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

• 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.

• 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.

• 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.

• 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.

• 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).

Inclusion criteria

• 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).

Exclusion criteria

• 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.