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Serum Biomarker Human Epididymis Protein 4 (HE4)

Policy Number: MP-445

Latest Review Date: January 2019

Category: Laboratory                                                 

Policy Grade: B

                                                                                                                                                                       

Description of Procedure or Service:

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 carbohydrate antigen 125 (CA-125) for monitoring disease progression and recurrence. HE4 has also been proposed as a test to evaluate women with ovarian masses and to screen for ovarian cancer in asymptomatic women.

Ovarian Cancer

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 2013, an estimated 22,440 women will be diagnosed with ovarian cancer and 14,080 women will die of the disease. Stage at diagnosis is an important predictor of survival; however, most women are not diagnosed until the disease has spread. According to Surveillance Epidemiology and End Results (SEER) data, for the period 1999-2006, 62% of women with ovarian cancer were diagnosed when the disease had distant metastases (Stage IV) and this was associated with a 28.9% five-year survival rate. In contrast, the 14.8% of women diagnosed with localized cancer (Stage 1) had a 92.5% five-year survival rate. Epithelial ovarian tumors account for 85 to 90% of ovarian cancers.

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 after or during primary treatment. Patients undergo regular physical examinations and may have imaging studies. In addition, managing patients with serial measurement of the biomarker carbohydrate antigen 125 (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.

Human epididymis protein 4 (HE4) is a protein that circulates in the serum and has been found to be overexpressed in epithelial ovarian cancer (EOC), lung adenocarcinoma, breast cancer, pancreatic cancer, endometrial cancer, and bladder cancer. HE4 is made up of two whey acidic proteins with a four disulfide core domain and has been proposed as a biomarker for monitoring patients with epithelial ovarian cancer.

Evaulation of Adexal Masses

The evidence review also addresses use of the HE4 as a stand-alone test for evaluating women with ovarian masses who have not been diagnosed with ovarian cancer. Such patients undergo a diagnostic workup to determine whether the risk of malignancy is sufficiently high to warrant surgical removal. In patients in whom surgery is indicated, further evaluation may be warranted to determine if surgical referral to a specialist with expertise in ovarian cancer is warranted. The Risk of Ovarian Malignancy Algorithm (ROMA) combines HE4, CA-125 and menopausal status into a numeric score. ROMA has been cleared by FDA for predicting risk that an adnexal mass is malignant; this test is considered separately in policy #426, Proteomics-based Testing for the Evaluation of Ovarian (Adnexal) Masses.

Policy:

Measurement of human epididymis protein 4 (HE4) for any and all indications is considered not medically necessary and  investigational.

Key Points:

This policy was updated with a search of the literature through October 30, 2018. A review of the key literature is summarized below.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. The following is a summary of the key literature.

Biomarker Human Epididymis Protein 4 Testing for Ovarian Cancer

Clinical Context and Test Purpose

The purpose of testing serum biomarker human epididymis protein 4 levels is to provide an alternative to or an improvement on existing testing in patients with ovarian cancer.

The question addressed in this evidence review is: Does the use of testing with HE4 to monitor patient with ovarian cancer result in an improvement in net health outcomes.

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with epithelial ovarian cancer and who have had primary treatment.

Interventions

The test being considered is testing serum biomarker human epididymis protein 4 levels for surveillance of progression (response to primary treatment) or recurrence.

Comparators

Comparators of interest include measurement of cancer antigen 125 test and measurement of combination cancer antigen 125 plus human epididymis protein 4 for surveillance of progression or recurrence. Typically, patients undergoing primary chemotherapy after cytoreductive surgery will also have monitoring for response with CT scan. After the completion of primary treatment patients may have other monitoring imaging studies such as positron emission tomography (PET).

Outcomes

The general outcomes of interest are overall survival, disease-specific survival, test accuracy, test validity, and change in disease status.

Timing

The timing of follow-up after testing HE4 serum levels in patient with ovarian cancer is based on stage of disease, type of prior therapy and guideline recommendations.

Setting

Patients with ovarian cancer are managed by oncologists in an outpatient clinical setting.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Study Selection Criteria

For the evaluation of clinical validity of the tests, studies that meet the following eligibility criteria were considered:

  • Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
  • Included a suitable reference standard
  • Patient/sample clinical characteristics were described
  • Patient/sample selection criteria were described
  • Included a validation cohort separate from development cohort.

FDA documents included information on the diagnostic performance of HE4 for monitoring the progression and recurrence of ovarian cancer. FDA materials addressed the noninferiority rather than the superiority of HE4 tests to CA-125. A study reported in the 510(k) substantial equivalence determination decision summary for the HE4 EIA assay evaluated whether this test was noninferior 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 (AUC) 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 that were being monitored after completion of chemotherapy.  The eligibility criteria included availability of at least three 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 previous 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 noted 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 included in the HE4 EIA assay materials defined a positive test as a level that is 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 decide whether to use the cut-offs in the studies or another cut-off that reflects their own preferences in the tradeoff between sensitivity and specificity.

