HE4-Another Marker for Gynecologic Cancers: Do We Really Need One?

The utility of any tumor marker should be evaluated in five areas: screening, diagnosis of an unknown condition, monitoring (of treatment or for recurrence of a disease), and prognostication. Since its discovery some 30 years ago by Bast,[1] cancer antigen 125 (CA 125) has been exhaustively evaluated in most of these areas with respect to epithelial ovarian cancer. Although it has some utility in many of these areas, it is far from perfect in any. Human epididymis protein 4 (HE4), another secreted protein, can be detected in the sera of patients with both ovarian and endometrial malignancies. The review by Bast and colleagues on this marker is replete with the words “may” and “hope”-with good reason, since how this “new” marker complements CA 125 remains mostly unclear.

With respect to screening, CA 125 has an unacceptably high false-negative rate in the most curable early stages of ovarian cancer, which predominate in premenopausal women. Many benign disorders cause CA 125 elevations in this cohort, resulting in a positive predictive value of only 10%. The addition of transvaginal ultrasound (TVS) has improved this to about 40%, but the accuracy of the results are dependent on the experience of the ultrasonographer; thus, TVS plus CA 125 is not recommended for general population screening. HE4 levels, which are directly proportional to age, may add to or supplant TVS in the screening algorithm, but studies to address this use of HE4 are just underway and are a decade from results. It appears that HE4 will detect cancer in some nonproducers of CA 125 (in the 40% to 50% of patients with early disease who test negative for CA 125) and is less commonly elevated in the premenopausal patient with benign disease. In this area, HE4 may actually have its greatest role. However, it is also possible that the HE4 assay will become another test that is ordered by primary care physicians outside guidelines, as has been shown to be the case with CA 125 and TVS.[2] The results of a British trial of the Risk of Ovarian Cancer Algorithm (ROCA), using serial changes in CA 125 to trigger TVS, have not been reported. Unless that trial, due to be reported in 2015, demonstrates a survival advantage, it seems unlikely that the addition of HE4 will further increase the ability of screening to improve survival.

Screening is only recommended for women with a strong family history of breast/ovarian cancer or deleterious BRCA mutations. Even in these patients, the prudent physician, understanding the current imperfect screening algorithm, will strongly encourage prophylactic surgery as soon as childbearing is complete. The role of HE4 in screening for endometrial cancer is in its infancy and likely will remain there, since the majority of patients present with postmenopausal bleeding, have an endometrial biopsy, and are diagnosed with stage I disease.

With respect to diagnosis of an unknown pelvic mass, HE4, in conjunction with CA 125, has been put into two separate algorithms that depend on menopausal status to develop a risk of malignancy (ROMA) predictive index. This algorithm has been approved by the US Food and Drug Administration (FDA), although a number of small studies have produced conflicting results. ROMA appears to perform better in premenopausal patients, in whom incidence is much lower but early disease more common. It is notable, however, that the National Comprehensive Cancer Network guidelines do not recommend the use of ROMA.[3] This is an area where future studies of HE4, with a goal of improving preoperative diagnosis, appear most promising. This use of the marker still will require ongoing education of the general gynecology community, to ensure that these patients are evaluated properly and that possible cancer patients are referred to the gynecologic oncologist preoperatively

Use of CA 125 to follow the course of treatment of ovarian cancer or to detect recurrence after primary treatment is complete has led some groups to use changes in this marker to define response to primary therapy[4] or to declare progression of disease with various incremental increases after completion of primary therapy.[5] These initial observations were codified in an international symposium[6] but have not been embraced by the FDA for the evaluation of outcomes of clinical trials of new agents. This particular use of CA 125 has also created a legion of CA 125–addicted patients who demand a change in therapy or initiation of salvage therapy in the absence of symptomatic or radiographic evidence of progression or recurrence. Having another marker to assess treatment outcomes seems unlikely to resolve this conundrum. Importantly, a single trial from the United Kingdom failed to demonstrate any survival advantage and a decrement in quality of life with institution of treatment of recurrence solely on the basis of increases in CA 125, yet this remains a common management approach in the United States.[7]

The data on HE4 as a prognosticator in both ovarian and endometrial cancer constitute, at most, an interesting observation, but most likely they are simply a reflection of total tumor burden. There are certainly not enough data to justify making major treatment decisions in ovarian or endometrial cancer on the basis of absolute marker levels. Proteomics and genomics seem more likely to make a difference in this area.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

REFERENCES

1. Bast RC, Klug TL, St John E, et al. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med. 1983;309:883-7.

2. Baldwin LM, Trivers KF, Matthews B, et al. Vignette-based study of ovarian cancer screening: do U.S. physicians report adhering to evidence-based recommendations. Ann Int Med. 2012;156:182-94.

3. National Comprehensive Cancer Network (NCCN) guidelines version 1.2013. Available from: http://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdfMS-5. Accessed May 27, 2013.

4. Rustin GJ, Nelstrop AE, McClean F, et al. Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol. 1996;14:1545-51.

5. Rustin GJ, Nelstrop AE, Tuxen MK, et al. Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group study. Ann Oncol. 1996;7:361-4.

6. Rustin GJ, Quinn M, Thigpen T, et al. New guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). J Natl Cancer Inst. 2004;96:487-8.

7. Rustin GJ, van der Burg ME, Griffin CI, et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV5/EORTC 55955):a randomised trial. Lancet. 2010;376:1155-63.