A Bidirectional Cohort Study on Prophylactic Resection Surgery in Populations at Moderate-to-High Risk for Hereditary Ovarian Cancer

Обзор

The goal of this multi-center observational study is to learn about the effectiveness and safety of different prophylactic (preventive) surgical options in women at moderate-to-high genetic risk for hereditary ovarian cancer (HOC). The main questions it aims to answer are: Does individualized prophylactic surgery (such as removing fallopian tubes now and delaying ovary removal) effectively reduce the risk of developing ovarian cancer compared to standard care or close monitoring? How do these different surgical interventions affect a woman's ovarian function and quality of life? What Participants Will Do: Participants who are healthy carriers of specific genetic mutations (such as BRCA1/2, RAD51C/D, etc.) will be followed in a bidirectional cohort. Depending on the medical care and surgical path they choose with their doctors (Standard RRSO, Delayed Oophorectomy, or Close Monitoring), researchers will collect their clinical data, surgical pathology results, and follow-up information regarding cancer incidence and quality of life for 3 years.

Подробное описание

1. Study Rationale and Background Epithelial ovarian cancer (OC) remains a significant health burden in China, with high mortality due to the lack of effective early screening methods. Approximately 20% of OC cases are attributed to hereditary factors, primarily germline pathogenic variants in BRCA1/2 and other homologous recombination repair (HRR) genes.

The traditional standard for risk reduction is Risk-Reducing Salpingo-Oophorectomy (RRSO). However, the "dualistic model" of ovarian carcinogenesis suggests that a significant proportion of high-grade serous carcinomas (HGSC) originate as Serous Tubal Intraepithelial Carcinoma (STIC) in the fallopian tubes. This provides a biological rationale for Prophylactic Salpingectomy with Delayed Oophorectomy (PSDO, also known as RS-DO). This study aims to establish a Chinese bidirectional cohort to evaluate the effectiveness, safety, and impact on quality of life (QoL) of individualized prophylactic surgical strategies. 2. Study Design and Cohort Construction This is a bidirectional (combined retrospective and prospective) cohort study.

Retrospective Component: Data will be extracted from clinical records dating back to 2020 for individuals who meet the high-risk genetic criteria and have previously undergone risk-reducing surgery or entered clinical monitoring.

Prospective Component: Eligible participants will be recruited and followed for a minimum of 5 years. Participants are categorized into three cohorts based on the clinical intervention received:

RRSO Group: Concomitant removal of fallopian tubes and ovaries.

RS-DO Group: Initial salpingectomy followed or not followed by delayed oophorectomy (typically at age 45-50 or based on mutation type).

Close Monitoring Group: For those declining surgery, intensive surveillance via transvaginal ultrasound and serum CA-125/HE4 testing. 3. Quality Assurance and Registry Procedures

To ensure the highest data integrity, the following procedures are implemented:

Centralized Pathology Review: All surgical specimens from prophylactic procedures must undergo the SEE-FIM (Sectioning and Extensively Examining the FIMbria) protocol to detect occult STIC or early invasive carcinoma.

Data Validation: An Electronic Data Capture (EDC) system is utilized with automated data checks for range, consistency, and logical errors.

Source Data Verification (SDV): Regular on-site or remote audits will be conducted on 20% of the registry entries to verify accuracy against primary medical records and genetic testing reports.

Data Dictionary: All variables are predefined in a comprehensive data dictionary. Genetic variants are classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Clinical complications are graded using the Clavien-Dindo classification. 4. Statistical Analysis Plan (SAP)

Sample Size: Based on the estimated incidence of OC in the Chinese high-risk population, the study aims to enroll approximately 480 participants (160 per arm) to provide sufficient power (80%) for survival analysis.

Primary Endpoint Analysis: The cumulative incidence of ovarian, fallopian tube, and peritoneal cancer will be estimated using the Kaplan-Meier method. Differences between intervention groups will be compared using the Log-rank test and Cox Proportional Hazards Models, adjusting for age, parity, and specific mutation types (e.g., BRCA1 vs. BRCA2 vs. RAD51C/D).

Secondary Endpoint Analysis: Changes in menopausal symptoms and sexual function scores (GCS, SF-36, FSFI) will be analyzed using Repeated Measures ANOVA (RM-ANOVA) or ANCOVA to adjust for baseline differences and hormone replacement therapy (HRT) use.

Missing Data: A multiple imputation approach will be used for missing covariates, while sensitivity analysis will be performed to assess the impact of loss to follow-up. 5. Standard Operating Procedures (SOPs)

The registry operates under standardized protocols for:

Standardized pre-test and post-test genetic counseling.

Uniform surgical techniques for salpingectomy and oophorectomy.

Standardized follow-up intervals (every 6-12 months).

Adverse event reporting and management of unexpected pathological findings (STIC).

Первичные конечные точки

• Incidence of Ovarian Cancer [Срок оценки: From the date of enrollment/surgery up to 15 years.]

Вторичные конечные точки (4)

• Incidence of Breast Cancer [Срок оценки: From the date of enrollment up to 15 years.]
• Incidence of Serous Tubal Intraepithelial Carcinoma (STIC) [Срок оценки: At the time of prophylactic surgery (approx. 1 day)]
• Comprehensive Assessment of Quality of Life and Menopausal Symptoms [Срок оценки: Baseline, 1 month, 6 months and 1 year post-enrollment.]
• Evaluation of Psychological Distress [Срок оценки: Baseline, 1 month, 6 months and 1 year post-enrollment.]

Критерии участия

Критерии включения

• Gender: Female. Age: 18 years or older at the time of enrollment.Genetic Risk: Documented carriers of pathogenic or likely pathogenic germline mutations in high-risk ovarian cancer susceptibility genes (including BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2). Data Availability: Willing to provide informed consent and allow access to clinical records, genetic testing reports, and follow-up data (bidirectional cohort). Psychosocial Status: Ability to complete quality of life and psychological assessment scales (e.g., GCS, SF-36, FSFI).

Критерии исключения

• Prior Malignancy: History of ovarian, fallopian tube, or primary peritoneal cancer prior to the baseline intervention. Synchronous Malignancy: Diagnosis of any other advanced-stage malignancy. Inability to Follow-up: Significant psychological, social, or geographical factors that would prevent regular long-term follow-up (3 years). Previous Extensive Pelvic Surgery: History of extensive pelvic surgery that precludes the feasibility of laparoscopic prophylactic salpingectomy or oophorectomy.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Китай · 1 центр

• Peking University Third Hospital — Пекин

Публикации

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Идентификаторы

NCT: NCT07532434 · M20250883

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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