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

• ClinicalTrials.gov Identifier: NCT02039388
• Recruitment Status: Completed
• First Posted: January 17, 2014
• Last Update Posted: September 2, 2022
• Sponsor: Medical University of Vienna
• 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

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:

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.

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

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 701 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
• Actual Study Start Date: November 2013
• Actual Primary Completion Date: December 31, 2021
• Actual Study Completion Date: December 31, 2021

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 :

1. 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

• 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

Locations

Austria

Medical University Graz - Universitätsklinik f. Frauenheilkunde u. Geburtshilfe

Graz, Austria, 8036

Kepler University Linz

Linz, Austria, 4040

Medical University Vienna, Dptm. of Obstetrics & Gynaecology

Vienna, Austria, 1090

Belgium

Catholic University Leuven - Department of Obstetrics and Gynaecology

Leuven, Belgium, 3000

Czechia

Gynecological Oncology Center Department of Obstetrics and Gynecology Charles University in Prague

Prague, Prague 2, Czechia, 12800

Masaryk Memorial Cancer Institute Brno

Brno, Czechia, 60200

Charles University Pilsen

Pilsen, Czechia, 30605

Denmark

Copenhagen University Hospital Rigshospitalet

Copenhagen, Denmark, 2100

Germany

Charité Univ., Berlin-Campus Virchow Clinic

Berlin, Germany, 13353

Klinik Essen Mitte (KEM)

Essen, Germany, 92 45136

Clinical Center University of Munich

München, Germany, 80799

Ireland

Trinity Centre for Health Sciences St. James's Hospital

Dublin, Ireland, 8

Netherlands

Radboud University Medical Centre

Nijmegen, Netherlands, 6525 GA

United Kingdom

University College London Cancer Institute

London, United Kingdom, WC1E 6HX

Sponsors and Collaborators

Medical University of Vienna

Investigators

• 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 Mullerian 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.

• 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
• Last Update Posted: September 2, 2022
• Last Verified: September 2022

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:

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; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders