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Lavage of the Uterine Cavity for the Diagnosis of Serous Tubal Intraepithelial Carcinoma (LUSTIC)

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ClinicalTrials.gov Identifier: NCT02039388

Recruitment Status : Recruiting

First Posted : January 17, 2014

Last Update Posted : February 17, 2020

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Sponsor:

Information provided by (Responsible Party):

Paul Speiser, Prof.MD,, Medical University of Vienna

Study Description

Brief Summary:

The current study aims at answering the scientific question, whether exfoliated cells from STICs get transported into the uterine cavity via the fallopian tube, and whether it is possible to detect those cells in the lavage fluid from the uterine cavity and proximal fallopian tubes.

To address this question, the investigators will study 20 lavage samples and their 20 corresponding STIC-positive tissue samples in women who opt for risk-reducing bilateral salpingo-oophorectomy (rrBSO) because of increased risk of high grade serous carcinoma of the pelvis (HGSC) (mostly carrying a BRCA mutation), without a history of tubal occlusion for sterilization. Women who opt to have the fallopian tubes removed but the ovaries preserved are eligible for the study too, as are women who opt for rrBSO plus hysterectomy.

Condition or disease	Intervention/treatment	Phase
Ovarian Epithelial Cancer Carcinoma in Situ Ovarian Cancer	Procedure: Lavage of the Cavum uteri and proximal Fallopian tubes, performed in the luteal phase of the female cycle	Not Applicable

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Detailed Description:

The term "high grade serous carcinoma" (HGSC) describes a group of ovarian, tubal and peritoneal cancers with an aggressive biological behavior. HGSC is the leading cause of death from gynecologic malignancy in western civilized countries. Women affected, usually have advanced stage disease with metastatic spread throughout the abdominal cavity at time of diagnosis. Five-year survival rates are in the range of 10 to 30 percent. The specificity of current diagnostic tools (CA-125 and transvaginal ultrasonography) is low and ineffective at detecting HGSC early enough to improve clinical outcomes. Definitive diagnosis of HGSC mostly relies on surgical confirmation. These findings underline the need for an effective test for early detection of HGSC. In the general population, the lifetime risk is 1.5 percent.

Women with germ line mutations in the BRCA1 and BRCA2 gene or a strong family history of epithelial ovarian cancer carry a high risk for breast cancer and/or HGSC development. Familial or inherited syndromes account for approximately 13 percent of cases of invasive epithelial ovarian and fallopian tube cancer. The lifetime risk of ovarian cancer is 35 to 46 percent in women with BRCA1 gene mutations and 13 to 23 percent in those with BRCA2 mutations. Again, even in this population with high-risk for HGSC, the specificity of CA-125 and transvaginal ultrasonography is still too low and ineffective to improve clinical outcomes.

Over the last years, increasing scientific evidence conglomerated that a large proportion of not only familial HGSC develop primarily in the lining of the fallopian tube, that resembles Müllerian epithelium. These precursor lesions are called "serous tubal intraepithelial carcinomas" (STICs) and are characterized by p53 overexpression on immunohistochemistry and high Ki-67 labelling index indicating a high proliferation index. In over 90 percent, STICs carry mutations in the TP53 tumor suppressor gene.

As for today, risk reducing bilateral salpingo-oophorectomy (rrBSO) is the most effective approach to reducing the risk of HGSC in high risk women. Among women with an increased risk of HGSC (most with BRCA mutations) who underwent rrBSO, 4 to 17 percent are found to have a STIC or even invasive neoplasm, and approximately 80 percent of these neoplasms are in the ampullar part of the fallopian tube.

Recent findings highlighted the malignant potential of STICs. On histopathological specimen, intraluminal shedding of tumor cells from STICs can be frequently demonstrated in the fallopian tube. This shedding of tumor cells from STICs appears to be a risk factor for early transperitoneal metastasis frequently found in HGSC. There is a strong clinical need for screening for STICs, since they are the precursor lesion of HGSC. These facts underline the importance of an effective - non-invasive - test for early detection of STICs.

The ovarian surface, the fallopian tubes, the uterine cavity and the peritoneal cavity all together form a communicating compartment. The physiological function of the ciliated lining of the tubes is to transport the egg into the uterine cavity after ovulation thus making it likely that exfoliated cells from STICs can be found in the uterine cavity.