Nonrandomized Observational Studies

Published observational studies on the diagnostic performance of HE4 for monitoring progression and/or recurrence of epithelial cancer are described next.

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 (OVCAD study). In 221 of 275 patients (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 cut-off value of 235 pM, the sensitivity was 76.6% and specificity was 47.4%. When the cut-off 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 0.64, nearly the same as for HE4. At a cut-off 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 cut-offs for HE4 (235 pM) and CA-125 (500 IU/mL), the combined combination of the two markers had sensitivity of 64.8% and specificity of 73.5%. An additional analysis of these data was published by Nassir et al in 2015. A total of 92 of 275 patients (33%), who had preoperative and follow-up plasma samples for analyzing HE4 and CA-125, were included in the analysis. (However, 13 preoperative HE4 samples and ten postoperative CA-125 samples were missing.) Both preoperative HE4 and CA-125 values significantly predicted 12-month recurrence or death. Among responders, median overall survival (OS) was worse among patients for whom both biomarkers were elevated (hazard ratio, 17.96; 95% CI, 4.00 to 80.85; p<0.001) compared with patients for whom no biomarker was elevated. The confidence interval for the OS analysis was wide, indicating an imprecise estimate. There was no significant association with median OS when only one biomarker was elevated; the sample size may have been inadequate for this analysis.

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. 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 an analysis of HE4 and CA-125 levels from samples taken 3 months after the end of 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 three and six months were significantly associated with poorer PFS. However, on multivariate analysis, HE4 was a significant predictor of PFS at six months but not at three months, and CA-125 was nonsignificant at both three and six 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.

Vallius et al (2017). 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. 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. Tables 1-4 summarize findings for this study.

Table 1. Summary of Observational Study Characteristics

Study

Study Type

Country

Dates

Participants N

Treatment1 N

Treatment2 N

Vallius (2017)NCT01276574

Observational cohort

Finland

2009-2014

FIGO Stage III-IV EOC49

PDS + platinum based chemotherapy22

NACT + IDS27

EOC: epithelial ovarian cancer; FIGO: Federation of International Gynecology and Obstetrics; IDS: interval debulking surgery; NACT: neoadjuvant chemotherapy; NCT: National Clinical Trial; PDS: primary debulking surgery

Table 2. Summary of Observational Study Results

Study

Treatment1

Treatment2

Vallius (2017)NCT01276574

Median (range)

Median (range)

HE4 (pmol/L) At diagnosis Pre-IDS Postoperative Nadir Post-primary therapyCA125 (U/mL) At diagnosis Pre-IDS Postoperative NadirPost-primary therapy

573 (59–1391)96 (34–856)48 (25–204)48 (25–431)1094 (17–17,992)181 (32–2023)12 (4–162)12 (4–127)

1070 (156–12128)104 (35–477)99 (39–384)69 (31–257)61 (31–175)1078 (156–20,897)43 (7–464)42 (6–589)15 (4–447)15 (4–37)

CA 125: cancer antigen 125; HE4: human epididymis protein 4; IDS: interval debulking surgery; NACT: neoadjuvant chemotherapy; PDS: primary debulking surgery; (pmol/L): picomole per liter; Treatment 1: PDS + platinum based chemotherapy; Treatment2: NACT +IDS; (U/mL): units per milliliter

Relevance and relevance design and conduct gaps are reported in Tables 3 and 4.

Table 3. Relevance Gaps

Study

Populationa

Interventionb

Comparatorc

Outcomesd

Duration of Follow-Upe

Vallius et al (2017)

3. Study population is mixed regarding risk factors

2. clinical context for primary debulking surgery +chemotherapy differs from neoadjuvant chemotherapy + interval debulking surgery

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.

b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.

c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.

d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.

e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 4. Study Design and Conduct Gaps

Study

Selectiona

Blindingb

Delivery of Testc

Selective Reportingd

Completeness of Follow-Upe

Statisticalf

Vallius et al (2017)

2. Broad date range for obtaining samples

2. Assessment of residual disease solely on based on surgeon evaluation

Not uniformly reported

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.

b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.

c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.

d Follow-Up key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).

e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.

f Statistical key: 1. Intervention is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Intervention is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Clinically Useful

The available observational studies have used HE4 alone or in combination with CA 125 to predict residual tumor mass and association with recurrence after primary chemotherapy. In addition, HE4 alone or in combination with CA 125 has been assessed for its association with residual disease and tumor progression during the course of primary chemotherapy after tumor debulking as well during neoadjuvant chemotherapy followed by interval debulking surgery. Improvement in health outcomes would depend on demonstrating that further assessment and management decisions or patients with ovarian cancer were initiated that would improve health outcomes. There is no clear chain of evidence demonstrating that incremental changes in ovarian cancer recurrence detection would lead to improved health outcomes. No prospective studies were identified that compared health outcomes in patients who had ovarian cancer managed with and without HE4 testing, alone or in combination with CA 125 or other disease markers.

