HE4 and CA 125 Information

Ovarian Cancer Facts

Ovarian cancer is one of the most deadly gynecological cancers in women. In 2007, there were over 230,500 new cases diagnosed worldwide and 141,400 deaths¹. The 5-year survival in Europe is about 37%, and despite advances in treatment and surgical techniques, mortality has not significantly decreased^1,2. The risk of developing ovarian cancer increases with age and most ovarian cancer cases occur in women over 50 years old². Diagnosing ovarian cancer can be difficult because the symptoms are non-specific and include abdominal fullness, pelvic pain, gastrointestinal distress or fatigue². Over 70% of ovarian cancers are diagnosed at an advanced stage³.

Histological Types of Ovarian Cancer

There are 3 main histological types of ovarian cancer – epithelial, stromal, and germ cell. Epithelial ovarian cancer is the most common, with approximately 80% of ovarian cancers diagnosed as epithelial ovarian cancer. Epithelial ovarian cancer can be further classified as serous, mucinous, endometrioid, clear cell, or undifferentiated tumors^3,4.

Ovarian Cancer Staging

Staging ovarian cancer is based on how severe and widespread the cancer is, and is broken down into 4 stages⁵:

Stage I	Cancer is contained to one or both ovaries.
Stage II	Cancer is in one or both ovaries and has spread to other organs within the pelvis.
Stage III	Cancer is in one or both ovaries and has either spread beyond the pelvis to the lining of the abdomen or has spread to the lymph nodes.
Stage IV	Cancer is found inside the liver, lungs, or pleural fluid or has spread outside the peritoneal cavity.

Staging is important because different stages of ovarian cancer have different prognoses, and are treated differently. Ovarian cancer is more treatable when it is found in early stages, with up to 90% of patients with stage I ovarian cancer surviving at least 5 years, compared to only 19% of patients with stage IV ovarian cancer⁶. An accurate staging assessment can impact a patient's chance of survival.

Role of CA125 in Ovarian Cancer

CA125 is one of the most widely studied serum-based tumor markers for ovarian cancer. Most oncology societies recommend the use of CA125 for the differential diagnosis of a suspected pelvic mass, monitoring efficacy of treatment, and detection of recurrence of ovarian cancer⁷. Other recommendations include using CA125 to in the early detection of ovarian cancer in women with BRCA1/2 gene mutations and in prognosis. None of the oncology societies recommend using CA125 for screening for ovarian cancer because CA125 does not have the sensitivity and specificity needed for widespread screening of women.

CA125 is elevated in about 90% of women with advanced ovarian cancer and correlates with tumor volume and cancer stage⁷. These characteristics make CA125 an excellent marker for monitoring response to therapy. However, CA125 does have some limitations. It is only elevated in 50 – 60% of women with early stage ovarian cancer. Also, CA125 can be elevated in several conditions not related to ovarian cancer, especially in premenopausal women. These conditions include endometriosis, pregnancy, hemorrhagic cyst, and pelvic inflammatory disease. CA125 can also be elevated in other cancers, such as colon, lung, and endometrial cancer6. Because of this, CA125 has low sensitivity and specificity in early stage cancers.

Unmet Needs in Ovarian Cancer Diagnostics

Since survival rates of patients with ovarian cancer are higher when the cancer is diagnosed in early stages, screening and early detection of ovarian cancer is a significant area of research. Researchers are evaluating ways to detect ovarian cancer earlier through the use of biomarkers, imaging techniques, or a combination of these modalities^8,9. For women that are diagnosed with a pelvic mass, it is important to determine if the mass is benign or malignant before they have surgery. This is discussed in the section below. Finally, since CA125 is only elevated in 80-90% of women with advanced ovarian cancer, it is important to find markers that are elevated in women with ovarian cancer that don't have elevated CA125 so that there is a way to monitor response to therapy and for detection of recurrence.

Survival Rate Improves with Specialist

Many studies have shown that women with ovarian cancer have improved survival rates when their surgery is performed by a gynecological oncologist, compared to having surgery performed by a gynecologist or general surgeon.

Paulsen et al showed that women that had surgery performed by a gynecological oncologist had a 20% increase in short-term survival compared to women that had surgery performed by a non-gynecological oncologist¹⁰. Carney et al. showed that among patients diagnosed with advanced disease, those operated on by a gynecological oncologist had a median survival of 26 months compared to a median survival of 15 months for those patients operated on by a non-gynecological oncologist¹¹.

