Genetic epidemiology of breast cancer (BC) risk genes from a diverse real-world oncology practice in Brazil.
Authors: Garicochea Bernardo , Christtanini Koyama Fernanda , Canato Ferracini Amanda , de Bustamante Fernandes Carolina , Souto Andreza Karine , Bulcao Marcela Lima , de Oliveira Nascimento Ivana Lucia , Branco Neves Silva Ana Carolina , Landeiro Luciana G. , Oliveira Leandro Carvalho , Starling Alessandra , Pessoa Elias Gonçalves Isabela , Elias Maia Rayana , Aragão Santana Thaiana , Testa Galindo Layla , Zalis Mariano , Ferrari Bruno Lemos , Dienstmann Rodrigo 
Published: June 2022

10594 Background: As germline testing in BC is becoming more accessible, a large body of evidence from distinct populations is revealing different prevalence of affected genes or recurrent and founder mutations. We evaluated a series of Brazilian BC patients from diverse regions of the country that were studied in a single laboratory facility for likely pathogenic/pathogenic variants (PV) and variants of unknown significance (VUS) in BRCA1/2 and other BC susceptibility genes (ATM, BARD1, CDH1, CHEK2, PALB2, RAD51C, RAD51D and TP53). Methods: We used multi-gene NGS panels covering from 35 to 105 genes, including copy number alterations, to perform sequencing in patients with diagnosis of BC from 2016 to 2021. With patient consent, we extracted clinical and pathological data from curated Real-World Database of Oncoclínicas Group to classify tumors according to hormone receptor (HR) and HER2 status and assess family history of cancer. Primary endpoint was prevalence of PV and VUS in BRCA1/2 and other breast cancer risk genes. Results: In total, 1,520 patients with BC were included in the analysis, 99% were female, median age at genetic testing was 46 years and 84% had family history of cancer. BC subtype was available in 717 cases (43% HR+/HER2-, 26% HER2+, 31% triple negative). Median age at genetic testing in HR+/HER2- population was 49 years and 44 years in HER2+ and triple-negative cases. Overall, 11.7% (CI95% 10.1-13.4) of the population had at least one PV in any BC risk gene: 50 in BRCA1, 49 in BRCA2, 22 in TP53 (17 had Brazilian founder p.R337H haplotype), 19 in PALB2, 18 in CHEK2, 15 in ATM, 7 in other genes (BARD1, CDH1, RAD51C, RAD51D) and 4 patients had co-existing PV in 2 BC risk genes. BRCA1/2 PVs were found in 7% of BC patients and BRCA1/2 VUS in 3%, being higher in triple-negative cases (11% PVs) than HR+/HER2- (5% PVs) and HER2+ (3%). For other BC risk genes, 5% of the patients had a PV, without differences according to BC subtype, and the prevalence of VUS was 14%. The prevalence of TP53 Brazilian founder mutation in BC was 1.2%. Median age of genetic testing was younger in population with BRCA1 PV (43 years) than BRCA2 PV (47 years) and other genes PV (46 years). Conclusions: In this real-world cohort of BC patients enriched for high-risk features such as young age at diagnosis, positive family history and triple-negative disease, the prevalence of BRCA1 and BRCA2 PV was very similar and represented only 56% of all PV detected. Different from other studies, TP53 mutations are the third most common germline alteration in the Brazilian population, with close to 80% of the cases presenting the founder mutation p.R337H. BC with epidemiologic high-risk features should be offered a germline test in Brazilian patients due to the considerable chance of a PV detection.