Identification and Characterization of Endometrial Cancer With Specific Tumor Markers in Serum and Endometrial Tissue

• ClinicalTrials.gov Identifier: NCT03498924
• Recruitment Status: Completed
• First Posted: April 17, 2018
• Last Update Posted: February 11, 2020
• Sponsor: Fundación Investigación Sanitaria en León
• Information provided by (Responsible Party): Tatiana Cuesta-Guardiola, Fundación Investigación Sanitaria en León

Study Description

Brief Summary:

Endometrial cancer is the most common malignant tumor of the female genital tract in our means. The diagnosis is made by endometrial biopsy sampling with anatomopathological analysis which pinpoints the cell line and the level of cell differentiation. Its treatment is surgical with adjuvant treatment (chemotherapy or radiotherapy) besides, depending on the staging. Thus far, in the first diagnosis it is only request the tumor marker CA125 in serum, but there are studies that identify the HE4 protein in blood as a feasible marker for endometrial cancer. Furthermore, the staging changes the surgical and the adjuvant treatment: in its early stages, surgery is based on hysterectomy and double adnexectomy, however, in later stages it is necessary to add pelvic and paraaortic lymphadenectomy with the associated comorbidity. This makes extremely important that the preoperative diagnosis is accurate. The aim of this study is to identify and characterize the HE4, Ki67, p53 and other potential biomarkers in endometrial tissue in order to diagnose patients with disease only with a biopsy. Moreover, the investigators are searching for connections among these markers and prognostic factors such as grade of cell differentiation, cell line, lymphatic affectation, tumor stage or even features as survival or disease free survival.

Condition or disease	Intervention/treatment
Endometrial Neoplasm Malignant	Diagnostic Test: Measure of biomarkers in serum and endometrial tissue

Detailed Description:

List of abbreviations:

• HE4: Human Epididymis Protein 4
• CA125: Carbohydrate Antigen 125
• Ki67: antigen KI67
• EC: Endometrial Cancer
• CT: Computed Tomography
• NMR: Nuclear Magnetic Resonance
• FIGO: International Federation of Gynecology and Obstetrics

The purpose of this study is:

• The proportion of positive H-score of HE4, as quantified in endometrial tissue. It is significantly higher in patients with endometrial cancer than in non-EC patients.
• Percentage of HE4, CA125 and other markers positives in cases and controls.
• Concentration of HE4 in tissue, as measured by H-score, correlates linearly with HE4 concentration in serum, as measured in terms of ppmol/l.
• Differences in serum CA125 levels between cases and controls.
• Quantification of tissue tumor markers of EC patients, per disease stages.
• Relation of the immunohistochemistry intensity with survival and disease-free survival times.
• Analysis of other risk factors adjusting for known variables like age, menopausal status, hypertension, diabetes or obesity.
• Feasibility of the technique.

Steps in the study:

1. Patients enter the study when a diagnosis of endometrial cancer is done. As it is ordinary in the clinical practice the diagnosis is made with an endometrial tissue sample taken in the office which is afterwards studied by a pathologist, who makes the final diagnosis.
2. Patients undergo the regular preoperative study with pelvic ultrasound, CT and/or NMR for the extension study, blood tests and the preanaesthetic consultation. As it is registered in the protocol of Endometrial Cancer Treatment.
3. Then a matched control is selected from the group of patients that are going to be hysterectomized for other non-malignant reasons (abdominal way, vaginal, or laparoscopic way). Variables considered for matching are: age (variability of five years), pre or postmenopausal status, hypertension, obesity and diabetes.
4. Every patient then is asked for accept and sign the informed consent. The next step is to prepare the patient for the surgery. In this moment the serum sample is taken. Subsequently the surgery will be performed.
5. Then the anatomopathological study is conducted over the preoperative tissue sample. HE4 marker in endometrial tissue is defined by H-Score while Ki67 and p53 are defined as usual. Although Ki67 is matched in > or <25% of expression instead of 14% as it is made in breast cancer tissue samples.
6. After discharge, the patient will be follow-up for two years in order to register the evolution of the disease.

Study Design

• Study Type: Observational
• Actual Enrollment: 80 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: Prospective Identification and Characterization of Endometrial Cancer With Specific Tumor Markers in Serum and Endometrial Tissue Samples
• Actual Study Start Date: August 1, 2017
• Actual Primary Completion Date: August 1, 2018
• Actual Study Completion Date: June 1, 2019

Groups and Cohorts

Group/Cohort	Intervention/treatment
CASES; Patients with endometrial cancer	Diagnostic Test: Measure of biomarkers in serum and endometrial tissue; Blood sample and endometrial sample
CONTROLS; Matched controls without neoplasm disease	Diagnostic Test: Measure of biomarkers in serum and endometrial tissue; Blood sample and endometrial sample

Outcome Measures

Primary Outcome Measures :

1. The proportion of positive H-score of HE4. [ Time Frame: Two years ]
   HE4 quantified in endometrial tissue is significantly higher in patients with endometrial cancer than in non-EC patients

Secondary Outcome Measures :

1. Concentration of HE4 in tissue correlates linearly with HE4 in serum. [ Time Frame: Two years ]
   Comparison of tissue H-score with ppmol/L in serum
2. Difference in preoperative serum CA125 levels in cases and controls. [ Time Frame: Two years ]
   Measured in terms of U/mL
3. Difference in preoperative serum HE4 levels in cases and controls. [ Time Frame: Two years ]
   Measured in terms of ppmol/L
4. Disease stages [ Time Frame: Two years ]
   FIGO stages: postsurgical classification drawn up to define the extent of spread of genital cancer
5. Tissue tumor marker HE4 [ Time Frame: Two years ]

   H-score determination: Immunohistochemistry results can be evaluated by a semiquantitative approach used to assign an H-score (or "histo" score) to tumor samples. Cytoplasmic staining will be graded for intensity (0-negative, 1-weak, 2-moderate and 3-strong) and the percentage of positive cells was scored as 0 (0%), 1 (1-10%), 2 (11-50%) and 3 (51-100%).

