
Ferraro et al (2013) No. of Studies 4; Sensitivity (95% CI) 0.82 (0.78 to 0.86); Specificity (95% CI) 0.76 (0.72 to 0.80)
In all of the meta-analyses included in Table 2, the overall diagnostic performance (considering both sensitivity and specificity) of HE4 did not differ significantly from the performance of CA-125 for diagnosing ovarian cancer. However, both (Wang 2014;and Zhen, 2014) found that the specificity (but not sensitivity) of HE4 was significantly higher than CA-125.
Findings differed in the 2 meta-analyses comparing the diagnostic performance of HE4 and CA-125 versus CA-125 alone. Ferrero and colleagues did not find that the sensitivity and specificity of HE4 in combination with CA-125 differed significantly from that of CA-125 alone. Zhen and colleagues found that both the sensitivity and specificity of HE4 combined with CA-125 were significantly better than CA-125 alone. In the subgroup of 9 studies that directly made this comparison in the Zhen and colleagues meta-analysis, the sensitivity of HE4 plus CA-125 was 0.90 (0.87 to 0.92) versus 0.74 (0.69 to 0.78) for CA-125 alone and the specificity of HE4 plus CA-125 was 0.85 (0.82 to 0.87) versus 0.73 (0.69 to 0.76) for CA125 alone. In addition, in the Zhen and colleagues study, the overall diagnostic accuracy (measured by the diagnostic odds ratio [DOR)) was significantly higher for the combination of HE4 and CA-125 than for HE4 alone. Pooled DORs were 10.31 (95% CI: 6.18 to 17.21) for CA-125 and 53.92 (95% CI: 26.07 to 111.54) for the combination of HE4 and CA-125. Zhen and colleagues noted several limitations to their meta-analysis including substantial publication bias for HE4, heterogeneity among studies and a lack of consideration given to clinical factors such as menopausal status. In addition, there were a small number of studies evaluating the combination of HE4 and CA125 and wide confidence intervals in the DORs indicating unreliable estimates.
Multiple evaluating the diagnostic accuracy of HE4 for evaluating adnexal masses have been published and there are multiple meta-analyses of these studies. Four meta-analyses have compared the diagnostic accuracy of HE4 and CA-125. All found no significant difference in overall diagnostic accuracy but 2 of the meta-analyses found that HE4 had higher specificity than CA-125. Findings differed in the 2 meta-analyses that compared diagnostic accuracy of HE4 in combination with CA-125 versus CA-125 alone.
One of the 2 found that the combined test had significantly higher sensitivity and specificity than CA-125 alone. In addition, studies have not found that HE4 improves diagnostic accuracy beyond that of subjective assessment of transvaginal ultrasound.
A number of studies and meta-analyses of these studies have been published on HE4 for diagnosing ovarian cancer (although this is not an FDA-approved indication of the HE4 test). The evidence is insufficient to conclude that HE4 alone or in combination with CA-125 has significantly better diagnostic performance than CA-125 alone. Meta-analyses have generally found that HE4 and CA-125 have similar overall diagnostic accuracy (ie sensitivity and specificity) and several found that HE4 has significantly higher specificity than CA-125 but not sensitivity. Two meta-analyses had mixed findings on whether the combination of HE4 and CA-125 is superior to CA-125 alone for the initial diagnosis of ovarian cancer. The number of studies evaluating the combined test is relatively low and publication bias in studies of HE4 has been identified.
