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SAN ANTONIO -- Carriers of germline BRCA mutations diagnosed with breast cancer by age 40 who underwent risk-reducing surgeries had lower rates of mortality and breast cancer recurrence than those who did not undergo these surgeries, according to results from an international cohort study presented here.

Among more than 5,000 patients followed for a median of roughly 8 years, bilateral risk-reducing mastectomy (RRM) was associated with a 35% reduced risk of death and a 42% reduced risk of cancer recurrence, while risk-reducing salpingo-oophorectomy (RRSO) was associated with a 42% reduced risk of death and a 32% reduced risk of cancer recurrence.

While these cancer risk management strategies are "widely recommended" for BRCA carriers, additional challenges should be considered in counseling younger adult patients with a prior history of breast cancer, said Matteo Lambertini, MD, PhD, of the University of Genova-IRCCS Policlinico San Martino Hospital in Italy, who reported the findings at the San Antonio Breast Cancer Symposium.

For example, he pointed out that while RRSO has been shown to improve overall survival (OS) in BRCA carriers of all ages with a prior history of breast cancer, RRM -- while reducing the risk of breast cancer -- has no proven OS benefit. In addition, these surgeries can impact reproductive plans and quality of life.

Thus, the results of this study "may help to improve the counseling on cancer risk management strategies for BRCA carriers with young-onset breast cancer, but should not be used to counsel BRCA-healthy carriers nor BRCA carriers with a diagnosis of breast cancer at an older age," Lambertini said.

The study was an international, hospital-based retrospective cohort study that included patients from 109 centers across five continents. From January 2000 through December 2020, a total of 5,292 patients were diagnosed with stage I-II invasive breast cancer at the age of 40 or younger. The median age at breast cancer diagnosis was 35 years.

All harbored germline BRCA1 (63.6%) or BRCA2 pathogenic variants. A large proportion had node-negative (51.5%) and hormone receptor-positive (45.8%) breast cancer.

A little over half of the patients underwent RRM (55%) or RRSO (52.6%): 34.1% underwent both and 26.5% did not undergo either surgery. Time from diagnosis to RRM was 0.8 years and to RRSO was 3 years, with a median follow-up of 5.1 years after RRM and 4.9 years after RRSO.

Both RRM (HR 0.65, 95% CI 0.53-0.78) and RRSO (HR 0.58, 95% CI 0.48-0.71) were significantly associated with a reduced risk of OS, the primary study endpoint. Regarding RRM, the OS link was observed irrespective of the specific BRCA gene, age at diagnosis, tumor subtype, tumor size, and nodal status.

The link between RRSO and improved OS was observed regardless of age at diagnosis, tumor size, and nodal size. But a significant association was only seen in BRCA1 carriers:

• BRCA1 carriers: HR 0.44 (95% CI 0.34-0.57)
• BRCA2 carriers: HR 0.85 (95% CI 0.64-1.15)

As for the secondary endpoints of disease-free survival (DFS) and breast cancer-free interval (BCFI), RRM was associated with a reduced risk of both (DFS, HR 0.58, 95% CI 0.52-0.65; BCFI, HR 0.55, 95% CI 0.48-0.62), as was RRSO (DFS, HR 0.68, 95% CI 0.61-0.77; BCFI, HR 0.65, 95% CI 0.57-0.74).

Lambertini and colleagues found that the effect of RRM and RRSO on OS was independent, whereas the effect of RRSO on DFS and BCFI was more pronounced among patients who also underwent RRM.

"In interpreting these results, we should keep in mind that this is a young patient population with a high risk of developing a second primary breast cancer -- which counts as an event for DFS and breast cancer-free interval," Lambertini cautioned.

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