Does HE4 have a role in the recurrence of ovarian cancer? | 2012 ASCO Annual Meeting Abstracts (+ links to related ovarian abstracts)

Does HE4 have a role in the recurrence of ovarian cancer? | 2012 ASCO Annual Meeting Abstracts

Abstract:
Background: Human epididymis protein 4 (HE4) has been recently described as a new marker for early ovarian cancer, with higher sensitivity (76.9%) compared to CA125. This is the third study in literature on the role of HE4 in recurrence of ovarian cancer and the first evaluating the sensitivity of HE4 and CA125 in these patients  

Methods: Plasma was obtained 24 hours before secondary cytoreductive surgery from consecutive patients with suspicious recurrence ovarian cancer operated from November 2010 to April 2011 at University Campus Bio-Medico of Rome. CA125 levels were evaluated by a one-step "sandwich" radioimmunoassay. HE4 levels were determined using the HE4 enzymatic immune assay. The CA125 cut-off was less than 35 U/mL. Two cut-off were considered for HE4: less than 150 pmol/L (according to the manufacturer's indications) and less than 70 pmol/L.  

Results: Fourteen patients were histologically confirmed as recurrence ovarian cancer. Mean Ca125 plasma concentration was 31.95 ± 22.09 U/mL (range 1.1 – 64.3). Mean HE4 plasma concentration was 225.83± 286.82 pmol/L (range 21.61- 633.6). The sensitivity of CA125 was 35.7 %. The sensitivity of HE4 was 71.4% and 28.6% above the cut-off of 70 pmol/L and 150 pmol/L, respectively. The dual marker combination of CA125 and HE4 at 70 pmol/L cut-off yielded the highest sensitivity (85.7%) to detect recurrence ovarian cancer.  

Conclusions: Even if a standard cut-off point has not been determined, this study suggested that HE4 may potentially be a more sensible marker for recurrence ovarian cancer than CA125 and the association between CA125 and HE4 at cut-off of 70 pmol/L seems to yield the highest sensitivity.

  Other Abstracts in this Sub-Category:

	1. Randomized phase III study of erlotinib versus observation in patients with no evidence of disease progression after first-line platin-based chemotherapy for ovarian carcinoma: A GCIG and EORTC-GCG study. Meeting: 2012 ASCO Annual Meeting Abstract No: LBA5000 First Author: Ignace B. Vergote Category: Gynecologic Cancer - Ovarian Cancer
	2. Olaparib plus paclitaxel plus carboplatin (P/C) followed by olaparib maintenance treatment in patients (pts) with platinum-sensitive recurrent serous ovarian cancer (PSR SOC): A randomized, open-label phase II study. Meeting: 2012 ASCO Annual Meeting Abstract No: 5001 First Author: Amit M. Oza Category: Gynecologic Cancer - Ovarian Cancer
	3. AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC). Meeting: 2012 ASCO Annual Meeting Abstract No: LBA5002^ First Author: Eric Pujade-Lauraine Category: Gynecologic Cancer - Ovarian Cancer
	More...

paywalled: Two-marker Combinations for Preoperative Discrimination of Benign and Malignant Ovarian Masses

Two-marker Combinations for Preoperative Discrimination of Benign and Malignant Ovarian Masses

Abstract

Background: 

When caring for patients with ovarian neoplasms, correct preoperative discrimination of benign and malignant disease is deemed vital. In this study, we tested serum biomarkers' alone and in combination, to achieve this aim.

Conclusion: 

A combination of CA-125 with HE4 could facilitate the identification of women at risk for ovarian cancer.

paywalled: Role of HE4, CA72.4, and CA125 in monitoring ovarian cancer.

Role of HE4, CA72.4, and CA125 in monitoring ovarian cancer.

