Co-occurrence of germline pathogenic variants in a Brazilian cohort of patients with breast cancer.

Andreza Karine de Barros Almeida Souto Oncoclinicas & Co - Medica Scientia Innovation Research (MEDSIR), São Paulo, Brazil info_outline Andreza Karine de Barros Almeida Souto, Thaiana Aragao Santana, Leandro Jonata Carvalho Oliveira, Marcela Lima Bulcao, João Paulo Gonzaga de Farias, Carolina de Bustamante Fernandes, Fernanda Christtanini Koyama, Daniela Tiaki Uehara, Fernanda Orpinelli Ramos do Rego, Layla Testa Galindo, Bruno Lemos Ferrari, Max S. Mano, Rodrigo Dienstmann, Mariano Zalis, Bernardo Garicochea

Authors Andreza Karine de Barros Almeida Souto Oncoclinicas & Co - Medica Scientia Innovation Research (MEDSIR), São Paulo, Brazil info_outline Andreza Karine de Barros Almeida Souto, Thaiana Aragao Santana, Leandro Jonata Carvalho Oliveira, Marcela Lima Bulcao, João Paulo Gonzaga de Farias, Carolina de Bustamante Fernandes, Fernanda Christtanini Koyama, Daniela Tiaki Uehara, Fernanda Orpinelli Ramos do Rego, Layla Testa Galindo, Bruno Lemos Ferrari, Max S. Mano, Rodrigo Dienstmann, Mariano Zalis, Bernardo Garicochea Organizations Oncoclinicas & Co - Medica Scientia Innovation Research (MEDSIR), São Paulo, Brazil Abstract Disclosures Research Funding No funding sources reported Background: The estimated prevalence of germline pathogenic variants (PV) or likely pathogenic variants (LPV) in high and moderate penetrance genes is around 7-10% among women with breast cancer (BC). The emergence of next-generation sequencing (NGS) technology allowed multi-gene panel testing (MGPT) analysis at a lower cost. However, the detection of incidental findings with unknown significance (VUS) and challenges with variant interpretation increase substantially with MGPT. The effect of co-existing PV/LPV in two or more genes is still understudied. Here, we present the prevalence of concurrent germline LPV/PV in a cohort of Brazilian women with BC who underwent a MGPT in a single reference laboratory. Methods: Retrospective observational study using a laboratory cohort (Oncoclínicas Precision Medicine). This study includes women with BC who performed a germline MGPT (able to call SNVs, indels and CNVs) from 2019 to 2023. All patients were tested in a single reference laboratory (OC Precision Medicine) and originated from several Brazilian centers within the Oncoclínicas network. Two distinct germline NGS assays were used: breast and ovarian cancer (BOC) panel (36 genes) and a pan-cancer (PC) panel (105 genes). Results: In the overall cohort, 2,651 women with BC were included in this analysis. The median age at genetic testing was 51 years. 1,867 pts (70.4%) underwent a PC panel testing and the remaining 784 pts (29.6%) a BOC panel.Overall, 314 (12%) pts carrier of LP/PV in high- and/or moderate-penetrance genes. Two or more heterozygous LP/PV were found in 35 pts (1.32%), including 8 pts (1.02%) in the BOC panel and 27 pts (1.44%) in the PC panel subgroups. There were no differences in age of onset of BC in single vs co-occurring double mutants. The most frequent co-existing PV/LPV were found in BRCA2 (11) / BRCA1 (8) / PALB2 (4) / TP53 (3) and MUTYH (7) / CHEK2 (3) in the high and moderate penetrance genes, respectively. Six pts (0.23%) had a double heterozygous involving high and/or moderate penetrance genes. Interestingly, there was a case with four heterozygous variants in TP53, MUTYH, MUTYH and APC. Conclusions: In times of rapid incorporation of MGPT in the clinical practice, our real-world data showed that a small proportion of BC patients could be carriers of two or more germline heterozygous LP/PV in cancer genes. However, this represents a challenging scenario for patient and family management, especially in a co-occurrence of high and moderate penetrance genes.