CurrentCapital BluecrossPolicy MP 2.269

Serum Biomarkers for Human Epididymis Protein 4 (HE4)

This policy governs coverage and medical necessity determinations for measurement of serum HE4 as a biomarker (including standalone HE4 testing) for ovarian cancer evaluation, monitoring, and screening for members of Capital BlueCross programs to which the policy applies.

Policy Summary

PayerCapital Bluecross

PolicySerum Biomarkers for Human Epididymis Protein 4 (HE4)

Policy CodePolicy MP 2.269

Change TypeAdministrative update (no material clinical change)

Effective DateAug 1, 2025

Next Review DateN/A

Key ActionDo not bill procedure code 86305 for HE4 testing for covered members because HE4 measurement is considered investigational and not covered.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

Investigationalcoverage stance for HE4 testing

86305CPT code listed as investigational

Insufficientevidence summary

MultipleFDA-cleared assays

2020–2025

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

Coverage Determinations

Investigational / Not Covered

Measurement of HE4 is considered investigational and not supported by evidence for all indications because:

Rationale: Evidence does not demonstrate superiority of HE4 over CA125 or that HE4-guided management improves health outcomes; diagnostic accuracy studies and meta-analyses show similar accuracy to CA125 with variable findings and no established monitoring cutoffs

Includes lack of prospective controlled studies showing improved outcomes and variable cutoffs across studies.

Measurement of serum HE4 is considered investigational for all indications. The evidence does not demonstrate that HE4 is superior to CA125 for monitoring disease progression or recurrence, for evaluation of adnexal masses, or for screening asymptomatic, average-risk women; diagnostic accuracy studies and meta-analyses show similar accuracy to CA125 with variable findings and no established monitoring cutoffs. There are no prospective controlled studies showing that HE4-guided management improves health outcomes, and overall the evidence is insufficient to conclude that HE4 measurement provides a net health benefit.

An administrative update removed an NCCN statement from the policy (11/19/2024); the record of policy history documents this change. The cited policy history entries document updates to background and references across multiple reviews but do not introduce explicit clinical exclusions in the sections referenced.

Covered Indications

Assessment of Adnexal Masses and Ovarian Cancer Evaluation

Assay performance and clinical utility have been evaluated in the context of adnexal mass assessment and ovarian cancer diagnosis; however, evidence is insufficient to support coverage.

Assessment contexts evaluated in literature: Diagnostic accuracy studies and meta-analyses comparing HE4 with CA125 for differentiating benign and malignant adnexal masses and for preoperative risk assessment

Several meta-analyses found similar overall diagnostic accuracy; some found higher specificity for HE4 but not higher sensitivity.

Combination testing: Studies have evaluated HE4 combined with CA125 (and ROMA), with mixed findings on whether combination testing improves diagnostic accuracy compared with CA125 alone

Number of studies on combined testing is relatively low and publication bias has been identified.

Impact on management and outcomes: No prospective controlled studies demonstrate that HE4 testing (alone or in combination) changes clinical management in a way that improves health outcomes

Coding and Billing

Investigational therefore not coveredCPTNot Covered

86305

Immunoassay for analyte other than infectious agent antibody(ies), quantitative; multiple step procedure, each specimen

inv-07: Misc coding key-value entry

Inventory placeholderReserved key-value entry for coding inventory (no additional details in source).

Provider Actions and Billing Guidance

Note

Program/product applicability and coverage

This policy is only applicable to certain Capital BlueCross programs and products. Refer to product-specific variations (for example, FEP PPO follows the FEP Medical Policy Manual). Coverage is determined by the member's benefit plan — the inclusion of a code in the coding section does not guarantee coverage.

Applicable programs/products only — see Section II for product variations (e.g., FEP PPO).
Coverage determined by benefits — identification of a code in the coding section does not denote coverage; coverage is determined by the member benefit plan.

Prior Authorization

Prior authorization

No prior authorization requirements are specified in this policy section. Providers should follow any program- or product-specific prior authorization processes that apply to the member's benefit plan.

No explicit prior authorization requirement listed in this policy.

Not Covered

Measurement of HE4 is not covered — the policy states that HE4 testing is investigational for all indications. The procedure code 86305 (immunoassay for analyte other than infectious agent antibody, quantitative; multiple step procedure, each specimen) is listed as investigational and therefore not covered.

This portion of the document lists administrative updates and policy-history entries but does not enumerate additional specific tests or clinical indications that are explicitly not covered beyond the investigational designation already stated elsewhere in the policy.

Background and Rationale

HE4 (human epididymis protein 4) is a circulating protein that is overexpressed in epithelial ovarian cancer and in some other malignancies. It has been proposed as a serum biomarker for monitoring epithelial ovarian cancer and for evaluation of adnexal masses. ROMA (the Risk of Ovarian Malignancy Algorithm) combines HE4, CA125, and menopausal status and has been evaluated as a tool to predict the malignancy risk of an adnexal mass; however, available evidence has not established that HE4 testing alone improves clinical outcomes or is superior to existing approaches.

Definitions and Assays

inv-19: HE4 — definition of human epididymis protein 4

DefinitionHE4 = human epididymis protein 4, a circulating protein overexpressed in epithelial ovarian cancer and other malignancies.

Intended use describedProposed as a biomarker for monitoring epithelial ovarian cancer and evaluating adnexal masses.

Evidence summaryDiagnostic accuracy studies and meta-analyses evaluate HE4 but do not establish superiority to CA125 or improved health outcomes with HE4-guided management.

inv-17: ROMA — Risk of Ovarian Malignancy Algorithm

DefinitionROMA (Risk of Ovarian Malignancy Algorithm) = a numerical score combining HE4, CA125, and menopausal status to predict the risk that an adnexal mass is malignant.

Regulatory statusROMA has been cleared by FDA for predicting risk that an adnexal mass is malignant; addressed separately in policy MP 2.270.

Ordering and Documentation Requirements

Billing Rule

Verify benefits and medical necessity

Coverage and reimbursement depend on the member's benefit plan and a medical necessity determination; providers should verify product-specific applicability prior to ordering or billing.

Note

Ordering provider restrictions

No ordering provider restrictions (who may order the test) are specified in the provided document sections.

Frequency Limits

inv-22: Frequency limits placeholder (inventory item without details)

Inventory placeholderFrequency limits not specified in the policy document; reserved for future details.

inv-23: Frequency limits / policy history placeholder

Policy history placeholderPolicy history and administrative updates noted (entries from 2020–2024); no frequency limits specified in these history notes.

Recent updatesEntries include consensus reviews and updates to background, coding, references, and product variation statements (2020–2024).

ActionNo clinical frequency limits detailed; monitoring and coverage follow member benefits and medical necessity determinations.

Policy Revision History

The policy history and administrative updates are documented in the policy history section (entries from 2020–2025). These history entries record consensus reviews, background and references updates, and administrative edits (including removal of an NCCN statement) but do not specify provider documentation requirements.