Abstract

The aim of this study was to investigate the role of biomarkers CA125, HE4, and CA72.4 at diagnosis and throughout the follow-up in patients with epithelial ovarian cancer (EOC). Thirty-nine patients with EOC were deemed eligible, and 20 were followed up. CA125, HE4, and CA72.4 serum levels were determined for all patients at initial diagnosis of EOC. Among these patients, the number of cases with an elevated level of each individual marker was CA125 77 %, HE4 85 %, and CA72.4 72 %. A statistically significant difference was observed between the level of HE4 when compared to CA72.4 (p < 0.02). In the follow-up phase, we observed tumor marker levels fluctuating according to response to chemotherapy. When combining two out of the three biomarkers together, we observed increased values of CA125 and CA72.4 in 55 % of the patients, increased values of CA125 and HE4 in 65 % of the patients, and finally increased HE4 and CA72.4 in 75 % of the patients. A statistically significant difference was observed when combining HE4 and CA72.4, but not CA125 and CA 72.4 (p < 0.002). In conclusion, our study demonstrates that the association of three biomarkers CA125, HE4, and CA72.4 provides a valuable contribution in the follow-up of EOC patients.

abstract: Serum HE4 levels are less frequently elevated than CA125 in women with benign gynecologic disorders

Serum HE4 levels are less frequently elevated than CA125 in women with benign gynecologic disorders: Publication year: 2012


Objective
The human epididymis protein 4 (HE4) is a novel biomarker for ovarian cancer. This study measured the HE4 and CA125 levels in women with benign gynecological disorders. 

Study Design 
Sera were obtained from women prior to surgery for a pelvic mass and HE4 and CA125 levels were determined. The proportions of patients with elevated biomarker levels were compared.

Results 
There were 1042 women with benign disease. HE4 levels were less often elevated than CA125 (8% vs 29%) . A marked difference was observed in patients with endometriosis in which HE4 was elevated in 3% of patients and CA125 in 67% . Serous ovarian tumors were associated with elevated levels of HE4 in 8% of patients and CA125 in 20%; uterine fibroids in 8% vs 26% ; dermoids in 1% vs 21% ; and inflammatory disease in 10% vs 37% .

Conclusion
HE4 is elevated less frequently than CA125 in benign disease, particularly in premenopausal patients.

abstract: HE4 combined with MDCT imaging is a good marker in the evaluation of disease extension in advanced epithelial ovarian carcinoma.

HE4 combined with MDCT imaging is a good marker in the evaluation of disease extension in advanced epithelial ovarian carcinoma

Abstract

The purpose of the study was to evaluate the expression of the biomarkers CA125 and HE4 combined with imaging, in patients with advanced epithelial ovarian cancer (EOC). Forty-six women with EOC were included in the study all affected with peritoneal carcinomatosis. ................The availability of biomarkers, particularly HE4, together with sophisticated imaging techniques, strengthens the clinical relevance of this study, for the follow-up of patients with peritoneal carcinomatosis.

                        ~~~~~~~~~~~~~~~~~~~~~~~

carcinomatosis - definition of carcinomatosis in the Medical ...

medical-dictionary.thefreedictionary.com/carcinomatosis

carcinomatosis /car·ci·no·ma·to·sis/ (kahr″sĭ-no-mah-to´sis) the condition of widespread dissemination of cancer throughout the body.

abstract: Evaluation of ovarian cancer remission markers HE4, MMP7 and Mesothelin by comparison to the established marker CA125 (includes graphic/study of 23 patients)

 Highlights
(in study of 23 patients)

► Three new markers were compared to CA125 for lead time to ovarian cancer recurrence.
► HE4 elevates at recurrence when CA125 does not.
► Mesothelin has less marker potential, MMP7 shows promise and requires confirmation.
  
Evaluation of ovarian cancer remission markers HE4, MMP7 and Mesothelin by comparison to the established marker CA125: Publication year: 2012

Objective 
Evaluate and compare the effectiveness of CA125, HE4, Mesothelin and MMP7 marker levels to monitor ovarian cancer patients after surgery and chemotherapy. Evaluate the lead time of a rise of marker levels before recurrence.

