Abstract P6-02-11: Implementation of multigene panel testing in triple-negative breast cancer. The PERSONA-breast trial
Authors: fontana sabrina K. kahler ribeiro , bonetti emanuele , bernard loris , calvello mariarosaria , Bonanni Bernardo , Bonizzi ppina , Veronesi Paolo , Mazzarella Luca , Galimberti Viviana , sangalli claudia 
Published: March 2023

Kahler Ribeiro Fontana S1, Bonetti E2, Bernard L3, Calvello M4, Bonanni B4, Bonizzi G 5, Veronesi P1,6, Mazzarella L 2, Galimberti V1

Introduction Triple-negative breast cancer (TNBC) is frequently associated with germline genetic variants associated with cancer predisposition. Approximately 20% of TNBC carry a germline BRCA1 or BRCA2 mutation. Germline mutations in other genes involved in DNA repair, specifically Homologous Recombination (HRR), including ATM, BARD1, BRIP1, CHEK2, PALB2, RAD50, RAD51C, RAD51D may be associated with TNBC however remain imprecise in several populations as in Italy. In recent years, there has been an increase in multigenic panel testing thanks to better technology and the fact that genetic testing is no longer done just for prevention but they have become relevant in the clinical setting and this is especially true for triple negative disease. At the European Institute of Oncology, we conducted a prospective clinical trial, the PERSONA Breast trial, aimed at providing a more comprehensive picture of the mutational landscape and cancer risk in patients with TNBC by multigene germline genetic testing. Methods PERSONA is a prospective observational trial conducted between June 2018 and January 2022 on 313 patients with a diagnosis of TNBC ≤ 60 years and able to undergo surgery (primary or post-neoadjuvant). Peripheral blood DNA was sequenced with the Illumina TruSight Cancer panel (94 cancer predisposition genes). Genes were classified as germline actionable (n. 15) or non-actionable (n. 79) according to their associated relative risk of cancer. Genetic variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines and the databases of genetic variants (ClinVar, LOVD, BRCA-Exchange,). All enrolled patients were followed up six-monthly for 10 years from informed consent or to death or withdrawal of consent. Results We present preliminary germline results from a 94-gene panel testing performed on a cohort of 313 TNBC patients. The clinical data of these patients was considered for a descriptive analysis of the cohort. Data on outcome such as overall survival and disease-free survival were not yet available. Germline multigene testing detected 62 unique (i.e., n. 49 in actionable, n. 13 in non-actionable genes) pathogenic (C5) and likely pathogenic (C4) variants in 25.2% of TNBC patients (79/313). As expected, 53.2% (42/79) of TNBC patients were carriers of a C5/C4 in BRCA1. C4/C5 were identified also in other actionable genes: 13.9% (11/79) in BRCA2, 8.9% (7/79) in MUTYH, 3.8% (3/79) in PALB2, 2.5% (2/79) in MSH2, 1.3% (1/79) in PMS2, and 1.3% (1/79) in TP53. In addition, 12 TNBC patients had C4/C5 variants in non-actionable genes, and 4 were carriers of both C4/C5 variants in actionable and non-actionable genes. Multigene testing resulted in the identification of 655 (i.e., n.82 in actionable, n. 573 in non-actionable genes) variants of uncertain significance (C3 or VUS) in 89.8% (281/313) of patients. Of the 281 C3 carriers, 60 had other variants (C4 and/or C5), of an uncertain result (in whom C3 was the highest class of variant) only in 70.6% (221/313) of TNBC patients. In 13 patients (13/313; 4.1%) only benign (C1) or likely benign (C2) variants were identified. Regarding family history, 67% of BRCA1 carriers versus 30% of BRCA2 carriers were familial. Conclusion Germline multigene testing in TNBC can identify C4/C5 in actionable genes providing information for a more tailored management of TNBC. Our study showed that the rate of VUS remains high using multigene testing. Of note, VUS were mainly identified in non-actionable genes supporting the rationale of the use in the clinical setting of phenotype-specific multigene panels, including a minor, but more appropriate, number of genes.

Citation Format: sabrina K. kahler ribeiro fontana, emanuele bonetti, loris bernard, mariarosaria calvello, Bernardo Bonanni, ppina Bonizzi, Paolo Veronesi, Luca Mazzarella, Viviana Galimberti, claudia sangalli. Implementation of multigene panel testing in triple-negative breast cancer. The PERSONA-breast trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-11.