This improved survival may have occurred because the surgery for ovarian cancer is complicated and gynecological oncologists are trained to perform the comprehensive debulking and surgical staging needed for optimal treatment of ovarian cancer¹².

The American College of Obstetricians and Gynecologists (ACOG) and the Society for Gynecological Oncologists (SGO) recommend that women that are suspected to have ovarian cancer should be referred to a gynecological oncologist for their surgery¹³.

A Novel Ovarian Cancer Biomaker

There has been significant research in the past 10-15 years towards finding ways to improve the detection of ovarian cancer. Ultrasound continues to be evaluated in the detection of ovarian cancer. Ultrasound is used to evaluate the size and the morphology of the ovarian mass, however, ultrasound can be subjective with differences in interpretation and scoring, so that it can be difficult to obtain consistent results between laboratories¹⁴.

Some researchers have found that serial measurements of CA125 are useful in the early detection of ovarian cancer. Since CA125 levels correlate well with tumor volume and stage, this may be an effective way to detect early ovarian cancer¹⁵.

Finding new biomarkers in ovarian cancer has been an area of interest for many researchers. Moore et al evaluated a panel of 9 biomarkers that had been previously identified as potential markers for ovarian cancer and found that HE4 exhibited the best performance, even better than CA125. He further showed that the combination of HE4 and CA125 had improved performance over either HE4 or CA125 alone¹⁶. Nolen et al evaluated a panel of 65 potential biomarkers and found that the combination of CA125 and HE4 had the best discriminatory power for distinguishing between benign and malignant disease than any other marker or marker combination¹⁷. Yurkovetsky et al evaluated a panel of 96 potential biomarkers and concluded that with additional validation CA125, HE4, CEA, and VCAM-1 could become an initial stage in screening strategy for epithelial ovarian cancer¹⁸.

HE4

HE4 (Human Epididymal Protein 4) is a useful biomarker for the detection of ovarian cancer with only minimal expression in normal ovarian tissue. In addition to the expression of HE4 on a cellular level, high levels of HE4 have been detected in the serum of ovarian cancer patients¹⁹.

HE4 can be used in the monitoring of recurrence and disease progression in patients with epithelial ovarian cancer. In a retrospective study of 80 patients undergoing treatment or being monitored for ovarian cancer, 93% of patients with greater than a 25% change in HE4 level showed disease progression. Total concordance of HE4 concentration change to disease state was 76%20. Furthermore, Moore et al found that HE4 was elevated in over half of the ovarian cancer patients that did not have elevated CA125¹⁶.

In combination with CA125, HE4 can be used as an aid in risk stratification for women presenting with pelvic mass by using the Risk of Ovarian Malignancy Algorithm (ROMA).

ROMA: Risk of Ovarian Malignancy Algorithm

The ROMA value estimates the probability of ovarian cancer in women with a pelvic mass based on the patient's HE4 and CA125 levels, and their menopausal status²¹. There are different ROMA formulas and cutoffs based on the patient's menopausal status. After ROMA is evaluated, women with ROMA levels above the cutoff have an increased risk of ovarian cancer and should be evaluated by a gynecological oncologist prior to surgery. ROMA must be used in conjunction with other clinical methods to triage patients to the appropriate surgeon for their care.

In a study by Moore et al., ROMA was compared to RMI (Risk of Malignancy Index), another algorithm that is used in the detection of ovarian cancer. RMI uses CA125, menopausal status and ultrasound findings to distinguish between benign and malignant pelvic mass. ROMA was found to have higher sensitivity than RMI for detecting epithelial ovarian cancer¹⁴.

Many studies have shown that HE4 and ROMA improve the detection of ovarian cancer.

Moore et al have shown that at 75% specificity, ROMA exhibits sensitivities of 76.5% and 81.3% for premenopausal women in a gynecological oncologist setting and a primary care setting, respectively. In postmenopausal women, the sensitivities at 75% specificity were 92.3% and 90.2% for women in a gynecological oncologist setting and a primary care setting, respectively^21,22.
Kim et al concluded that their findings suggest that measuring HE4 concentrations along with CA125 concentration may provide higher accuracy for detecting ovarian cancer²³.
Ruggeri et al concluded that the ROMA algorithm showed a good accuracy for discriminating women at high risk for epithelial ovarian cancer²⁴.
Molina et al showed that HE4 had better specificity than CA125 or ROMA, and that ROMA had higher sensitivity than CA125 and HE4 at distinguishing between benign disease and ovarian cancer ²⁵.
Lenhard et al showed that ROMA had the highest sensitivity at 95% specificity compared to CA125 and HE4, especially in early stage disease²⁶.