Methods 
The study consists of 23 patients with advanced stage ovarian/fallopian tube cancer. Blood was drawn after front line surgery and chemotherapy treatment and at 3 month intervals thereafter. One patient had chemoresistant disease, two patients remained in remission and 20 patients had recurring disease and were used for marker evaluation.

Results
In five patients HE4 was the only marker to elevate before recurrence with a lead time of up to 4½ months including one patient who did not have a CA125 response at all. In a further two patients, HE4 increased before CA125 did. In four of these seven patients, HE4 levels were consistently at or above threshold during remission when both CA125 and imaging results were negative. MMP7 elevated before recurrence in one patient who was negative for the other markers. Mesothelin elevated in two patients who were also positive for CA125 and HE4.

Conclusions 
HE4 can predict ovarian cancer recurrence earlier than CA125 and it can be elevated in patients that do not express CA125 at sufficient levels to make a clinical decision. MMP7 and Mesothelin have lower potential as markers for ovarian cancer recurrence to complement CA125. A failure of HE4 levels to normalize at completion of standard therapy may indicate a poor prognosis.

Graphical Abstract

Highlights

► Three new markers were compared to CA125 for lead time to ovarian cancer recurrence.
► HE4 elevates at recurrence when CA125 does not.
► Mesothelin has less marker potential, MMP7 shows promise and requires confirmation.

abstract: Serum HE4 as a diagnostic and prognostic marker for lung cancer (study included ovarian cancer patients)

Abstract

We evaluated the diagnostic and prognostic efficacy of human epididymis protein 4 (HE4) for lung cancer patients by using our novel enzyme-linked immunosorbent assay (ELISA) system. We measured serum HE4 levels of cancer patients including 49 lung cancer and 18 ovarian cancer patients. Furthermore, we evaluated the relationship between serum HE4 levels and overall survival after chemotherapy of 24 lung cancer patients. Serum HE4 levels were significantly higher for non-small, small cell lung cancer and ovarian cancer patients than for healthy controls. The area under the receiver operating characteristic curve (AUC) was calculated for differentiation of lung cancer patients and healthy controls. AUC for serum HE4 was 0.988 for differentiating lung cancer patients from healthy controls, with a cutoff value of 6.56 ng/ml (sensitivity = 89.8%, specificity = 100%).
Serum HE4 levels were elevated in 36/40 (90.0%) non-small cell lung cancer patients, 8/9 (88.9%) small cell lung cancer patients and 8/18 (44.4%) ovarian cancer patients. High levels of serum HE4 (>15 ng/ml) after chemotherapy were significantly correlated with worse overall survival after the treatment. These findings suggest that serum HE4 is a potential diagnostic and prognostic marker for lung cancer patients.

abstract: Reference ranges for HE4 and CA125 in a large Asian population by automated assays and diagnostic performances for ovarian cancer

"The new automated HE4 assay showed good analytical and diagnostic performances. The reference limits established in our study could be used as cutoff levels to facilitate more accurate diagnosis of ovarian cancer in Asian population."

No benefit from combining HE4 and CA125 as ovarian tumor markers in a clinical setting

of interest: "HE4 was not elevated in endometriosis"
CONCLUSIONS:
The major advantage of HE4 lies in its specificity and improved detection of borderline tumors and early stage ovarian and tubal cancers. HE4 is superior to CA125 with or without RMI and ROMA indices. However, we see no benefit from combining both markers in clinical practice.

abstract: HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm

Conclusion:
This independent validation study demonstrated similar performance indices to those recently published. However, in this study, HE4 and ROMA did not increase the detection of malignant disease compared with CA125 alone. Although the initial reports were promising, measurement of HE4 serum levels does not contribute to the diagnosis of ovarian cancer

The ROMA (Risk of Ovarian Malignancy Algorithm) for estimating the risk of epithelial ovarian cancer in women presenting with pelvic mass: is it really useful? (HE4/CA125/pre-post menopausal)

Conclusions: The ROMA is a simple scoring system which shows excellent diagnostic performance for the detection of EOC in post-menopausal women, but not in pre-menopausal women. Moreover, the dual marker combination of HE4 and CA125 (ROMA) does not show better performance than HE4 alone.