Section Summary: Individuals with Ovarian Cancer 

Several studies, including those submitted to FDA, have addressed HE4 for monitoring ovarian cancer progression and recurrence. There is insufficient evidence that the diagnostic accuracy of HE4, alone or in combination with CA-125, is superior to CA-125 alone. Moreover, there is a lack of clarity about the cutoff of HE4 to use for disease progression/recurrence. No direct evidence from prospective studies was identified that compared health outcomes in patients who had ovarian cancer managed with and without HE4 testing, alone or in combination with CA 125 or other disease markers. In addition, there is no clear chain of evidence that shows changes in management based on HE4 testing would improve health outcomes.

Biomarker Human Epididymis Protein 4 Testing for Adnexal Masses

Clinical Context and Test Purpose

The purpose of testing serum biomarker human epididymis protein 4 levels is to provide a diagnostic option that is an alternative to or an improvement on existing testing in patients with adnexal masses.

The question addressed in this evidence review is: does testing with serum HE4 levels as adjunctive testing for diagnosing patients with adnexal masses improve net health outcomes?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with adnexal masses.

Interventions

The test being considered is testing serum biomarker human epididymis protein 4 levels.

Comparators

Comparators of interest include measurement of cancer antigen 125 test and measurement of combination cancer antigen 125 plus human epididymis protein 4.

Outcomes

The general outcomes of interest are overall survival, disease-specific survival, test validity, and other test performance measures.

Timing

The timing of follow-up after testing for serum HE4 for the evaluation of an adnexal mass would be determined by whether or not the patient has surgical management. Typical clinical follow-up in the absence of a pathological diagnosis would be every six months.

Setting

Patients with adnexal masses are managed by oncologists in an outpatient clinical setting.

Study Selection Criteria

For the evaluation of clinical validity of HE4 testing, methodologically credible studies were selected using the following principles:

  • Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
  • Included a suitable reference standard
  • Patient/sample clinical characteristics were described
  • Patient/sample selection criteria were described
  • Included a validation cohort separate from development cohort.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid

Because CA 125 is the marker most often recommended for evaluation of adnexal masses, this evidence review addresses whether the diagnostic performance of HE4 is superior to CA 125 and whether combined HE4 and CA 125 is superior to CA 125 alone.

Systematic Reviews and Meta-Analyses

A number of meta-analyses have assessed studies on the accuracy of HE4 for diagnosing ovarian cancer. Table 5 presents the pooled sensitivities and specificities of HE4 from meta-analyses that conducted quality assessments of individual studies and that limited their selections to studies using pathologic findings as the reference standard for ovarian cancer diagnosis.

Table 5. Meta-Analyses of Studies on HE4 for Diagnosing Ovarian Cancer

Meta-Analyses (Year)

No. of Studies

Pooled Sensitivity (95% CI), %

Pooled Specificity (95% CI), %

Dayyani et al (2016)

5

82 (68 to 90)

85 (72 to 93)

Maceda et al (2014)

45

78 (77 to 79)

86 (85 to 87)

Wang et al (2014)

28

76 (72 to 80)

93 (90 to 96)

Zhen et al (2014)

25

74 (72 to 76)

90 (89 to 91)

Yang et al (2013)

31

73 (71 to 75)

89 (88 to 90)

Ferraro et al (2013)

14

79 (76 to 81)

93 (92 to 94)

Yu et al (2012)

12

80 (77 to 83)

92 (90 to 93)

CI: confidence interval; HE4: human epididymis protein 4.

Meta-analyses differed somewhat in their study inclusion criteria, search dates and other factors but, as shown in Table 5, had similar results in terms of diagnostic value of HE4; pooled sensitivities ranged from 0.73 to 0.82, and pooled specificities ranged from 0.85 to 0.93.

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 6.

