Background: BRCA1/2 genes play a critical role in genome stability and DNA repair in human cells, including cardiomyocytes. In animal models, loss of cardiomyocyte-specific BRCA1/2 is associated with DNA damage, apoptosis, cardiac dysfunction, and cardiac mortality following anthracyclines (A) exposure. However, whether these preclinical findings translate to humans still remains unclear. We conducted the BRCAN study to assess the impact of gBRCA1/2 status on AIC in a cohort of patients with eBC. Methods: This is a single center retrospective/prospective study including patients diagnosed with HER2-negative eBC treated with A based chemotherapy in the neo/adjuvant setting, known gBRCA1/2 status, left ventricular ejection fraction (LVEF) ≥ 50% at baseline and no previous significant cardiovascular events. During follow-up, we performed myocardial dysfunction blood biomarkers (MDBB), cardiac ultrasound and quality of life questionnaires (QoL). Primary objective was to assess the absolute LVEF change from baseline in BRCA1/2 mutation carriers (gBRCA1/2mut) versus non-carriers (gBRCA1/2wt). Secondary objectives were comparing MDBB and QoL in these groups. Results: 137 patients with eBC were included in the study (103 gBRCA1/2wt and 34 gBRCA1/2mut). Patients’ characteristics were similar between both groups in terms of age, baseline LVEF, radiotherapy (RT) on left side, total A accumulative dose, time from A exposure, antihypertensive or hypolipidemic agents use and smoking habit. Compared to baseline, LVEF % reduction was -4.7 [-12.0, 0.0] versus -9.5 [-18.0, -5.0] in gBRCA1/2wt and gBRCA1/2mut, respectively (p=0.027). To correct for confounding, we fit a regression model for the variables smoking habit, antihypertensive and hypolipidemic agents use. On average, LVEF % reduction in gBRCA1/2mut group was -4.5 [CI 95% -8.6, -0.4, p=0.032] compared to gBRCA1/2wt. No differences between MDBB (protein C-reactive, hsTn, NT-ProBNP, D-Dimer, ST-2 or Galectine-3) and QoL (MLHFQ and EQ5-D index) were detected between groups. Conclusions: Our data suggest that gBRCA1/2mut patients could represent a high risk population for AIC. A baseline comprehensive cardiovascular risk assessment and a closer follow-up should be recommended in these patients. Further research is needed on order to identify early predictive biomarkers for AIC.

*Mean (standard deviation); ^mg/m².