Medical News: Cancer Biomarkers Missing in Action - Ovarian Cancer - Medscape

With a handful of possible exceptions, Diamandis wrote, "very few, if any, molecules have been identified that are expressed only by a cancer tissue but not by the corresponding normal tissue."
Cancer biomarkers are missing in action despite the availability of "highly sophisticated and powerful technologies" to discover them, as well as large investments, Diamandis wrote, adding that the last biomarker approved by the FDA -- in 2009 -- was HE4 protein, indicated for monitoring recurrence but not early detection of ovarian cancer."

Action Points  

---

• Note that this commentary documents the hazards of reports on promising biomarkers for cancer screening.



• The author points out that one of the major problems is finding biomarkers released in significant amounts from asymptomatic (usually small) tumors, but not from normal tissues.

HE4 and Mesothelin: Novel Biomarkers of Ovarian Cancer

"Addition of mesothelin to this combination did not show any improvement in the sensitivity. Conclusions: As a single marker, HE4 had the highest sensitivity for detecting ovarian carcinoma specially early stage disease. Combined CA125 and HE4 was a more accurate predictor of ovarian malignancy than either alone."

full free access: Biomarkers in Medicine - The dire need to develop a clinically validated screening method for the detection of early-stage ovarian

Note:  I remember the LPA very well (breakthrough screening test for ovarian cancer and the resulting media hype extraordinaire)

Key Excerpts:
Multiple initiatives have been undertaken to discover strategies that detect and diagnose early-stage EOC, including the search for novel serum biomarkers and the development of new technologies, such as contrast-enhanced ultrasonography, with a number of them demonstrating hopeful results. The ideal screening test for ovarian cancer would be a simple measurement of biomolecules in bodily fluids, such as blood, serum or urine, whose absolute concentrations could differentiate cancer from noncancer and be organ specific. In the last decade, insights into the EOC microenvironment, as well as technological advances, such as microarrays and proteomics, have triggered the discovery of hundreds of potential clinically valuable biomarkers:


▪ Lysophosphatidic acid (LPA) is a phospholipid derivative consisting of a glycerol backbone, a single fatty acid chain and a free phosphate group. LPA has a variety of isoforms depending on fatty acid-chain variability at the sn-1 position. LPA was found to be elevated in the serum, plasma and malignant effusions of women with ovarian cancer and has known functions in cell proliferation, invasion and angiogenesis [3]. This molecule initially became of interest in 1998 for its reported high sensitivity and specificity to detect early-stage ovarian cancer [3]; however, its utility as a screening biomarker has been limited owing to the difficulty of isolating and detecting the different isoforms in patients’ serum and its specificity for ovarian cancer;


▪ Human epididymal protein (HE)4 is a relatively new biomarker used to monitor disease recurrence and disease progression in patients with ovarian cancer. It is the product of the WFDC2 (HE4) gene, which is overexpressed in ovarian cancer. HE4 has exhibited increased sensitivity to detect stage I disease [4] and has demonstrated promise as a sensitive and specific biomarker when combined with CA125 and other molecules [5]; although, more studies remain to be done to warrant its use as a biomarker for the detection of early-stage EOC;


▪ Osteopontin (OPN) is a glycoprotein involved in cell adhesion, inflammation and tumorigenesis, with elevated levels seen in ovarian cancer [6]. Similar to HE4, OPN has been used in combination assays to identify ovarian cancer [7]; however, OPN is also elevated in other cancers and benign conditions, limiting its specificity to be used as an ovarian cancer biomarker;


▪ Kallikreins (KLKs) are serine proteases that function in cell growth, angiogenesis and invasion. KLKs are elevated in patient serum with ovarian cancer. KLK8 was reported to be associated with early disease, while KLK5, -6, -10 and -13 have been combined with CA125 to improve the accuracy of ovarian cancer detection [8,9];


▪ Claudins are components of tight junctions that create selective barriers and maintain cell polarity. Multiple claudins have been found to be elevated in ovarian cancer; however, their specificity has yet to be determined and verified [10].