2016 Update
A literature search conducted through February 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Nassir and colleagues published additional data on the OVCAD study (Braicu. 2013) in 2015 (Nassir, 2015). A total of 92 of 275 patients (33%), who had preoperative and followup plasma samples for analyzing HE4 and CA-125, were included in the analysis. (However, 13 preoperative HE4 samples and 10 postoperative CA-125 samples were missing). Of the 92 included patients, 70 (76%) were responders to initial treatment and 22 (23%) were non-responders. In the first year post-treatment, 36 out of 79 patients in whom preoperative HE4 values were available experienced recurrence or death. The AUC for predicting 12-month recurrence or death based on preoperative HE4 values was 0.658 (95% CI: 0.535 to 0.781, p=0.016). With a cutoff of 165pM, the sensitivity was 86.1% and specificity was 34.9%. In addition, 41 of 89 patients with preoperative CA-125 values experienced recurrence or death in the first year. The AUC for CA-125 was 0.62 (95% CI: 0.51 to 0.74, p=0.056). At a cutoff of 400 U/ml, CA-125 had a sensitivity of 81% and a specificity of 50%. Both preoperative HE4 and CA-125 values significantly predicted 12-month recurrence or death. Among responders, median overall survival (OS) was worse among patients in whom both biomarkers were elevated (HR: 17.96, 95% CI: 4.00-80.85, p<0.001) compared with patients in whom no biomarker was elevated. The confidence interval for the OS analysis was wide, indicating an imprecise estimate. There was not a significant association with median OS when only 1 biomarker was elevated; the sample size may have been inadequate for this analysis.
2017 Update
A literature review conducted using the MEDLINE database did not reveal any new literature that would prompt a change in the coverage statement. There were no randomized controlled trials identified that address the accuracy and clinical utility of HE4 as a serum biomarker in patients with ovarian cancer or adnexal masses.
In 2016, Steffensen et al evaluated the ability of HE4 and CA 125, individually and together, to predict ovarian cancer recurrence after first-line chemotherapy (Steffensen, 2016). The study included 88 patients with serum samples drawn at the end of chemotherapy and at least twice during the follow-up period. Median length of follow-up for patients still living was 47 months. During the study, 55 (62.5%) of 88 patients had recurrences and 38 (43%) died. HE4 values at the end of chemotherapy classified 70 (84.3%) patients as at high risk of relapse and 13 (15.7%) as at low risk. The sensitivity of HE4 was 90.0% (95% CI, 79.0% to 96.8%) and specificity was 25.8% (95% CI, 11.9% to 44.6%). The combination of HE4 and CA 125 levels classified 69 (83%) patients as high risk of relapse and 14 (16.9%) as low risk, with a sensitivity of 90.0% (95% CI, 79.0% to 96.8%) and a specificity of 29% (95% CI, 14.2% to 48.0%). Based on analysis of HE4 and CA 125 levels from samples taken 3 months after chemotherapy, an increase of at least 50% relative to baseline was considered the cutoff for predicting a significant worsening of progression-free survival (PFS). Both HE4 and CA 125 as individual markers at 3 and 6 months were significantly associated with poorer PFS. However, on multivariate analysis, HE4 was a significant predictor of PFS at 6 months but not at 3 months, and CA 125 was nonsignificant at both 3 and 6 months. For the combination of CA 125 and HE4, there were too few patients positive on both markers at 3 months (n=7) to conduct an analysis of the combination’s association with PFS.
Although HE4 levels are associated with the presence of recurrent ovarian cancer, improvement in health outcomes would depend on subsequent management decisions that would improve health outcomes. There is not a clear chain of evidence demonstrating that incremental changes in ovarian cancer detection would lead to improved health outcomes. No prospective studies were identified that compared health outcomes in patients with ovarian cancer managed with and without HE4 testing, alone or in combination with CA 125 or other disease markers.
There is a lack of evidence to determine the effects of HE4 serum biomarker testing on health outcomes in the diagnosis or screening of ovarian cancer and adnexal masses.
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2018. No new literature was identified that would prompt a change in the coverage statement.
2019 Update
A literature search was conducted through March 2019. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Vallius et al reported a study that was designed to assess fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) imaging and serum tumor markers in epithelial ovarian cancer staging and chemotherapy response (Vallius, 2017). A substudy analysis evaluated the use of HE4 profiles to predict treatment outcomes during the first line of chemotherapy after primary cytoreductive surgery. HE4 and CA125 was measured in patients with FIGO III/IV EOC who received primary debulking surgery followed by platinum based chemotherapy or neoadjuvant chemotherapy followed by interval debulking surgery. HE4 at the time of diagnosis was not associated with PFS (p = 0.24), whereas lower CA125 at the time of diagnosis predicted longer PFS (p = 0.01, hazard ratio (HR) = 1.45, 95% confidence interval (CI) = 1.09-1.94). When patients who underwent either surgical approach were combined (N=40), those with no macroscopic residual disease after cytoreductive surgery were more likely to have lower postoperative HE4 values. Both HE4 and CA 125 nadir values were associated with a greater complete response to chemotherapy.