Table 6. Meta-Analyses of Studies on CA-125 and the Combination of HE4 and CA-125 for Diagnosing Ovarian Cancer

Meta-Analyses (Year)

No. of Studies

Pooled Sensitivity (95% CI), %

Pooled Specificity (95% CI), %

CA 125 alone

Dayyani et al (2016)

5

80 (66 to 89)

83 (66 to 92)

Wang et al (2014)

28

79 (74 to 84)

82 (77 to 87)

Zhen et al (2014)

25

74 (72 to 76)

83 (81 to 84)

Ferraro et al (2013)

13

79 (77 to 82)

78 (76 to 80)

Yu et al (2012)

10

66 (62 to 70)

87 (85 to 89)

HE4 and CA 125

Zhen et al (2014)

9

90 (87 to 92)

85 (82 to 87)

Ferraro et al (2013)

4

82 (78 to 86)

76 (72 to 80)

CA 125: cancer antigen 125; CI: confidence interval; HE4: human epididymis protein 4.

All of the meta-analyses included in Table 6, with the exception of Dayyani et al (2016), reported statistical comparisons between the diagnostic performance of HE4 and CA125. None of these found that the performance (combination of sensitivity and specificity) of HE4 and CA-125 differed significantly. However, both Wang et al and Zhen et al found that the specificity (but not sensitivity) of HE4 was significantly higher than CA-125.

Findings differed in the two meta-analyses comparing the diagnostic performance of HE4 and CA-125 versus CA-125 alone. Ferrero et al did not find that the sensitivity and specificity of HE4 in combination with CA-125 differed significantly from that of CA-125 alone. Zhen et al found that both the sensitivity and specificity of HE4 combined with CA-125 were significantly better than CA-125 alone. In the subgroup of nine studies that directly made this comparison in the Zhen et al 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 et al 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 et al 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.

Nonrandomized Observational Studies

Several studies have 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 (2014) enrolled 389 patients with a suspicious pelvic mass who were scheduled for surgery. 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 cut-off 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 (2013) retrospectively reviewed records on 253 women with adnexal masses. 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 cut-off 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.

Nikolova et al (2017) conducted a study to measure the effectiveness of HE4 compared with CA125 for differentiating ovarian endometriosis from EOC in premenopausal women. In the observational study, 164 patients were divided into three study groups-ovarian endometriosis (n=37), other benign pelvic masses (n=57), and EOCs (n=11)-and a control group (n=59). Analysis of biomarkers in blood samples from all four groups determined that HE4 performed the best at differentiating endometriosis from EOC (specificity=100%, accuracy=95.83%), while CPH-I also performed well (specificity=97.30%, accuracy=93.75%). CA125 was found to have significantly lower specificity and accuracy. Limitations of the study include the relatively small cohort.

Table 7. Characteristics of Diagnostic Studies Evaluating HE4 as a Test for Ovarian Cancer

Study

Country

Participants

Evaluated Tests

Kaijser et al (2014)

EU

Women with adnexal masses scheduled for surgery (n=289)

HE4

Moszynski et al (2013)

EU

Women with adnexal masses (n=253)

HE4, CA 125, individually

Teh et al (2018)

Malaysia

Women with adnexal masses scheduled for surgery or biopsy (n=129)

HE4, CA 125, ROMA

Nikolova et al (2017)

Macedonia, Serbia

Women with ovarian endometriosis, benign pelvic masses, EOCs (n=164)

HE4, CA 125, individually

CA 125: cancer antigen 125; EOC: epithelial ovarian cancer; HE4: human epididymis protein 4; ROMA: Risk of Ovarian Malignancy Algorithm

Table 8. Clinical Validity of HE4 as a Test for Ovarian Cancer

Study

Initial N

Final N

Excluded Samples

Prevalence of Condition

Clinical Validity (95% Confidence Interval)

Sensitivity

Specificity

PPV

NPV

Kaijser (2014)

389

360

29

40%

HE4

74%

85%

SA

97%

90%

Moszynski (2013)

253

41.4%

HE4

80.0%

91.7%

87.3%

86.7%

SA

93.3%

90.6%

87.5%

95.1%

ROMA

88.9% (p=1.0)

89.2% (p<0.001)

68.6%

96.8%

Nikolova (2017)

164

CA125

81.8% (48.2-97.7)

48.7% (31.9-65.6)

32.1% (15.9-52.4)

90.0% (68.3-98.8)

HE4

81.8% (48.2-97.7)

100% (90.5-100)

100% (66.4-100)

94.87% (82.7-99.4)

ROMA

90.9% (58.7-99.8)

83.8% (68-93.8)

62.5% (35.4-84.8)

96.9% (83.8-99.9)

NPV: negative predictive value; PPV: positive predictive value; SA: subjective assessment.

Relevance and relevance design and conduct gaps are reported in Tables 9 and 10.

