What is the role of the Human Epididymis protein 4 (HE4) tumor marker in ovarian cancer management?

Role of HE4 Tumor Marker in Ovarian Cancer Management

HE4 (Human Epididymis protein 4) should not be used routinely to assess response and progression in ovarian cancer due to conflicting results, though it may have value in specific clinical scenarios as a complementary marker to CA-125.

Diagnostic Applications of HE4

HE4 has been evaluated primarily in two clinical contexts:

• Initial diagnosis of pelvic masses:

  • The FDA has approved the use of HE4 and CA-125 for estimating the risk of ovarian cancer in women with a pelvic mass 1
  • However, the NCCN Panel does not currently recommend these biomarkers for determining the status of an undiagnosed pelvic mass 1
  • When used for diagnosis, HE4 shows high specificity (90%) with moderate sensitivity (74-83%) depending on the control group 2

• Detection of recurrent disease:

  • HE4 demonstrates higher specificity (91.5-100%) compared to CA-125 in detecting recurrent ovarian cancer 3, 4
  • When combined with CA-125, HE4 improves overall sensitivity (76.47%) and specificity (100%) for recurrence detection 3

Monitoring Treatment Response

• Current guideline recommendations:

  • ESMO-ESGO consensus explicitly states that HE4 should not be used routinely to assess response and progression due to conflicting results (Level of evidence: IV, Strength of recommendation: A) 1
  • CA-125 remains the standard marker for monitoring treatment response in high-grade serous ovarian cancer, though it has limitations in non-high-grade serous histologies 1

• Emerging evidence on HE4 for monitoring:

  • A >80% decline in HE4 levels during treatment may predict better progression-free survival 4
  • Failure of HE4 levels to normalize after standard therapy may indicate poor prognosis 5
  • HE4 may detect recurrence 5-8 months earlier than CA-125 in some patients 5

Prognostic Value

• Baseline HE4 levels may be predictive of platinum sensitivity (ROC AUC 0.64) and optimal interval debulking surgery (ROC AUC 0.70) 1
• HE4 appears to be an independent predictive factor for surgical outcomes at secondary cytoreductive surgery 5
• HE4 maintains its prognostic role even after disease recurrence 5

Practical Considerations for Clinical Use

• Analytical performance:

  • HE4 assays demonstrate good analytical performance with intra- and inter-assay precision showing coefficients of variation less than 10% 6
  • Two commonly used cut-off values are 70 pmol/L and 150 pmol/L, with the lower threshold providing higher sensitivity but lower specificity 3

• Limitations:

  • Several tumor markers (including HE4) do not increase early enough to be useful in detecting early-stage ovarian cancer 1
  • Most studies evaluating HE4 have small sample sizes (8-73 women) and limited follow-up 5
  • Lack of standardization across studies limits widespread implementation 1

Algorithm for HE4 Use in Clinical Practice

1. For initial diagnosis: Rely primarily on imaging and CA-125; consider HE4 as complementary but not definitive
2. For treatment monitoring: Use CA-125 as the primary marker; consider adding HE4 if:
   • CA-125 was not elevated at diagnosis
   • Patient has non-high-grade serous histology where CA-125 may be less reliable
3. For recurrence detection: Consider dual monitoring with both CA-125 and HE4, especially in patients with previously elevated HE4
4. For prognostication: Evaluate the degree of HE4 decline during treatment (>80% decline suggests better outcomes)

While HE4 shows promise, particularly for recurrence detection, larger prospective randomized multicentric studies are needed before it can be recommended for routine clinical use in ovarian cancer management.