   Single scale with scores 0-9 will be obtained by multiplying the intensity and the percentage staining score, and a total score will be calculated by grouping score 0 in total score 0, 1-3 in total score 1, 4-6 in total score 2 and 7-9 in total score 3.

   The assumption is that as higher is the score the level of cell differentiation would be minor.

6. Relation of the immunohistochemistry intensity in H-score with overall survival [ Time Frame: Through study completion, an average of 2 years ]
   HE4 biomarker measured with H-score in endometrial tissue, explained in outcome 5, in relation to length of time of survival
7. Relation of the immunohistochemistry intensity in H-score with disease-free survival [ Time Frame: Through study completion, an average of 2 years ]
   HE4 biomarker measured with H-score in endometrial tissue, explained in outcome 5, in relation to length of time after primary treatment that the patient survives without any signs or symptoms of that cancer.
8. Analysis of outcomes in relation to age [ Time Frame: Two years ]
   Age of patients is one of the known risk factors for EC, we are going to analysis the results of the study with this variable. As elder the relative risk is higher though there is no accurate cut-off point.
9. Analysis of outcomes in relation to menopausal status [ Time Frame: Two years ]
   Menopausal status is determined by questionnaire during the preoperative consultant. It is another risk factor for EC, the postmenopausal status has higher relative risk than premenopausal status.
10. Analysis of outcomes in relation to hypertension [ Time Frame: Two years ]
    Hypertension is diagnosed previously to surgery as Blood Pressure over 140/90 mm Hg in several measures. There is a known high relative risk of EC in patients diagnosed with hypertension.
11. Analysis of outcomes in relation to diabetes [ Time Frame: Two years ]
    Diabetes is a disease previously diagnosed by high glucose levels in blood. There is a known high relative risk of EC in patients diagnosed with diabetes.
12. Analysis of outcomes in relation to obesity [ Time Frame: Two years ]
    Obesity is defined as BMI >27 kg/m2. There is a known high relative risk of EC in patients diagnosed with obesity.

Biospecimen Retention:   Samples With DNA

Serum and endometrial tissue sample of every patient

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes
• Sampling Method: Probability Sample

Study Population

Every patient who is treated in Hospital de Leon of endometrial disease between August 2017 and the end of the recruitment

Criteria

Inclusion Criteria:

• Female
• Of legal age (≥ 18 years)
• Wish to participate in the research study and sign consent forms voluntarily
• Patients diagnosed of endometrial cancer derived to hysterectomy

Exclusion Criteria:

• Patients that underwent surgery for other malignant pathologies, whether for ovarian carcinoma, cervical carcinoma or uterine sarcoma.

Contacts and Locations

Locations

Spain

Tatiana Cuesta-Guardiola

Leon, Spain, 24080

Sponsors and Collaborators

Fundación Investigación Sanitaria en León

Investigators

• Principal Investigator: Tatiana Cuesta-Guardiola, Medicine; Hospital de Leon

More Information

Publications of Results:

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018 Jan;68(1):7-30. doi: 10.3322/caac.21442. Epub 2018 Jan 4.

Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer. 1987 Oct 15;60(8 Suppl):2035-41.

Li X, Gao Y, Tan M, Zhuang H, Gao J, Hu Z, Wang H, Zhu L, Liu J, Lin B. Expression of HE4 in Endometrial Cancer and Its Clinical Significance. Biomed Res Int. 2015;2015:437468. doi: 10.1155/2015/437468. Epub 2015 Oct 11. Erratum in: Biomed Res Int. 2018 Sep 12;2018:6795629.

Bignotti E, Ragnoli M, Zanotti L, Calza S, Falchetti M, Lonardi S, Bergamelli S, Bandiera E, Tassi RA, Romani C, Todeschini P, Odicino FE, Facchetti F, Pecorelli S, Ravaggi A. Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients. Br J Cancer. 2011 Apr 26;104(9):1418-25. doi: 10.1038/bjc.2011.109. Epub 2011 Apr 5.

• Responsible Party: Tatiana Cuesta-Guardiola, Principal investigator, Fundación Investigación Sanitaria en León
• ClinicalTrials.gov Identifier: NCT03498924
• Other Study ID Numbers: STUDY17104
• First Posted: April 17, 2018
• Last Update Posted: February 11, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tatiana Cuesta-Guardiola, Fundación Investigación Sanitaria en León:

tumor marker; HE4; CA125; staging; diagnosis; Endometrial Cancer

Additional relevant MeSH terms:

Endometrial Neoplasms; Neoplasms; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Uterine Diseases