Table 9. Relevance Gaps

Study

Population

Intervention

Comparator

Outcomes

Duration of Follow-Up

Kaijser et al (2014)

3. 7% of data unavailable from population

Moszynski et al (2013)

Nikolova et al (2017)

Key

1. Intended use population unclear

2. Clinical context for test is unclear

3. Study population unclear

4. Study population not representative of intended clinical use

5. Study population is subpopulation of intended use

1. Classification thresholds not defined

2. Version used unclear

3. Not version currently in clinical use

1. Classification thresholds not defined

2. Not compared to credible reference standard

3. Not compared to other tests in use for same purpose

1. Study does not directly assess a key health outcome

2. Evidence chain or decision model not explicated

3. Key clinical validity outcomes not reported (sensitivity, specificity, predictive values)

4. Reclassification of diagnostic or risk categories not reported

5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests)

1. Follow-up duration not sufficient with respect to natural history of disease (TP, TN, FP, FN cannot be determined)

Table 10. Relevance Design and Conduct Gaps

Study

Selectiona

Blindingb

Delivery of Testc

Selective Reportingd

Completeness of Follow-Upe

Statisticalf

Kaijser et al (2014)

2. Selection retrospective and not randomized

1. Results were not blinded

1. P-values/ CI not reported

Moszynski et al (2013)

2. Selection retrospective and not randomized

1. Results were not blinded

1. P-values/ CI not reported

The et al (2018)

2. Selection not randomized

1. Results were not blinded

Nikolova et al (2017)

2. Selection not randomized; small corhort

1. Results were not blinded

1. P-values reported

Key

1. Selection not described

2. Selection not random nor consecutive (i.e., convenience)

1. Not blinded to results of reference or other comparator tests

1. Timing of delivery of index or reference test not described

2. Timing of index and comparator tests not same

3. Procedure for interpreting tests not described

4. Expertise of evaluators not described

1. Not registered

2. Evidence of selective reporting

3. Evidence of selective publication

1. Inadequate description of indeterminate and missing samples

2. High number of samples excluded

3. High loss to follow-up or missing data

1. Confidence intervals and/or p values not reported

2. No statistical test reported to compare to alternatives

Clinically Useful

Although HE4 levels are associated with presence of ovarian cancer, the test does not have high sensitivity or specificity. Thus it cannot be used to rule in or rule out ovarian cancer before surgery. There is not a strong chain of indirect evidence demonstrating that clinical decisions based on HE4 testing would improve patient outcomes. No prospective studies were identified that compared health outcomes in patients with adnexal masses managed with and without HE4 testing, alone or in combination with CA-125 or other disease markers. There is no strong chain of evidence demonstrating that clinical decisions based on HE4 testing would improve patient outcomes.

Section Summary: Individuals with Adnexal Masses

Multiple studies evaluating the diagnostic accuracy of HE4 for evaluating adnexal masses have been published and there are several 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 two of the meta-analyses found that HE4 had higher specificity than CA-125. Findings differed in the two meta-analyses that compared diagnostic accuracy of HE4 in combination with CA-125 versus CA-125 alone. One of the two 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. The indirect chain of evidence supporting use of HE4 testing is weak. There is not a strong chain of indirect evidence demonstrating that clinical decisions based on HE4 testing would improve patient outcomes. Moreover, no direct evidence from prospective studies were identified that compared health outcomes in patients with adnexal masses managed with and without HE4 testing, alone or in combination with CA-125 or other disease markers.

Biomarker Human Epididymis Protein 4 Screening for Asymtomatic Individuals Not at High Risk of Ovarian Cancer

Clinical Context and Test Purpose

The purpose of screening with a serum biomarker human epididymis protein 4 levels is to provide a diagnostic option that is an alternative to or an improvement on existing testing in patients who are asymptomatic and not at high risk of ovarian cancer.

The question addressed in this evidence review is: does screening with serum HE4 levels in asymptomatic individuals not a high risk of ovarian cancer improve net health outcomes?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are asymptomatic individuals not at high risk of ovarian cancer.

Interventions

The test being considered is screening with a serum biomarker human epididymis protein 4 levels.

Comparators

Comparators of interest include no ovarian cancer screening.

Outcomes

The general outcomes of interest are overall survival, disease-specific survival, test accuracy, test validity, and other test performance measures.

Timing

Though not completely standardized, follow-up for patients who are asymptomatic and not at high risk of ovarian cancer would typically occur in the years before diagnosis.

Setting

Patients who are asymptomatic and not at high risk of ovarian cancer are managed by primary care providers in an outpatient clinical setting.

Study Selection Criteria

For the evaluation of clinical validity of the tests, studies that meet the following eligibility criteria were considered:

  • Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
  • Included a suitable reference standard
  • Patient/sample clinical characteristics were described
  • Patient/sample selection criteria were described
  • Included a validation cohort separate from development cohort.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid

No published studies were identified that evaluated the diagnostic performance of the HE4 biomarker for screening asymptomatic women for ovarian cancer compared to a reference standard. In addition, no studies prospectively compared health outcomes in asymptomatic women managed with and without HE4 screening.

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 (RCT) with smokers at increased risk of lung cancer. Blood samples were available for the women between zero 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 three 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. 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 six 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 fourth screen so they were taken from the third year for the women diagnosed with ovarian cancer between the third and fourth screens.) The investigators evaluated the associations between CA-125, HE4, and levels of five 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).

In 2016, Terry et al retrospectively analyzed prospectively collected data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a multicenter cohort study investigating the relationship between diet and cancer. The analysis used a nested case-control design. A total of 197 women who developed invasive ovarian cancer were matched with 725 randomly selected ovarian-cancer free controls. Baseline and follow-up blood samples were analyzed for levels of several biomarkers (i.e., CA-125, HD4, CA15.3, CA72.4) and the sensitivity, specificity, and AUC ROC were calculated. CA-125 was best able to discriminate between cases and controls within six months of ovarian cancer diagnosis (C statistic=0.92), followed by HE4 (C statistic=0.84). The ability of the markers to discriminate between cases and controls decreased with longer intervals between blood draws and cancer diagnosis. For example, with a one to two year time lag, the C statistic values were 0.72 for CA-125 and 0.65 for HE4 and for a three to six year time lag, the C statistic value was 0.55 for CA-125. (Data on HE4 were not available for the three to six year time-lag analysis).

Clinically Useful

No RCTs or nonrandomized comparative studies evaluating the clinical utility of screening asymptomatic women with HE4 were identified. The studies have not estimated sensitivity and specificity of HE4 in the screening setting and thus the indirect chain of evidence supporting screening is incomplete.

Section Summary:  Screening Asymptomatic Individuals Not at High Risk of Ovarian Cancer

There is insufficient evidence from prospective or controlled studies that HE4 is an effective screening tool for identifying ovarian cancer in asymptomatic women. 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 RCT’s that evaluate the impact of screening on health outcomes.

Summary of Evidence

For individuals who have ovarian cancer who receive measurement of serum biomarker human epididymis protein 4, the evidence includes a prospective study and several retrospective studies comparing the diagnostic accuracy of HE4 and CA-125 for predicting disease progression and/or recurrence. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, other test performance measures, and change in disease status. Data submitted to the U.S. Food and Drug Administration for approval of commercial HE4 tests found that HE4 was not inferior to CA-125 for detecting ovarian cancer recurrence. However, the superiority of HE4 to CA-125 (alone or in combination), the key question in the evidence review, was not demonstrated in the available literature. In addition, there is no established cutoff in HE4 levels for monitoring disease progression, and cutoffs in studies varied. There is not a clear chain of indirect evidence that changes in management based on HE4 would lead to improved health outcome and no direct evidence from prospective controlled studies on the impact of HE4 testing on health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have adnexal masses who receive measurement of serum biomarker human epididymis protein 4, the evidence includes diagnostic accuracy studies and meta-analyses. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and other test performance measures. Meta-analyses have generally found that HE4 and CA-125 have similar overall diagnostic accuracy (i.e., sensitivity, 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. In addition, studies have not found that HE4 improves diagnostic accuracy beyond that of subjective assessment of transvaginal ultrasound. There is not a clear chain of indirect evidence that changes in management based on HE4 would lead to improved health outcome and no direct evidence from prospective controlled studies on the impact of HE4 testing on health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who are asymptomatic and not at high risk of ovarian cancer who receive screening with serum biomarker HE4, the evidence includes several retrospective comparative studies and no prospective studies comparing health outcomes in asymptomatic women managed with and without HE4 screening. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and other test performance measures. The retrospective studies found that levels of HE4 increased over time in women ultimately diagnosed with ovarian cancer. Prospective comparative studies are needed to definitively determine whether HE4 is a useful screening tool. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) ovarian cancer guidelines (v.2.2018) 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”. The guideline does not specify any marker other than CA-125 for monitoring patients after treatment.

The NCCN guideline states the following on evaluating undiagnosed pelvic masses:

“The FDA has approved the use of HE4 and CA-125 for estimating the risk for 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.”

The NCCN guideline states the following on screening for ovarian cancer:

“The literature does not 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.”

