Clinical Behavior of Breast Cancer in Young <i>BRCA</i> Carriers and Prediagnostic Awareness of Germline <i>BRCA</i> Status.

Abstract

To investigate the clinical behavior of breast cancer in young <i>BRCA</i> carriers according to the specific <i>BRCA</i> gene (<i>BRCA1 v BRCA2</i>) and the association of the timing of genetic testing (before <i>v</i> at diagnosis) with prognosis. This was an international, multicenter, hospital-based, retrospective cohort study that included 4,752 patients harboring germline pathogenic/likely pathogenic variants (PVs) in <i>BRCA1</i> or <i>BRCA2</i>, who were diagnosed with stage I-III invasive breast cancer at 40 years or younger between January 2000 and December 2020 in 78 centers worldwide (ClinicalTrials.gov identifier: NCT03673306). Compared with <i>BRCA2</i> carriers (n = 1,683), <i>BRCA1</i> carriers (n = 3,069) had more frequently hormone receptor-negative (74.4% <i>v</i> 15.5%) and high-grade (77.5% <i>v</i> 49.1%) tumors. Similar outcomes were observed in <i>BRCA1</i> and <i>BRCA2</i> carriers but with a different pattern and risk of disease-free survival events over time. Compared with patients tested for <i>BRCA</i> at diagnosis (ie, between 2 months before and up to 6 months after diagnosis; n = 1,671), those tested before diagnosis (ie, any time up to 2 months before diagnosis; n = 411) had smaller tumors (T1: 61.3% <i>v</i> 32.4%), less nodal involvement (N0: 65.9% <i>v</i> 50.8%), less frequently received chemotherapy (84.4% <i>v</i> 92.9%), and axillary dissection (37.5% <i>v</i> 47.4%). Patients tested before diagnosis had better overall survival (OS; unadjusted hazard ratio [HR], 0.61 [95% CI, 0.40 to 0.92]); however, this result lost statistical significance after adjustment for potential confounders including tumor stage (adjusted HR, 0.74 [95% CI, 0.47 to 1.15]). This global study provides evidence on the different clinical behavior of breast cancer in young <i>BRCA1</i> and <i>BRCA2</i> carriers. Identifying a <i>BRCA</i> PV in healthy individuals was associated with earlier-stage breast cancer diagnosis and lower treatment burden, as well as better unadjusted OS.