For further information on the ROMA calculations and HE4, see the links below.

References

¹Garcia M, et al. Global Cancer Facts & Figures 2007. Atlanta, GA: American Cancer Society, 2007.

²Roett MA and Evan R. Ovarian Cancer: an overview. Am Fam Physician. 2009;80:609-616.

³Cho KR and Shih IM. Ovarian Cancer. Annu Rev Pathol: Mech Dis. 2009;4:287-313.

⁴Johns Hopkins Pathology. Ovarian Cancer. http://ovariancancer.jhmi.edu/typesca.cfm, accessed 11/16/2011.

⁵American Cancer Society. Ovarian Cancer: How is ovarian cancer staged. http://www.cancer.org/Cancer/OvarianCancer/DetailedGuide/ovarian-cancer-staging, accessed 11/16/2011.

⁶Clarke-Pearson DL Screening for ovarian cancer. New Engl J Med. 2009;361:170-177.

⁷Sturgeon CM et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for the use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem 2008;54:e11-e79.

⁸Buys SS et al. Effect of screening on ovarian cancer mortality. JAMA 2011;395:2295-2303.

⁹Menon U, et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet 2009;10:327-40.

¹⁰ Paulsen T. et al. Improved short-term survival for advance ovarian, tubal, and peritoneal cancer patients operated at teaching hospitals. Int J Gynecol Cancer. 2006;16(Suppl 1):11-17

¹¹Carney ME, et al. Population-based study of pattern of care for ovarian cancer: who is seen by a gynecologic oncologist and who it not? Gynecol Oncology 2002;84:36-42.

¹²Chobanian, N and Dietrich C. Ovarian Cancer. Surg Clin A Am. 2008;88:285-299.

¹³American College of Obstetricians and Gynecologists (ACOG). ACOG Practice Bulletin: Management of Adnexal masses. No. 83, July 2007.

¹⁴Moore RG et al. Comparison of a novel multiple marker assay vs the Risk of Malignancy Index (RMI) for the prediction of epithelial ovarian cancer in patients with a pelvic mass. Am J Obstet Gynecol 2010;203:228.e1-6.

¹⁵Menon U, et al. Prospective study using the Risk of Ovarian Cancer algorithm to screen for ovarian cancer. J Clin Oncol. 2005;23:7919-26.

¹⁶Moore RG et al. Use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol Oncol 2008;108:402-408.

¹⁷Nolen B et al. Serum biomarker panels for the discrimination of benign from malignant cases in patients with an adnexal mass. Gynecol Oncol 2010; 117: 440-445.

¹⁸Yurkovetsky Z et al. Development of a multimarker assay for the early detection of ovarian cancer. J Clin Oncol. 2010; 28:2159-21668.

¹⁹Hellstrom I et al. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res. 2003;63:3695-3700.

²⁰Allard J et al. Use of a novel biomarker HE4 for monitoring patients with epithelial ovarian cancer. J Clin Oncol. 2008;26 (May 20 Suppl);abstract 5535.

²¹Moore RG, et al. A novel multiple marker bioassay utilizing HE4 and CA 125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol 2009;112:40-6.

²²Moore RG, Miller MC, Disilvestro P, et al. Evaluation of the diagnostic accuracy of the Risk of Ovarian Malignancy Algorithm in women with a pelvic mass. Obstet Gynecol 2011;118:280-8

²³Kim YH, Whang DH, Park J, et al. Evaluation of the accuracy of serum human epididymis protein 4 in combination with CA 125 for detecting ovarian cancer: a prospective case-control study in a Korean population. Clin Chem Lab Med 2011;49:527-34.

²⁴Ruggeri G, Bandiera E, Zanotti L, et al. HE4 and epithelial ovarian cancer: comparison and clinical evaluation of two immunoassays and a combination algorithm. Clin Chim Acta 2011;412:1447-53.

²⁵Molina R, Escudero JM, Auge JM, et al. HE4 a noval tumour marker for ovarian cancer: comparison with CA125 and ROMA algorithm in patients with gynaecological diseases. Tumor Biol. 2011;32:1087-95.

²⁶Lenhard M, Steiber P, Hertlein L et al. The diagnostic accuracy of two human epididymis protein 4 (HE4) testing systems in combination with CA125 in the differential diagnosis of ovarian masses. Clin Chem Lab Med 2011:DOI 10.1515/CCLM.2011.709