Is Risk-Reducing Surgery Necessary for Inherited Non-BRCA Genetic Mutations?

A New Debate Begins in Ovarian Cancer Prevention

Ovarian cancer remains a common gynecological cancer in women and is often diagnosed at an advanced stage. An inherited genetic predisposition is identified in approximately 20% of patients with ovarian cancer, with the BRCA1 and BRCA2 genes among the best-known determinants of this risk. Today, however, “risk-reducing surgery” is increasingly being performed in people carrying non-BRCA genetic mutations to lower this risk.

An important question arises, however: Is preventive removal of the ovaries and fallopian tubes really necessary in people with non-BRCA genetic mutations? The results of a new multicenter study investigating this question offer valuable clues that may help guide decisions in this area.

Three pie charts summarizing genetic predisposition and the distribution of mutations in ovarian cancer

Study Summary: Women With BRCA and Non-BRCA Mutations Compared

The study, presented at the United States and Canadian Academy of Pathology (USCAP) 2025 meeting, compared 152 women carrying non-BRCA mutations with 388 women carrying a BRCA1 or BRCA2 mutation. Both groups had undergone risk-reducing bilateral salpingo-oophorectomy (removal of the ovaries and fallopian tubes).

• HGSC (High-Grade Serous Carcinoma): This is the most aggressive and common subtype of ovarian cancer. It is usually diagnosed at an advanced stage and spreads rapidly.
• STIC (Serous Tubal Intraepithelial Carcinoma): This is a precancerous process that develops in the fallopian tubes and is considered a precursor to HGSC. It is identified microscopically by high-grade cellular atypia.

Study Data:

• Non-BRCA group:

  • Mean age: 54.8 (range 30-81 years)

  • Mutations: PALB2 (45%), BRIP1 (33%), ATM (8%), CHEK2 (4%), RAD51 (4%)

  • Other mutations: BARD1, Li-Fraumeni syndrome, Lynch syndrome

  • Most common reasons for genetic testing: Personal history of breast cancer (51%), family history (27%)

  • Operations performed: 97% bilateral salpingo-oophorectomy, 3% hysterectomy + salpingo-oophorectomy

  • Result: No patient had high-grade serous carcinoma (HGSC) or serous tubal intraepithelial carcinoma (STIC)

• BRCA1/2 group:

  • Mean age: 47.7

  • BRCA1 (51%), BRCA2 (48%), both (1%)

  • Operations performed: 65% bilateral salpingo-oophorectomy, 27% hysterectomy + salpingo-oophorectomy

  • Results:

    • STIC in 3 cases

    • High-grade serous carcinoma in 7 cases (approximately 3%)

    • Additionally, 1 endometrial cancer and 3 other pathological findings

Postoperative Follow-up and Findings:

• Non-BRCA group (149 patients followed):

  • Mean follow-up: 23.3 months

  • No evidence of disease in any patient (100%)

• BRCA1/2 group (388 patients):

  • Mean follow-up: 60.1 months

  • No evidence of disease in 96% of patients

How Necessary Are These Operations?

No cases of high-grade serous carcinoma or STIC were found in the group of 152 patients with non-BRCA mutations. In contrast, these cancer precursors were found in 3% of patients carrying BRCA1/2 mutations.

These data raise questions about how necessary preventive surgery is for non-BRCA mutations. Decisions about surgery should be made more cautiously, particularly in view of serious adverse effects such as loss of fertility and early menopause.

What Do Clinical Guidelines Say About Non-BRCA Mutations?

Some clinical guidelines also recommend surgery for genetic variants such as BRIP1, RAD51C, and PALB2. However, these recommendations are generally based on low-quality evidence . Therefore, when considering surgery for people carrying non-BRCA mutations, their personal and family history of cancer, age at menopause, fertility status, and expectations should be taken into account.

Conclusion: Surgery May Not Always Be the Best Option

This study indicates that routine risk-reducing surgery in people with non-BRCA genetic mutations needs to be reconsidered . Evidence-based medicine once again highlights the importance of individualized decisions and a patient-centered approach.

The decision to operate should be based on a combined assessment of genetic, pathological, epidemiological, and clinical data , rather than simply a genetic test result. Stronger prospective studies in this area will be vitally important for both clinical decision-makers and patients.