Pattern di metastatizzazione del carcinoma mammario a recettori ormonali positivi HER2-negativo in base allo stato mutazionale di BRCA1/BRCA2: uno studio retrospettivo monocentrico

Background: It is well known that, in the context of metastatic breast cancer, different breast cancer subtypes (as defined by hormone receptor and HER2 status) are associated with different metastatic patterns. To date, very limited evidence has been reported suggesting that germline BRCA1/BRCA2 mutations might be associated with a higher frequency of involvement of specific metastatic sites (e.g. brain). The aim of this study is to assess the potential association between germline BRCA1/BRCA2 mutational status and metastatic patterns of HR+/HER2- metastatic breast cancer. Patients and method: This retrospective monocentric study included patients treated for metastatic HR+/HER2- breast cancer at Istituto Oncologico Veneto I.R.C.C.S. between 2007 and 2025 and with a known germline BRCA1/BRCA2 mutational status. Germline BRCA1/BRCA2 variants were considered as significant if classified as class IV or V according to ENIGMA criteria. Metastatic sites at time of first diagnosis of metastatic breast cancer and at time of last follow-up were classified according to the following categories: bone, liver, lung, lymph nodes and central nervous system (CNS, which included both parenchymal brain and meningeal metastases). Time to CNS metastases was defined as time from date of first metastatic breast cancer diagnosis to first diagnosis of CNS metastases or last follow-up. Overall survival from metastatic breast cancer diagnosis (OS) was defined as time from date of first metastatic breast cancer diagnosis to death from any cause or last follow-up. Results: This study cohort included 131 patients diagnosed with metastatic HR+/HER2- breast cancer and with known germline BRCA1/BRCA2 mutational status. Of these, 35 patients were carriers of BRCA1/BRCA2 pathogenetic variants, while 96 were noncarriers. Clinicopathological features were generally similar between BRCA1/BRCA2 mutations carriers and non-carriers, but germline BRCA1/BRCA2 mutations carriers were more frequently diagnosed with grade 3 breast cancer than noncarriers (p=0,031). Considering metastatic sites at first diagnosis of metastatic breast cancer, BRCA1/BRCA2 mutations carriers showed a lower incidence of bone metastases as compared to noncarriers (31,4% versus 51,0%; p=0,046). Considering metastatic sites at time of last follow-up, BRCA1/BRCA2 mutations carriers showed a higher incidence of CNS involvement as compared to noncarriers (31,4% versus 14,6%, p=0,030). Moreover, time to CNS metastases was significantly shorter in BRCA1/BRCA2 mutations carriers as compared to noncarriers (p=0,024). No significant difference in terms of OS from first diagnosis of metastatic breast cancer was observed according to germline BRCA1/BRCA2 mutational status (median OS 39.2 months for carriers versus 47.6 months for noncarriers; p=0,246). Conclusions: In this monocentric retrospective study, germline BRCA1/BRCA2 mutations carriers diagnosed with HR+/HER2− metastatic breast cancer presented a significantly higher incidence of CNS metastases and a significantly shorter time to CNS involvement. If confirmed in larger cohorts, this might potentially inform tailored radiological surveillance strategies.