A 3D Bioprinted Hormone-producing Model for BRCA Mutated Patients After Risk Reducing Surgery: the DISC-OVARY Trial (DISC-OVARY)

October 21, 2024 updated by: MARCHETTI CLAUDIA, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Selecting theca and granulosa cells from removed ovaries of BRCA1/2mut patients undergoing Risk-reducing salpingo-oophorectomy (RRSO) and developing a 3D bioprinted hormone-producing bioprosthetic model. If efficacy and tolerability are confirmed in vivo, this bioprosthetic model might be used to replace hormones' production in BRCA mutated patients undergoing prophylactic surgery.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Background and Rationale Women carrying germline BReast CAncer gene (BRCA) 1/2 mutations have an increased lifetime risk of breast and ovarian cancers (72% and 44% for BRCA1 and 69% and 17% for BRCA2, respectively). Risk-reducing salpingo-oophorectomy (RRSO) by the age of 40 (postponable to age of 45 for BRCA2mut) is the standard of care in ovarian cancer risk reduction (about 80%). Although potentially lifesaving, RRSO may negatively affect quality of life and impair long-term health (cardiovascular disease, osteoporosis and impairment of immune response).

To overcome these side effects, hormone replacement therapy (HRT) is crucial but remains a major concern, especially due to its negative effects (potential breast cancer risk, thromboembolic events) and, overall, due to the long-term safety lack of data. Synthetic and animal-derived hormones seem to be associated with breast cancer risk. Although breast cancer risk is lower for bioidentical hormones (i.e. estriol), data continue to be discordant. Several evidence still sustain estriol's impact on breast cancer (especially for lobular histotype; OR 2.0, 95% CI 1.3-3.2) and endometrial disease (endometrial cancer: OR 3.0, 95% CI 2.0-4.4 and endometrial atypical hyperplasia: OR 8.3, 95% CI 4.0-17.4, respectively). Furthermore, estriol's efficacy on cardiovascular disease and osteoporosis is still unclear when compared to other estrogen compounds. Side effects of estriol therapy may include breast tenderness, nausea, bloating, mood changes, headache, and vaginal bleeding or spotting. Moreover, all the HRT's administration routes (oral, transdermal, and vaginal) need daily/frequent assumption, thus compliance of the patients is essential and adherence to long-term therapy in developed countries is reported around 50% with a high risk of forgetfulness or discontinuation. Each route also has specific disadvantages (i.e. the risk of thromboembolism in the oral one). Finally, HRT may influence other hormones' production: it increases T4 dosage requirements of women being treated for primary hypothyroidism as well as alter the pituitary-thyroid axis in euthyroid women. While for cortisol level findings are still inconsistent, hormone exogenous intake does not permit to follow the daily hormonal fluctuation. Aging and hypoestrogenism, in postmenopausal women, determine immune system changes which may play a crucial role in the development of postmenopausal diseases (diabetes or atherosclerosis) and may be negatively influenced by HRT. Preliminary data of a recent MITO group survey revealed that only 70% of gynecologists recommend HRT after RRSO due to oncological safety concerns and low women's requests (more than 70% of cases were oral prescriptions, while only 24% preferred local administration).

In conclusion, for some women, the concern of menopause risks act as a deterrent for a lifesaving procedure (RRSO). In this scenario, it is fundamental to provide a new strategy for BRCA mutated patients, in order to reduce menopausal drawbacks without exposing participants to a higher breast cancer risk, reproducing the physiological hormonal rhythm without compliance issue. The 3D bioprinted hormone-producing model from patients' own autologous cells could meet this need.

HYPOTHESIS The investigators hypothesize to select theca and granulosa cells from removed ovaries of BRCA1/2mut patients undergoing RRSO, avoiding the epithelial ones at risk of developing cancer, and use those cells to develop a 3D bioprinted hormone-producing bioprosthetic model in order to replace patients' own production.

AIMS Primary endpoint: Restore normal estrogen and progesterone serum level in participants undergoing RRSO by the 3D bioprinted hormone-producing model's implant.

EXPERIMENTAL DESIGN No study has previously investigated the feasibility of 3D bioprinted hormone-producing model, hence this configures as a pilot study which, as such, does not need any formal sample size calculation.

The proposed research project aims to select theca and granulosa cells from patients' removed ovaries, combine them with different ratios of extracted mesenchymal cells; print them onto the prosthetic model scaffolds and assess the hormone production.

IMPACT ON CANCER The results of the pilot project will provide a 3D bioprinted model able to produce estrogens and progesterone in vitro. If functionality is confirmed in vivo, the model might be used in BRCA mutated patients allowing them to avoid surgery induced menopause's side effects. Specifically, a 3D bioprinted hormone-producing bioprosthetic model would provide patients with a viable alternative to surgery-induced menopause and traditional HRT.

Study Type

Interventional

Enrollment (Estimated)

3

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Rome, Italy, 00168
        • Day Hospital Tumori Femminili, Policlinico Universitario Fondazione Agostino Gemelli, IRCCS

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Women between 18-40 years old;
  • BRCA1/2 germline mutations;
  • Completed childbearing;
  • Willing to undergo RRSO;
  • Negative final histological examination;
  • No previous breast cancer.

Exclusion Criteria:

  • Other malignancies;
  • Final histological examination reporting malignant disease (any);
  • Desire of fertility sparing.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: BRCAmut patients
germinal BRCA1/2 mutated (BRCAmut) patients undergoing risk reducing salpingo-oophorectomy whose ovaries will be used to select theca and granulosa cells for the 3D bioprinted device.
Procedure: Theca and Granulosa Cell Isolation
These patients will receive standard procedure during the risk reducing surgery but their ovaries will be used to extract theca and granulosa cells which will be used for the 3D bioprinted device's realisation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
oestrogens and progesterone's levels
Time Frame: minumum 3 months
(Unit: pg/mL for both hormones)
minumum 3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Investigators

  • Principal Investigator: Claudia Marchetti, Professor, Policlinico Universitario Fondazione Agostino Gemelli, IRCCS, Rome, Italy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 10, 2024

Primary Completion (Estimated)

June 1, 2026

Study Completion (Estimated)

June 1, 2027

Study Registration Dates

First Submitted

June 26, 2024

First Submitted That Met QC Criteria

July 9, 2024

First Posted (Actual)

July 11, 2024

Study Record Updates

Last Update Posted (Actual)

October 23, 2024

Last Update Submitted That Met QC Criteria

October 21, 2024

Last Verified

October 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DISC-OVARY

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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