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence (NICE) issued guidance in 2011 on the recognition and initial management of ovarian cancer. The guideline includes the following recommendations:

  • Measure serum CA125 in primary care in women with symptoms that suggest ovarian cancer.
  • If serum CA125 is 35 IU/ml or greater, arrange an ultrasound scan of the abdomen and pelvis.
  • If the ultrasound suggests ovarian cancer, refer the woman urgently for further investigation.
  • For any woman who has normal serum CA125 (less than 35 IU/ml), or CA125 of 35 IU/ml or greater but a normal ultrasound:
    • assess her carefully for other clinical causes of her symptoms and investigate if appropriate
    • If no other clinical cause is apparent, advise to return to her GP if her symptoms become more frequent and/or persistent.

Malignancy indices

  • Calculate a risk of malignancy index I (RMI I) score (after performing an ultrasound). (The RMI 1 combines CA-125, menopausal status and the ultrasound score).

The NICE guidance does not mention HE4.

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force (USPSTF) updated recommendations for screening for ovarian cancer in February 2018.  USPSTF recommended against screening for ovarian cancer in asymptomatic women (D recommendation).  HE4 was not specifically discussed.

Key Words:

Human epididymis protein 4, HE4, HE4 EIA test, ARCHITECT HE4

Approved by Governing Bodies:

Multiple HE4 test kits have been cleared by the Food and Drug Administration through the 510(k) process and summarized in Table 11. 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-approved 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.

Table 11. Serum HE4 Tests Cleared by FDA

Test

Manufacturer

Location

Date Cleared

510(k) No.

HE4 EIA Kit

Fujirebio Diagnostics

Malvern, PA

06/09/2008

K072939

ARCHITECT HE4 assay (CMIA)

Fujirebio Diagnostics

Malvern, PA

03/18/2010

K093957

ELECSYS HE4 (CMIA)

Roche Diagnostics

Indianapolis, IN

09/10/2012

K112624

Lumipulse G HE4 Immunoreaction Cartridges

Fujirebio Diagnostics

Malvern, PA

11/24/2015

K151378

CMIA: chemoluminescent microparticle immunoassay; HE4: human epididymis protein 4; EIA: enzymatic immunoassay; FDA: Food and Drug Administration.

FDA product code: OIU.

Benefit Application:

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

ITS: Home Policy provisions apply

FEP:  Special benefit consideration may apply.  Defer to member’s benefit plan.  FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

Current Coding: 

CPT Codes:

86305 Human epididymis protein 4 (HE4)

 

References:

