CurrentBlue Cross Blue Shield - Rhode IslandPolicy N/A

Human Epididymis Protein 4 (HE4) Testing Coverage Policy

This policy governs coverage and medical necessity determinations for serum HE4 testing (CPT 86305) for monitoring epithelial ovarian cancer, evaluating adnexal masses, and screening, and applies to BCBSRI products and members.

Policy Summary

PayerBlue Cross Blue Shield - Rhode Island

PolicyHuman Epididymis Protein 4 (HE4) Testing Coverage Policy

Policy CodePolicy N/A

Change TypeNo material change

Effective DateN/A

Next Review DateN/A

Key ActionVerify member benefits and eligibility via the member's Evidence of Coverage or subscriber agreement before ordering HE4 testing.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

86305CPT code for HE4 test

Not covered / NMNCoverage stance

FDA-clearedRegulatory status

InsufficientEvidence

Coverage determinations for HE4 testing

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Medicare Advantage coverage: Measurement of Human epididymis protein 4 (HE4) is not covered for all indications because the evidence is insufficient to determine the effects of the technology on health outcomes.

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Commercial products coverage: Measurement of Human epididymis protein 4 (HE4) is considered not medically necessary for all indications because the evidence is insufficient to determine the effects of the technology on health outcomes.

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FDA-cleared indication: HE4 test kits have FDA 510(k) clearance as an aid in monitoring disease progression or recurrence in patients with epithelial ovarian cancer, but available evidence does not demonstrate that use of HE4 improves health outcomes (no established cutoff, mixed comparative accuracy vs CA-125, and no direct evidence of impact on management or outcomes).

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Adnexal mass evaluation: For evaluation of adnexal masses, diagnostic accuracy studies and meta-analyses show mixed results versus CA-125 (similar overall accuracy; possible higher specificity for HE4), and HE4 has not been shown to improve diagnostic accuracy beyond subjective transvaginal ultrasound or to improve health outcomes.

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Screening asymptomatic women: HE4 screening in asymptomatic, average-risk women lacks prospective comparative evidence demonstrating benefit and is therefore unsupported due to insufficient evidence of improved health outcomes.

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For members covered under Medicare Advantage plans, measurement of Human Epididymis Protein 4 (HE4) is not covered for all indications because the evidence is insufficient to determine the effects of the technology on health outcomes.

For Commercial products, measurement of HE4 is considered not medically necessary for all indications due to insufficient evidence that its use improves health outcomes. Providers should refer to the member's benefit booklet or Evidence of Coverage for any plan-specific variations.

Monitoring disease progression or recurrence in patients with epithelial ovarian cancer (FDA-cleared indication).

Covered only in the limited FDA-cleared context; evidence does not show improved outcomes.

ALL of the following

Indication: Patient has epithelial ovarian cancer and testing is for monitoring disease progression or recurrence (serial HE4 measurements intended to be used in conjunction with other clinical methods).
FDA 510(k) clearance supports use as an aid in monitoring; serial testing should be done with other clinical methods [[chunk 8]]
Evidence limitations: There is no established HE4 cutoff for monitoring, studies provide mixed comparisons with CA-125, and there is no direct prospective evidence that HE4 monitoring changes management or improves health outcomes.
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Not covered / Not medically necessary uses

Routine HE4 testing for purposes such as serial monitoring, routine evaluation of adnexal masses, or screening of asymptomatic, average-risk women is not covered / considered not medically necessary. Diagnostic accuracy studies and meta-analyses show HE4 and CA-125 have similar overall accuracy, with mixed results on added value of HE4 or combined testing; there is no direct prospective evidence demonstrating that HE4 use improves clinical outcomes in these settings.

Specifically, for adnexal mass evaluation, studies have not demonstrated that HE4 provides outcome benefit beyond existing methods (including subjective transvaginal ultrasound assessment), and for screening asymptomatic women there are no prospective studies showing improved health outcomes from HE4 screening.

Billing and code information

Denial Risk

Coverage and billing guidance

Claims for CPT 86305 are not covered for Medicare Advantage Plans and are considered not medically necessary for Commercial products. Providers should not submit claims for HE4 testing under CPT 86305 for covered indications without prior authorization where applicable and should verify member benefits and product-specific coverage.

