Risk-Reduction Surgery Benefit in Non-BRCA Ovarian Cancer?

BOSTON — Patients with non-BRCA gene mutations undergoing risk-reduction surgery to prevent tubo-ovarian cancers showed no signs of tubo-ovarian high-grade serous carcinoma or serous tubal intraepithelial carcinoma compared with about 3% incidence of these carcinomas in patients with BRCA mutations in a multi-center study.

“We need to define the role of risk-reduction surgery in reducing tubo-ovarian cancer risk for non-BRCA gene mutations to balance the benefit of cancer risk reduction with the risks associated with unnecessary surgery,” said first study author Aysha Mubeen, MD, an assistant professor of pathology at The University of New Mexico, in Albuquerque, New Mexico.

Bilateral salpingo-oophorectomy surgery to remove healthy ovaries and fallopian tubes is an established prophylactic measure utilized to reduce ovarian cancer risk in patients carrying BRCA1 and BRCA2 mutations, however, the surgery is increasingly also being performed in patients with non-BRCA genetic variants and is recommended for those patients in some clinical guidelines.

However, the evidence regarding the approach in non-BRCA carriers consists of weaker case control studies and research regarding the benefits vs risks of the surgery in these patients is lacking.

Ovarian cancer represents one of the deadliest gynecologic cancers, with a 5-year survival rate of only about 50%. And while only about 20% of cases are considered hereditary, interest in any preventive measures that can be taken based on genetic risk is high.

BRCA1 and BRCA2 are among the best-known genetic risks, with carriers of BRCA1 having an approximate 39%-44% lifetime risk for tubo-ovarian cancer and carriers of BRCA2 having an 11%-17% risk, Mubeen explained at the United States and Canadian Academy of Pathology (USCAP) 2025 Annual Meeting.

Non-BCRA Cohort 

To compare the pathologic findings in non-BRCA genetic carriers with BRCA carriers undergoing the risk-reduction surgery, Mubeen and colleagues evaluated clinicopathologic data on 152 patients with non-BRCA mutations who underwent the surgery at three institutions.

Those patients were compared with a control group of 388 patients who were BRCA1 or BRCA2 genetic carriers.

The non-BRCA patients, who had an average age of 54.8 years, (range 30-81 years), had non-BRCA genetic mutations including PALB2 (45%), BRIP1 (33%), ATM (8%), CHEK2 (4%), and RAD51 (4%).

Other indications for the risk reduction surgery included BARD1 mutation, Li Fraumeni syndrome, and Lynch syndrome.

The main indications for the non-BRCA patients to receive genetic testing included a personal history of breast cancer (51%) or a positive family history (27%).

The risk-reducing surgeries that were performed included bilateral salpingo-oophorectomy (97%) and hysterectomy/bilateral salpingo-oophorectomy (3%).

In the non-BRCA cohort, the surgeries revealed one secretory cell outgrowth, one p53 signature, one serous tubal intra-epithelial lesion, and three serous borderline tumors, but no serous tubal intraepithelial carcinoma or high-grade serous carcinomas.

The remaining 146 patients (96%) showed no pathologic changes.

There were 2 abnormal concurrent pelvic washings; one suspicious for involvement by serous borderline tumor and the other atypical.

BRCA1/2 Cohort

In the BRCA1/2 cohort of 388 patients, 51% had BRCA1 and 48% had BRCA 2, with 1% having BRCA1 and BRCA2. Their mean age was somewhat younger than that in the non-BRCA cohort, at 47.7 years.

Of the BRCA1/2 patients, 65% had bilateral salpingo-oophorectomy, 27% had hysterectomy/bilateral salpingo-oophorectomy, and 7% had other surgeries.

Among these patients, one had a p53 signature, three had serous tubal intra-epithelial lesions, three had serous tubal intraepithelial carcinomas, and seven had high-grade serous carcinomas. In addition, one had endometrial cancer and three had other pathologic diagnoses. None of the other 370 patients (95%) had pathologic changes.

With a mean follow-up of 23.3 months in the non-BRCA group, of the 149 patients available for follow-up (three patients had no follow-up available), all 149 had no evidence of disease.

And with a mean follow-up of 60.1 months in the BRCA1/2 group, 374 of 388 (96%) in the group had no evidence of disease.

“In our cohort of 152 patients with non-BRCA mutations, we did not find any [high-grade serous carcinomas] or [serous tubal intraepithelial carcinoma] cases,” Mubeen said. “In comparison, in the BRCA1 and 2 cohort, there was about a 3% rate” of these carcinomas.

The fact that data was even available on 152 patients with non-BRCA mutations who had risk-reducing surgery demonstrates that such surgeries are indeed being commonly performed, Mubeen noted.

However, the results beg the question of whether such surgeries are necessary and whether they carry more risks than benefits, particularly in terms of fertility and early menopause.

The answer is complicated, she said.

“When a patient undergoes risk-reducing surgery, it’s a very complex decision that not only involves a genetic mutation in the BCRA gene but also needs to take into account the patient’s personal history of cancer or family history,” Mubeen explained.

“Furthermore, it’s important to remember that prediction data is continuously evolving,” she added.

The pathology data “are just part of the equation,” said Mubeen, “But there is also a lot of genetic, epidemiology, and oncology [data] that is intricately important.”

Mubeen had no disclosures to report.