Several retrospective studies aimed at determining the potential value of using HE4 and other biomarkers in early identification of ovarian cancer in asymptomatic women. In 2010 Anderson et al published data on 34 women with ovarian cancer and 70 matched controls, all of whom were participating in an unrelated randomized controlled trial on smokers at increased risk of lung cancer (Anderson, 2010). Blood samples were available for the women between 0 years and 18 years before ovarian cancer diagnosis. In descriptive analyses, individual serum markers, including HE4, CA 125, and mesothelin, showed increasing accuracy over time approaching the diagnosis of ovarian cancer. Mean concentrations of these markers, which were measured by visually read immunoassays, began to increase approximately 3 years before diagnosis but attained detectable levels only within the final year before diagnosis. The study had a small sample size, limiting the ability to conduct quantitative analysis, and included only heavy smokers and therefore may not be representative of the population of women at risk of ovarian cancer.
2020 Update
A literature search was conducted through March 2020. There was no new information identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Salminen et al conducted a prospective observational study in 143 women with histologically confirmed high-grade serous carcinoma (a common and aggressive form of EOC) to assess biomarkers, including CA 125 and HE4, for treatment monitoring and prognostic stratification (Salminen, 2020). Included patients received primary treatment with either primary debulking surgery followed by chemotherapy (n=58) or neoadjuvant chemotherapy with interval debulking surgery plus adjuvant chemotherapy (n=85). Chemotherapy regimens consisted of carboplatin plus a taxane (n=125), carboplatin alone (n=16) or other/unknown (n=2). Follow-up times ranged between 1.5 months to 10.2 years. At the time of progression, multivariate analysis showed that HE4 concentration elevations greater than 199.20 pmol/L were significantly associated with a reduction in overall survival (hazard ratio, 5.85; 95% CI, 2.07 to 16.51; p=0.0001); elevations in CA 125 greater than 162.00 U/mL were not (hazard ratio, 1.39; 95% CI, 0.59 to 3.28; p=0.45). Serum HE4 concentrations were also found to be significantly higher at baseline in patients with a higher tumor burden compared to those with less extensive tumor growth (p<0.0001) while CA 125 concentrations were not (p=0.067). At baseline after cytoreductive surgery, neither CA 125 (p=0.641) or HE4 (p=0.054) concentrations were significantly associated with the amount of residual disease. Nadir CA 125 and HE4 levels were both found to be significantly elevated in patients who developed platinum-resistant disease (p<0.0001).
Gentry-Maharaj et al (2020) performed a cohort study nested within the screening population of a larger multicenter randomized controlled trial to assess the ability of HE4 and CA 125 to diagnose ovarian cancer in postmenopausal women with adnexal masses (Gentry-Maharaj, 2020). The initial trial (United Kingdom Collaborative Trial of Ovarian Cancer Screening; UKCTOCS) randomized 202,638 postmenopausal women to be screened for ovarian cancer to multimodal screening with CA 125 levels, transvaginal ultrasound, or no screening. Women who were randomized to 1 of the screening groups who had an abnormality received a repeat of the initial screening test that they received, and those with persistent abnormalities were further assessed by a clinical team subsequently managed with surgery or conservative management, and had serum CA 125 and HE4 levels taken within 6 months of the scan. A total of 1590 women met these criteria and were found to have adnexal masses. Follow-up occurred for a median of 10.9 years. Reported area under the curve values at a specificity of 90% were as follows: 0.896 (95% CI, 0.847 to 0.935) for ultrasound plus CA 125 pls HE4, 0.893 (95% CI, 0.844 to 0.933) for ultrasound plus CA125, 0.854 (95% CI, 0.8 to 0.9) for ROMA, and 0.854 (95% CI, 0.802 to 0.9). Reported AUC values were significantly lower for the ROMA and ultrasound plus HE4 groups compared to the ultrasound plus CA 125 plus HE4 group (p=0.0554 and 0.033, respectively); AUC values were not significantly different when comparing the ultrasound plus CA 125 plus HE4 group to the ultrasound plus CA 125 group (p=0.4527). These 2 groups were also reported to have a similar sensitivity at 90% specificity (p=0.564); comparison of sensitivity among other groups was not provided.