  1. Anderson GL, McIntosh M, Wu L et al. Assessing lead time of selected ovarian cancer biomarkers: a nested case-control study. J Natl Cancer Inst 2010; 102(1):26-38.
  2. Braicu EI, Fotopoulou C, Van Gorp T et al. Preoperative HE4 expression in plasma predicts surgical outcome in primary ovarian cancer patients: results from the OVCAD study. Gynecol Oncol 2013; 128(2):245-51.
  3. Dayyani F, Uhlig S, Colson B, et al. Diagnostic performance of risk of ovarian malignancy algorithm against CA125 and HE4 in connection with ovarian cancer: a meta-analysis. Int J Gynecol Cancer. Nov 2016; 26(9):1586-1593.
  4. FDA. 510(k) substantial equivalence determination decision summary: assay only (K072939). Available on-line at www.accessdata.fda.gov/cdrh_docs/reviews/K072939.pdf. Last accessed January 2014.
  5. FDA. 510(k) substantial equivalence determination decision summary: assay only (K093957). Available on-line at www.accessdata.fda.gov/cdrh_docs/reviews/K093957.pdf.
  6. Ferraro S, Braga F, Lanzoni M et al. Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review. J Clin Pathol 2013; 66(4):273-81.
  7. Kaijser J, Van Gorp T, Smet ME et al. Are serum HE4 or ROMA scores useful to experienced examiners for improving characterization of adnexal masses after transvaginal ultrasonography? Ultrasound Obstet Gynecol 2013.
  8. Macedo AC, da Rosa MI, Lumertz S, et al. Accuracy of serum human epididymis protein 4 in ovarian cancer diagnosis: a systematic review and meta-analysis. Int J Gynecol Cancer. Sep 2014; 24(7):1222-1231.
  9. Moszynski R, Szubert S, Szpurek D et al. Usefulness of the HE4 biomarker as a second-line test in the assessment of suspicious ovarian tumors. Arch Gynecol Obstet 2013; 288(6):1377-83.
  10. Nassir M, Guan J, Luketina H, et al. The role of HE4 for prediction of recurrence in epithelial ovarian cancer patients-results from the OVCAD study. Tumour Biol. Sep 29 2015.
  11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer Version 1.2016.  Available online at: www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed November, 2016.
  12. National Institute for Health and Clinical Excellence. NICE clinical guideline 122: The recognition and initial management of ovarian cancer. 2011. Available online at: www.nice.org.uk/nicemedia/live/13464/54194/54194.pdf.
  13. Nikolova T, Zivadinovic R, Evtimovska N, et al. Diagnostic performance of human epididymis protein 4 compared to a combination of biophysical and biochemical markers to differentiate ovarian endometriosis from epithelial ovarian cancer in premenopausal women. J Obstet Gynaecol Res. Dec 2017;43(12):1870-1879.
  14. Plotti F, Capriglione S, Terranova C et al. Does HE4 have a role as biomarker in the recurrence of ovarian cancer? Tumour Biol 2012; 33(6):2117-23.
  15. Rustin GJ, van der Burg ME, Griffin CL et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet 2010; 376(9747):1155-63.
  16. SEER. SEER Stat Fact Sheets: Ovary. Available online at: seer.cancer.gov/statfacts/html/ovary.html.
  17. Steffensen KD, Waldstrom M, Brandslund I, et al. Identification of high-risk patients by human epididymis protein 4 levels during follow-up of ovarian cancer. Oncol Lett. Jun 2016; 11(6):3967-3974.
  18. Surveillance Epidemiology and End Results Program (SEER). SEER Stat Fact: Ovarian Cancer. n.d.; seer.cancer.gov/statfacts/html/ovary.html. Accessed November 8, 2017.
  19. Terry KL, Schock H, Fortner RT, et al. A prospective evaluation of early detection biomarkers for ovarian cancer in the European EPIC cohort. Clin Cancer Res. Sep 15 2016; 22(18):4664-4675.
  20. U.S. Preventive Services Task Force. Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement. 2012. Available online at: www.guideline.gov.
  21. Urban N, Thorpe JD, Bergan LA et al. Potential role of HE4 in multimodal screening for epithelial ovarian cancer. J Natl Cancer Inst 2011; 103(21):1630-4.
  22. Vallius T, Hynninen J, Auranen A, et al. Postoperative human epididymis protein 4 predicts primary therapy outcome in advanced epithelial ovarian cancer. Tumour Biol. Feb 2017;39(2):1010428317691189.
  23. Wang J, Gao J, Yao H, et al. Diagnostic accuracy of serum HE4, CA125 and ROMA in patients with ovarian cancer: a meta-analysis. Tumour Biol. Jun 2014; 35(6):6127-6138.
  24. Wu L, Dai ZY, Qian YH et al. Diagnostic value of serum human epididymis protein 4 (HE4) in ovarian carcinoma: a systematic review and meta-analysis. Int J Gynecol Cancer 2012; 22(7):1106-12.
  25. Yang Z, Wei C, Luo Z et al. Clinical value of serum human epididymis protein 4 assay in the diagnosis of ovarian cancer: a meta-analysis. Onco Targets Ther 2013; 6:957-66.
  26. Yu S, Yang HJ, Xie SQ et al. Diagnostic value of HE4 for ovarian cancer: a meta-analysis. Clin Chem Lab Med 2012; 50(8):1439-46.
  27. Zhen S, Bian LH, Chang LL, et al. Comparison of serum human epididymis protein 4 and carbohydrate antigen 125 as markers in ovarian cancer: A meta-analysis. Mol Clin Oncol. Jul 2014; 2(4):559-566.

Policy History:

Medical Policy Group, September 2009 (2)

Medical Policy Group, August 2010 (2)

Medical Policy Panel, August 2010

Medical Policy Administration Committee, August 2010

Available for comment September 4-October 18, 2010

Medical Policy Group, October 2010

Medical Policy Panel, August 2011

Medical Policy Group, September 2011 (2): Description, Key Points, Reference updated

Medical Policy Panel, August 2012

Medical Policy Group, April 2013 (1): Update to Key Points and References; Material on evaluation of ovarian (adnexal) masses removed as this is addressed in policy 426; no change to policy statement

Medical Policy Panel, August 2013

Medical Policy Group, September 2013 (1): Update to Descriptions, Key Points and References; no change to policy statement

Medical Policy Panel, March 2014

Medical Policy Group, March 2014 (1): Update to Key Points and References; no change to policy statement

Medical Policy Panel, March 2015

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

Medical Policy Panel, December 2015

Medical Policy Group, January 2016 (3):  2015 Updates to Key Points & References; no change in policy statement

Medical Policy Panel, December 2016

Medical Policy Group, December 2016 (3): 2016 Updates to Description, Key Points & References; no change in policy statement.

Medical Policy Panel, December 2017

Medical Policy Group, December 2017 (3): 2017 Updates to Description, Key Points & References; no change in policy statement

Medical Policy Panel, December 2018

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

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

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

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

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

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

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

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

3. The technology must improve the net health outcome;

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

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

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

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

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

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

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