2333P Associating BRCA1 hypermethylation with clinicopathological and molecular variables in triple-negative breast cancers

The aim of this study was to investigate the correlation of BRCA1 promoter methylation status (BRCA1met) in patients with triple-negative breast cancer (TNBC) to clinicopathological and molecular variables, patient prognosis, patient response to neoadjuvant chemotherapy (NAC), and potential therapy resistance mechanisms in NAC treated patients. 145 patients enrolled 2015-2018 in the Sweden Cancerome Analysis Network - Breast (SCAN-B) study (ClinicalTrials.gov ID NCT02306096) were included. 109 had chemotherapy (>90% with sequential epirubicin + cyclophosphamide and a taxane, EC–T) according to national guidelines either as NAC (32%) or adjuvant (68%) therapy. Pathogenic BRCA1/2 variants were detected in 11 of 54 cases. Microsatellite instability and BRCA1met using pyrosequencing were investigated in all cases, including analyses of pre-treatment biopsies and surgical resections for NAC patients with residual disease (RD). The NAC patient cohort was extended with six additional SCAN-B patients to further explore treatment response in relation to BRCA1met. Clinicopathological and molecular variables were obtained through clinical review and complementary RNA-seq data. MSI and BRCA1met was observed in 2% and 17% of patients, respectively. BRCA1met was correlated to younger age and the PAM50 Basal phenotype (92%) and was frequent (40%) in women without pathogenic BRCA1/2 germline variants. No association was observed between BRCA1met and distant recurrence-free interval in adjuvant treated patients (log-rank p=0.77), nor between BRCA1met and pathological response in NAC patients (p=0.69). BRCA1met NAC cases revealed differences in methylation level and BRCA1 mRNA expression in pre-treatment versus surgically resected tissue in patients with RD. No BRCA1 gene fusions were detected. Genetic alterations between pre-treatment vs surgically resected tissue are further analyzed using whole genome sequencing. BRCA1met is associated with young age in TNBC but hold no predictive nor prognostic value in this patient cohort. We observe a difference in BRCA1met patterns and BRCA1 mRNA expression in NAC patients with RD that may potentially be related to treatment resistance.