A promising approach for the detection of STICs has been established by Paul Speiser and Robert Zeillinger (Molecular Oncology Group, Department of General Gynaecology and Gynaecologic Oncology, Medical University of Vienna, Austria). This approach is called the ALPINE technique (Austrian Lavage Procedure for the Detection of tubal Intraepithelial Neoplasms) (manuscript under preparation). To facilitate an quick and easy lavage of the uterine cavity and proximal tubes, a special catheter was developed (MEDICOPLAST, MF 13005, catheter for uterine and tubal lavage). The ALPINE technique includes a lavage of the uterine cavity and proximal fallopian tubes and subsequent analysis of this lavage fluid for the presence of pre-malignant and malignant cells.

For the proof of principle that tumor cells from ovarian cancer are shed and can be found in the lavages of the uterine cavity, uterine lavages were collected before a surgical intervention for suspected ovarian malignancy at our institution and at the Catholic University Leuven, Division Gynaecological Oncology, Belgium. After malignancy was confirmed, genetic changes in the TP53 and KRAS genes were determined in tumor tissue. In a set of 9 epithelial ovarian cancer patients (EOC) and 1 ovarian metastases of a signet ring carcinoma, the presence of these genetic changes was examined in lavage samples, using digital droplet PCR (ddPCR). 10 genetic changes were identified in tumor tissue of these patients and 9/10 (90%) of these changes were detected in the corresponding lavage specimen too.

Furthermore, a filter approach, followed by p53 immunofluorescence staining was established, confirming the presence of tumor cells in the lavage sample of one additional patient.

In a next step, lavage samples of 23 ovarian carcinoma patients, and if applicable corresponding tumor tissue, were analysed through deep sequencing by the group of Bert Vogelstein (Johns Hopkins University, Baltimore, USA). The presence of genetic changes, indicative for ovarian cancer, could be confirmed in 18/23 (78.3%) lavage specimen including both, early and advanced stages.

These results are proof that ovarian cancer cells are shed into the fallopian tubes and uterine cavity, and can be collected through our ALPINE technique. The fact that ovarian cancer cells were detected with high sensitivity in the lavage of the uterine cavity and proximal tubes shows that this approach has potential in early diagnosis. Therefore, the investigators are confident that this method could be applied in detection of premalignant changes in high risk patients, as well.

Aim of the study:

Methods:

To address this question, the investigators will study 20 lavage samples and their 20 corresponding STIC-positive tissue samples in women who opt for rrBSO because of increased risk of HGSC (mostly carrying a BRCA mutation), without a history of tubal occlusion for sterilization. Women who opt to have the fallopian tubes removed but the ovaries preserved are eligible for the study too, as are women who opt for rrBSO plus hysterectomy.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	600 participants
Allocation:	N/A
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Diagnostic
Official Title:	Pilot Study of the Lavage of the Uterine Cavity for the Diagnosis of Serous Tubal Intraepithelial Carcinoma
Study Start Date :	November 2013
Estimated Primary Completion Date :	November 2020
Estimated Study Completion Date :	January 2021

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Ovarian cancer

Genetic and Rare Diseases Information Center resources: Ovarian Cancer Ovarian Epithelial Cancer

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
High risk patients for breast and/or ovarian cancer	Procedure: Lavage of the Cavum uteri and proximal Fallopian tubes, performed in the luteal phase of the female cycle

Outcome Measures

Primary Outcome Measures :

Detection of "Serous Tubal Intraepithelial Carcinomas (STICs)" in the lavage fluid from the uterine cavity and proximal fallopian tubes. [ Time Frame: preoperative ]
Women who opt for rrBSO or opt to have the fallopian tubes removed but the ovaries preserved, and women who opt for rrBSO plus hysterectomy. The lavage can be done either in an outpatient setting or in the operating theatre under general anaesthesia.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 80 Years (Adult, Older Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

BRCA1/2 mutation carriers
strong family history of breast and/or ovarian cancer suggestive for a germ line mutation in a relevant gene

Exclusion Criteria:

pregnant
incapacitated persons

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02039388

Contacts

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Contact: Paul Speiser, Univ.Prof.Dr.med.	+436765367608	paul.speiser@meduniwien.ac.at
Contact: Claudia Duwe	+436765536415	c.duwe@ovartec.at