..................

Of particular note, traditional genetic pedigree analysis of ovarian cancer patients may provide information to help identify high-risk populations; for example, inherited BRCA1 and -2 mutations  increase the risk for women to develop ovarian and/or breast cancer [12]. In addition, molecular profiling at the epigenetic level, such as miRNA profiling, may allow for the identification of novel biomarkers for early detection of ovarian cancer, given that these epigenetic changes might be detectable before the development of the physical tumor.
................
Despite these advances, at present, no clinically validated screening protocol for the detection of early-stage EOC exists. The discovery of novel biomarkers relies on obtaining a better understanding of the initiation and progression of EOC. Clinical validation and implementation of biomarkers will also benefit from advancements in new molecular and imaging technologies as patient care is optimized. Fortunately, hundreds of biomarkers have been identified; however, their clinical utility remains to be determined. In addition, the enhanced imaging capabilities of the ovary by ultrasound are providing practitioners with the ability to more accurately and precisely identify changes specific to the newly transformed ovary. The combination of these two modalities, biomarker panels and biologically based imaging may be the future. Therefore, we must forge ahead to develop a validated early-detection protocol that will not only decrease the number of advanced-stage diagnoses and deaths attributed to ovarian cancer but, most importantly, positively impact the future of women’s healthcare.

p53 autoantibodies as potential detection and prognostic biomarkers in serous ovarian cancer

IMPACT: Although their utility as a preoperative diagnostic biomarker, beyond CA 125 and HE4, is limited, p53-AAb are prognostic for improved overall survival.

2nd media article: HE4: Abbott gets FDA approval for ovarian cancer test - Chicago Breaking Business

"Abbott partnered with Fujirebio Diagnostics Inc. to develop the test. It also is approved for use in Europe, and other countries in the Asia Pacific and Latin American regions."

media article on HE4: FDA approves new test to monitor ovarian cancer

Comparison of a novel multiple marker assay vs the Risk of Malignancy Index for the prediction of epithelial ovarian cancer in patients with a pelvic

"CONCLUSION: The dual marker algorithm utilizing HE4 and CA125 to calculate a ROMA value achieves a significantly higher sensitivity for identifying women with EOC than does RMI."

Epithelial Ovarian Cancer Clinical Trial: A Trial Using Novel Markers to Predict Malignancy in Elevated-Risk Women [Conditions: Epithelial Ovarian Cancer; Interventions

Epithelial Ovarian Cancer Clinical Trial:

Brief Summary

Official Title: “A Randomized Controlled Trial Using Novel Markers to Predict Malignancy in Elevated-Risk Women”

Condition Keyword(s):

• Epithelial Ovarian Cancer

Intervention(s):

• Procedure: CA125 assay on Abbott Architect i1000SR platform
• Procedure: HE4 assay on Architect i1000SR platform
• Procedure: Transvaginal Ultrasound

The Novel Markers Trial will compare the safety, feasibility and effectiveness of two different epithelial ovarian cancer screening strategies that use CA125 and add HE4 as either a first or second line screen. This study is the next step in a larger research effort to develop a blood test that can be used as a screening method for the early detection of epithelial ovarian cancer.

Detection of the HE4 protein in urine as a biomarker for ovarian neoplasms

Abstract

The HE4 protein is overexpressed in ovarian carcinomas and can be detected in serum by an ELISA with sensitivity similar to CA125 and higher specificity for malignant disease. We now demonstrate that HE4 can also be detected in the urine at a specificity level of 94.4%, including 13/15 (86.6%) with stage I/II and 57/64 (89.0%) with stage III/IV disease and including 90.5% of patients with serous ovarian carcinoma. Assaying serum and urine from the same patients showed similar sensitivity. Our data indicate that measuring HE4 in urine may aid diagnosis and the monitoring of response to therapy.