Affected code: 86305 — Human epididymis protein 4 (HE4)
Coverage status: Medicare Advantage: Not covered; Commercial: Not medically necessary

Actions providers should take

Prior Authorization

Prior authorization not applicable — verify benefits

Prior authorization is not applicable under this policy for CPT 86305; however, benefits vary by contract so providers should confirm member-specific authorization requirements in the Benefit Booklet or Evidence of Coverage.

Note

Check contract-specific benefits and exclusions

Benefits and coverage vary between groups and contracts; refer to the member's Benefit Booklet, Evidence of Coverage, or Subscriber Agreement for applicable coverage determinations and any contract-specific exclusions.

Documentation Required

Verify member benefits and eligibility

Verify the member's benefits and eligibility prior to ordering HE4 testing; benefit limitations in the member contract govern coverage decisions.

Call the provider call center or review the member's subscriber agreement for member-specific coverage and eligibility.

Denial Risk

High denial risk for CPT 86305 (HE4)

Claims for CPT 86305 (HE4) are routinely not covered for Medicare Advantage and are considered not medically necessary for Commercial products — submitting claims for these products carries a high risk of denial.

Requirements for ordering HE4 testing

Billing Rule

Ordering requirements — verify benefits; no specific provider type required

Providers must verify member benefits and eligibility before ordering HE4; the policy does not mandate a specific provider type to place the order.

Refer to the Benefit Booklet, Evidence of Coverage, or Subscriber Agreement for contract-specific rules.

Key definitions

HE4 (Human epididymis protein 4) — definition and regulatory note

DefinitionHuman epididymis protein 4 (HE4) is a circulating serum biomarker overexpressed in epithelial ovarian cancer; it has been cleared by the U.S. Food and Drug Administration (FDA) as an aid in monitoring disease progression or recurrence in patients with epithelial ovarian cancer when used with other clinical methods.

FDA regulatory noteMultiple HE4 test kits have received FDA 510(k) clearance; the FDA indicated HE4 is substantially equivalent to CA-125 for use as an aid in monitoring disease progression or recurrence, and serial HE4 testing should be performed in conjunction with other clinical methods.

Clinical limitationsThere is no established HE4 cutoff for monitoring disease progression; study cutoffs vary and no prospective controlled evidence shows that HE4 use improves health outcomes (no demonstrated superiority to CA-125).

Other malignanciesHE4 has been reported to be overexpressed in other cancers (eg, lung adenocarcinoma, breast, pancreatic, endometrial, bladder) in addition to epithelial ovarian cancer.

CodingCPT code 86305 corresponds to Human epididymis protein 4 (HE4).

ROMA (Risk of Ovarian Malignancy Algorithm) — definition and relation to HE4/CA-125

DefinitionROMA (Risk of Ovarian Malignancy Algorithm) is an algorithm that combines CA-125 level and menopausal status into a numeric score to assess risk of ovarian malignancy.

Relation to HE4 and CA-125ROMA incorporates CA-125 and menopausal status; HE4 has been evaluated alongside CA-125, but ROMA specifically combines CA-125 with menopausal status and is not addressed by this policy.

Test performance contextStudies and meta-analyses have found HE4 and CA-125 have similar overall diagnostic accuracy for adnexal masses; some analyses suggest HE4 may have higher specificity but not higher sensitivity compared with CA-125, and combinations (including algorithms like ROMA) have mixed evidence for superiority over CA-125 alone.

Policy scopeThis policy notes ROMA but does not provide coverage determinations for ROMA; HE4-related evaluations (including ROMA use) lack sufficient evidence of improved health outcomes for routine clinical use in adnexal mass evaluation or screening.

Background and clinical context

Human Epididymis Protein 4 (HE4) is a circulating serum biomarker that is overexpressed in many cases of epithelial ovarian cancer. Several HE4 assay kits have received FDA 510(k) clearance for use as an aid in monitoring disease progression or recurrence in epithelial ovarian cancer.

Although HE4 has an FDA-cleared indication as an adjunctive aid for monitoring patients with epithelial ovarian cancer, available evidence has not established that HE4 is superior to the commonly used marker CA-125 or that using HE4 leads to improved patient outcomes. HE4 has also been studied for adnexal mass evaluation and for screening asymptomatic women, but evidence is insufficient to support routine clinical use in those indications.