Guidelines from the American College of Obstetricians and Gynecologists on evaluation and management of adnexal masses state that measurement of CA 125 is the most extensively studied serum marker to be used in combination with imaging to determine the likelihood of malignancy (Eskander, 2016). The authors also suggest that measurement of CA 125 is most useful for identification of nonmucinous epithelial cancer in postmenopausal women. Although the guideline mentions that HE4 has recently been identified as a biomarker that may be useful for distinguishing between benign and malignant masses, no further recommendations regarding HE4 are provided.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Potenza et al retrospectively assessed 78 patients with EOC to determine whether HE4 and CA 125 measured at diagnosis and before each platinum-based chemotherapy cycle could predict lack of response to chemotherapy and disease recurrence (Potenza, 2020). The proportions of patients who were sensitive, partially resistant, and refractory to chemotherapy were 73%, 16.6%, and 6.4%, respectively. After a median follow-up of 10 months, both HE4 and CA 125 had a positive correlation to PFS when measured after the third chemotherapy cycle (both p=.0001). At the time of diagnosis, HE4 and CA 125 levels lower than the population mean value were also positively correlated to PFS (both p<.05).
Plotti et al studied 69 patients with high-grade serous ovarian cancer to determine whether HE4 (cutoff, 70 pmol/L) could predict response to platinum chemotherapy (Plotti, 2021). All patients had undergone debulking surgery prior to receiving chemotherapy. Breast cancer resistance gene (BRCA) status was assessed (n=53 wild-type, n=16 mutated) along with HE4 during every chemotherapy cycle. Recurrence occurred within 12 months in 48% of patients and after 12 months in 52% of patients. HE4 had a sensitivity of 79% and specificity of 97% for predicting response to platinum chemotherapy. Among patients who were BRCA wild-type, HE4 had a sensitivity and specificity of 80% and 100%, respectively, for predicting chemotherapy response. Among patients with BRCA mutations, HE4 had a sensitivity and specificity of 100% and 100%, respectively, for predicting chemotherapy response.
Rong et al conducted a retrospective study that assessed the prognostic value of HE4 and CA 125 in 89 patients with EOC (Rong, 2021). All patients received 6 to 8 cycles of platinum-based chemotherapy after surgery. HE4 (cutoff, 70 pmol/L) and CA 125 (cutoff, 35 U/mL) were measured before treatment, after each cycle, and at the time of recurrence. After a median follow-up of 35 months, 73 patients were platinum-sensitive, and 16 patients were platinum-resistant. The sensitivity and specificity of HE4 in predicting platinum responsiveness after the third chemotherapy cycle were 75% and 80.8%, respectively. HE4 had a positive predictive value of 54.5% and negative predictive value of 93.7%. The sensitivity, specificity, and positive and negative predictive values of CA 125 after the first chemotherapy cycle were 75%, 71.2%, 36.4%, and 92.9%, respectively. The combination of both biomarkers had a sensitivity and specificity for predicting platinum responsiveness of 50% and 94.5%, respectively, with a positive predictive value of 66.7% and negative predictive value of 89.6%. HE4 predicted 2-year PFS after the third and sixth chemotherapy cycles (p=.001 and p=.011, respectively). CA 125 predicted 2-year PFS only after the first chemotherapy cycle (p=.023). Prolonged PFS and OS were significantly associated with HE4 after the third cycle (p<.0001) and CA 125 after the first cycle (p<.0001).
Han et al published a systematic review and meta-analysis on the value of HE4 in predicting chemotherapy resistance in patients with ovarian cancer (Han, 2021). An analysis of 8 studies (I2=74%) found that preoperative HE4 had a sensitivity of 80% (95% CI, 65% to 90%) and specificity of 67% (95% CI, 54% to 77%) in predicting resistance to platinum chemotherapy. After the third cycle of chemotherapy (5 studies; I2=49%), the sensitivity and specificity were 86% (95% CI, 72% to 94%) and 85% (95% CI, 70% to 93%), respectively.