Locations

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Austria
Medical University Graz - Universitätsklinik f. Frauenheilkunde u. Geburtshilfe	Active, not recruiting
Graz, Austria, 8036
Kepler University Linz	Not yet recruiting
Linz, Austria, 4040
Contact: Wolfgang Geiling wolfgang.geiling@kepleruniklinikum.at
Medical University Vienna, Dptm. of Obstetrics & Gynaecology	Recruiting
Vienna, Austria, 1090
Contact: Paul Speiser, Prof., M.D. +436765367608 paul.speiser@meduniwien.ac.at
Contact: Valentina Paspalj, M.D. +43 69917258148 valentina.paspalj@meduniwien.ac.at
Principal Investigator: Paul Speiser, M.D.
Belgium
Catholic University Leuven - Department of Obstetrics and Gynaecology	Recruiting
Leuven, Belgium, 3000
Contact: Ignace Vergote, Prof.Dr. +32/1634 ext 4208 ignace.vergote@uzleuven.be
Contact: Joke de Roover +32 16 34 ext 74 19 joke.deroover@uz.kuleuven.ac.be
Sub-Investigator: Adriaan Vanderstichele, M.D.
Czechia
Gynecological Oncology Center Department of Obstetrics and Gynecology Charles University in Prague	Recruiting
Prague, Prague 2, Czechia, 12800
Contact: David Cibula, Prof.
Contact: Zikan Michael, MD., PhD +420 224 967 451 Michal.Zikan@lf1.cuni.cz
Masaryk Memorial Cancer Institute Brno	Recruiting
Brno, Czechia, 60200
Contact: Gabriel Jelenek, MUDr. gabrieljelenek@gmail.com
Charles University Pilsen	Recruiting
Pilsen, Czechia, 30605
Contact: Jiri Bouda, Dr. Jiří Bouda <boudaj@medima.cz>
Denmark
Copenhagen University Hospital Rigshospitalet	Terminated
Copenhagen, Denmark, 2100
Germany
Charité Univ., Berlin-Campus Virchow Clinic	Terminated
Berlin, Germany, 13353
Klinik Essen Mitte (KEM)	Terminated
Essen, Germany, 92 45136
Clinical Center University of Munich	Terminated
München, Germany, 80799
Ireland
Trinity Centre for Health Sciences St. James's Hospital	Active, not recruiting
Dublin, Ireland, 8
Netherlands
Radboud University Medical Centre	Terminated
Nijmegen, Netherlands, 6525 GA
United Kingdom
University College London Cancer Institute	Recruiting
London, United Kingdom, WC1E 6HX
Contact: Martin Widschwendter, Prof. m.widschwendter@ucl.ac.uk
Contact: Adam Rosenthal, M.D. adam.rosenthal@ucl.ac.uk

Sponsors and Collaborators

Medical University of Vienna

Investigators

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Principal Investigator:	Paul Speiser, Univ.Prof.Dr.med.	Medical University Vienna, Dptm. of Obstetrics & Gynaecology

More Information

Publications:

Maritschnegg E, Wang Y, Pecha N, Horvat R, Van Nieuwenhuysen E, Vergote I, Heitz F, Sehouli J, Kinde I, Diaz LA Jr, Papadopoulos N, Kinzler KW, Vogelstein B, Speiser P, Zeillinger R. Lavage of the Uterine Cavity for Molecular Detection of Müllerian Duct Carcinomas: A Proof-of-Concept Study. J Clin Oncol. 2015 Dec 20;33(36):4293-300. doi: 10.1200/JCO.2015.61.3083. Epub 2015 Nov 9.

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Responsible Party:	Paul Speiser, Prof.MD,, Univ.Prof.Dr.med., Medical University of Vienna
ClinicalTrials.gov Identifier:	NCT02039388
Other Study ID Numbers:	EK 1766/2013
First Posted:	January 17, 2014 Key Record Dates
Last Update Posted:	February 17, 2020
Last Verified:	February 2020

Keywords provided by Paul Speiser, Prof.MD,, Medical University of Vienna:


Ovarian Epithelial Cancer Serous Intraepithelial Carcinoma (STIC) BRCA1 gene BRCA2 gene Mutation Neoplasms	Glandular and Epithelial Ovarian Neoplasms Ovarian cancer Carcinoma in situ family history breast cancer family history ovarian cancer

Additional relevant MeSH terms:

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Carcinoma Ovarian Neoplasms Carcinoma, Ovarian Epithelial Carcinoma in Situ Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Endocrine Gland Neoplasms	Neoplasms by Site Ovarian Diseases Adnexal Diseases Genital Diseases, Female Genital Neoplasms, Female Urogenital Neoplasms Endocrine System Diseases Gonadal Disorders

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