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

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

NCT ID: NCT06497270

Condition: BRCA Mutation
Estrogen Deficiency
Surgical Menopause
Menopause Related Conditions
Menopause, Premature
Ovarian Cancer

Conditions: Official terms:
Ovarian Neoplasms
Menopause, Premature
Primary Ovarian Insufficiency

Conditions: Keywords:
BRCA mutation
Surgical menopause
ovarian cancer prevention
estrogen deficiency

Study type: Interventional

Study phase: N/A

Overall status: Active, not recruiting

Study design:

Allocation: N/A

Intervention model: Single Group Assignment

Intervention model description: PILOT study

Primary purpose: Prevention

Masking: None (Open Label)

Intervention:

Intervention type: Procedure
Intervention name: Theca and Granulosa Cell Isolation
Description: 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.
Arm group label: BRCAmut patients

Summary: 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.

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.

Criteria for eligibility:
Criteria:
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.

Gender: Female

Gender based: Yes

Minimum age: 18 Years

Maximum age: 40 Years

Healthy volunteers: No

Locations:

Facility:
Name: Day Hospital Tumori Femminili, Policlinico Universitario Fondazione Agostino Gemelli, IRCCS

Address:
City: Rome
Zip: 00168
Country: Italy

Start date: October 10, 2024

Completion date: June 1, 2027

Lead sponsor:
Agency: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Agency class: Other

Source: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Record processing date: ClinicalTrials.gov processed this data on November 12, 2024

Source: ClinicalTrials.gov page: https://clinicaltrials.gov/ct2/show/NCT06497270