A portrait of germline pathogenic variants from a large real-world cohort of Brazilian patients with breast cancer.
Authors: Oliveira Leandro Jonata Carvalho , Rego Fernanda Orpinelli Ramos do , Garicochea Bernardo , Christtanini Koyama Fernanda , de Bustamante Fernandes Carolina , Souto Andreza Karine de Barros Almeida , Santana Thaiana Aragao , Farias João Paulo Gonzaga de , Bulcao Marcela Lima , de Oliveira Nascimento Ivana Lucia , Silva Ana Carolina Branco Neves , Elias Isabela , Elias Maia Rayana , Azevedo Renata Gondim Meira Velame de , Testa Galindo Layla , Pachito Daniela Vianna , Simon Patricia , Zalis Mariano , Ferrari Bruno Lemos , Dienstmann Rodrigo 
Published: June 2024

10593 Background: The estimated prevalence of germline pathogenic/likely pathogenic variants (P/LP) in high and moderate penetrance (HMP) genes is around 7-10% among women with breast cancer (BC). Up to 50% of all hereditary BC cases are due to germline variants in BRCA1/2, but other HMP genes are increasing in relevance. The prevalence and spectrum of BC P/LP variants are affected by age at diagnosis, race/ethnicity, geographical region, BC molecular subtype. Methods: Retrospective cohort study to evaluate the germline profile of P/LP variants in HMP genes ( BRCA1, BRCA2, PALB2, TP53, CDH1, NF1, PTEN, STK11, CHEK2, ATM, BARD1, RAD51C and RAD51D) in women diagnosed with BC in Brazil. All patients were tested in a single reference laboratory (Oncoclinicas [OC] Precision Medicine) using multi-gene NGS panels covering from 35 to 105 genes. Primary endpoint was the prevalence of P/LP variants and VUS in BRCA1/2as well as in other HMP BC genes, in overall population and according to age and BC subtype. Clinical and pathological data were retrieved from curated Real-World Database of OC Group and used as reference for demographics comparisons. Results: This cohort involved 2,207 women with BC from 2019 to 2023. The majority of pts (79.7%) were from Southeastern Brazil, followed by Midwestern (5.6%), Southern (5.0%) and Northeastern (4.8%) Brazil. The median age at genetic testing was 47 years and most patients (59.4%) were ≤ 50 years. As reference, median age is 57 years in the overall BC population treated at OC (> 20,000 during the study period). BC subtype was available in 641 cases, 264 pts (41.2%) were HR+/HER2-, 116 (18.1%) were HER2+ and 261 (40.7%) were triple negative (TNBC). In the OC Database, TNBC represents only 15% of all new BC cases. Overall, 217 (9.8%) had a P/LP in HMP genes, including 131 (5.9%) pts who had a BRCA1/2 P/LP variant and 86 (3.9%) who had a P/LP variant in other HMP BC genes. The most frequent LP/PV variants were found in BRCA2 (31%) / BRCA1 (29%) / TP53 (13%) / PALB2 (9%) / CHEK2 (9%). A TP53founder pathogenic variant (R337H) accounted for 75% of all TP53 LP/PV. The deleterious variants were more common in pts ≤50 years (12%) than in pts > 50 (7%) as well as in patients with TNBC (14%) followed by HER2+ (9%) and HR+/HER2- (7%). The BRCA1/2 P/LP variants were higher in TNBC pts (8%) than in HR+/HER2- (4%) and HER2+ (3%). The overall VUS rate in the HMP genes was 20%. The most frequent VUS were found in ATM, BRCA2, NF1 and CHEK2genes. Conclusions: Studies involving germline profile of P/LP variants in cancer genes have provided a broader understanding of BC risk and have opened doors to new therapeutic or surveillance strategies across all subtypes. In Brazil, the prevalence of deleterious variants in HMP is comparable to published US and EU cohorts. However, in the real-world community practice, testing is still limited to populations with higher baseline risk for hereditary BC, such as young patients with TNBC.