A number of meta-analyses have assessed studies on the accuracy of HE4 for diagnosing ovarian cancer. Olsen et al conducted a meta-analysis of 7 studies (Olsen, 2021). The pooled sensitivity was 79.4 (74.1 to 83.8) and the pooled specificity was 84.1 (79.6 to 87.8). Suri et al conducted a meta-analysis of 25 studies (Suri, 2021). The pooled sensitivity was 73 (71 to 75) and the pooled specificity was 90 (89 to 91).
These studies also pooled data from studies on the diagnostic accuracy of CA 125 alone and/or in combination with HE4. Olsen et al looked at 8 studies with a pooled sensitivity of 81.4 (74.6 to 86.2) and pooled specificity of 56.8 (47.9 to 65.4) (Olsen, 2021). Suri et al looked at 26 studies with a pooled sensitivity of 84 (82 to 85) and pooled specificity of 73 (72 to 74) (Suri, 2021).
In 2017 (reaffirmed 2019), a committee opinion document from ACOG and the Society of Gynecologic Oncology stated that tumor markers such as CA 125 and transvaginal ultrasound, alone or in combination, have not improved early detection or survival in women with average risk for ovarian cancer (Committee Opinion, 2017). There is also a potential for harm if surgery is performed in response to a positive test result.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Samborski et al retrospectively examined the utility of HE4 in comparison to CA 125 in women undergoing surveillance after treatment for EOC between January 1997 to October 2010 (Samborski, 2022). A total of 129 women with a diagnosis of EOC were identified and included in the analysis, of which 11 women had stage I disease (8.5%), 12 had stage II disease (9.3%), 94 had stage III disease (72.9%), and 12 had stage IV (9.3%) disease. At a threshold of 25% change in serum biomarker level indicating progressive disease, HE4 had an overall accuracy for change in disease status of 81.8% (95% CI, 79.7% to 83.7%) with a specificity of 90.5% (95% CI, 88.7% to 92.1%), sensitivity of 45.2% (95% CI, 39.2% to 51.2%), PPV of 53.2% (95% CI, 46.6% to 59.7%) and a NPV of 87.4% (95% CI, 85.4% to 89.2%). The concordance comparison of HE4 accuracy (81.8%)/CA 125 accuracy (82.6%) was 0.990, indicating HE4 was not inferior to CA 125 (McNemar’s test p-value=.522).
Carreras-Dieguez retrospectively evaluated the performance of several serum biomarkers, including CA 125 and HE4, to preoperatively identify EOC or metastatic ovarian cancer in women with a diagnosis of an adnexal mass based on pelvic imaging (N=1071) (Carreras-Dieguez, 2022). In this study, the AUC for HE4 was higher than for CA 125 (0.91 vs. 0.87). Subgroup analysis showed that in premenopausal women (n=629), HE4 performed better than CA 125 (AUC, 0.86 vs 0.76, respectively; p<.05). Conversely, in postmenopausal women (n=442), HE4 and CA 125 AUCs did not significantly differ (0.91 and 0.93, respectively). In a subgroup of patients with inconclusive diagnosis (n=348), the AUC for HE4 and CA 125 was 0.84 and 0.810, respectively. Lastly, in a subgroup of patients with stage 1 EOC (n=58), the AUC for HE4 and CA 125 was 0.86 and 0.81, respectively.
Lof et al evaluated the role of HE4 in discriminating benign from malignant tumors in patients who presented with a pelvic mass on ultrasound that was suspected of ovarian origin (Lof, 2022). A total of 316 patients were included, of which 195 had a benign, 39 had a borderline and 82 had a malignant ovarian mass. HE4 performed better when age-based cut-offs were applied (sensitivity, 65%; specificity, 79%) instead of one cut-off at 70 pmol/L (sensitivity, 68%; specificity, 65%) or 150 pmol/L (sensitivity, 38%; specificity, 96%). CA 125 performed slightly better when menopausal-based cut-offs were applied (sensitivity, 72%; specificity, 53%) compared with one cut-off at 35 kU/L (sensitivity, 71%; specificity, 50%).
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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