BRCA mutations confer high risk of CNS metastases

By Susan London

Patients with newly recurrent breast cancer who carry a germline BRCA1 or BRCA2 mutation are about twice as likely as noncarriers to have central nervous system involvement, finds a single-center retrospective cohort study. And carrying a BRCA2 mutation independently predicts such involvement and death from the disease.

“Notably, our study included patients who received treatment before the regulatory approval of PARP [poly (ADP-ribose) polymerase] inhibitors for the treatment of metastatic, BRCA1-associated or BRCA2-associated breast cancer,” senior investigator Nancy U. Lin, MD, department of medical oncology, Dana-Farber Cancer Institute, Boston, and colleagues point out. “Data from other groups have suggested that homologous recombination deficiency and DNA repair pathways are also more likely to be dysregulated in breast cancer brain metastases overall.”
Data from other groups have suggested that homologous recombination deficiency and DNA repair pathways are also more likely to be dysregulated in breast cancer brain metastases overall.
“We would strongly encourage future trials enrolling patients with BRCA1-associated/ BRCA2-associated metastatic breast cancer to take the high prevalence of CNS involvement into account and allow patients with both active and stable/treated brain metastases to enroll, in line with recommendations from the American Society of Clinical Oncology–Friends of Cancer Research Broadening Eligibility Criteria Working Group and the Response Assessment in Neuro-Oncology guidelines,” they recommend.

For the study, Dr. Lin and the team used institutional registries to identify breast cancer patients with a first locoregional or metastatic recurrence diagnosed during 1981-2014 who had had BRCA testing. Analyses were based on 30 BRCA1 mutation carriers, 32 BRCA2 mutation carriers, and 270 noncarriers.

Study results, reported in Cancer, showed that the large majority of BRCA1 mutation carriers (73%) had triple-negative breast cancer, whereas the large majority of BRCA2 mutation carriers (72%) had hormone receptor–positive breast cancer.

CNS involvement was seen in 53% of the BRCA1 mutation carriers and 50% of the BRCA2 mutation carriers, compared with 25% of the noncarriers
(P less than .001). “If anything, given that our institutional practice is not to obtain routine brain imaging in the absence of symptoms or a clinical trial requirement, our results may even underestimate the true frequency of CNS involvement in BRCA1/BRCA2 mutation carriers,”
Dr. Lin and colleagues note.

In multivariate analysis controlling for tumor subtype, BRCA2 mutation was independently associated with CNS involvement (odds ratio, 3.33; P = .006). In contrast, BRCA1 mutation was not (OR, 2.11; P = .18).

Similarly, BRCA2 mutation independently predicted breast cancer–related death (hazard ratio, 1.82; P = .01), but BRCA1 mutation did not (HR, 1.21; P = .48). Additional predictors included triple-negative subtype, compared with other subtypes (HR, 4.22; P less than .001) and, relative to locoregional or contralateral disease as first recurrence, CNS involvement (HR, 10.91; P less than .001) and non-CNS distant site involvement (HR, 3.90; P less than .001).

Dr. Lin disclosed that she receives research funding (to her institution) from Pfizer, Kadmon, Array Biopharma, and Merck; research funding and personal fees from Roche/Genentech, Seattle Genetics, and Novartis; and personal fees from Shionogi Inc, Kadmon, Puma, and Daiichi Sankyo, all outside the study. The study was supported by grants from the Breast Cancer Research Foundation.