Since sequenced in 1994-1995, BRCA1 and BRCA2 are known to be phenotypically different. Whereas most BRCA1 tumors are high-grade and ER-negative, most BRCA2 tumors tend to be lower grade and ER+. Breast cancer subtypes also have been noted to differ in patterns of metastases. For instance, Her2+ and triple-negative breast cancers have an increase in the propensity for central nervous system (CNS) metastases. Current studies examining whether BRCA cancers have a propensity to metastasize to the CNS have been inconclusive. This study carried out at the Dana-Farber/Harvard Cancer Center examined the pattern of recurrences in associated and non-associated BRCA cancers to determine whether germline BRCA mutations are independently associated with CNS metastases.
The study population consisted of patients diagnosed with invasive breast cancer between 1979-2013 and with first loco-regional recurrence between 1981-2014. Eighty-seven percent of BRCA1 cancers were high-grade and 73% were triple-negative (TNBC). Of the BRCA2 cancers, 72% were hormone positive. Of the non-carriers, 52% were hormone positive, 22% Her2 positive and 19% TNBC.
The most common mutation sites for BRCA1 mutation carriers were lung and distant lymph nodes (50%) whereas in BRCA2 mutation carriers and noncarriers bone was the most common site. The frequency of CNS metastasis was significantly higher in BRCA1 and 2 mutation carriers than in noncarriers (P<0.001). However, the investigators did not find that BRCA1 mutations were independently associated with CNS disease in multivariate analysis possibly due to the high incidence of TNBC, a known risk factor for CNS metastasis. However, they did find an association between BRCA2 mutations and CNS involvement although most of these cancers were ER+. This suggests “a true causal relationship between BRCA2 loss and homing and/or growth.”.
The investigators postulate that “deficiencies in DNA repair, including but not limited to homologous recombination repair, may be causally related to the development of brain metastasis.” The data from this study suggests that about half of BRCA1 or BRCA2 metastatic cancers will develop CNS metastases. Furthermore, in multivariate analysis, they found that BRCA2 carriers had significantly shorter survival following metastatic disease compared to noncarriers, even allowing for tumor subtypes.