Abstract P3-09-11: Clinical characteristics associated withBRCA1/2mutations identified on routine tumor tissue genotyping in metastatic breast cancer
Authors: Vidula Neelima , Blouch Erica , Farahani Alexander , Marble Hetal , Niemierko Andrzej , Hesler Kathleen , Denault Elyssa , Juric Dejan , Ellisen Leif W. , Moy Beverly , Isakoff Steven , Lennerz Jochen , Bardia Aditya 
Published: March 2022

Background: Tumor tissue genotyping (TG) can identify actionable mutations for potential therapeutic intervention. PARP inhibitors are approved for the treatment of metastatic breast cancer (MBC) in germline BRCA1/2 carriers, and may have efficacy in somatic BRCA1/2-mutant MBC. We studied the clinical features of BRCA1/2 mutations detected on routine TG of tumors in patients with MBC. Methods: Consecutive patients with MBC at an academic medical center who underwent TG (institutional next generation sequencing (NGS), 91 gene assay; coverage includes BRCA1 exons 2-23 and BRCA2 exons 2-27) as part of routine clinical care from June 2016 to September 2020 were identified. The subset with BRCA1/2 mutations underwent further chart review to determine demographics, coexisting genomic landscape, germline genetic testing results, cell-free DNA (cfDNA) results, and treatment with a PARP inhibitor. Variant classification and presumed germline/somatic status was determined by pathologists, using a combination of automated bioinformatics tools and manual review of NGS read pile-ups, allele frequency, variant annotation, and by querying publically-available genomic databases including ClinVar, COSMIC, and gnomAD. Pathogenic status of mutations was determined via manual review by a molecular genetic pathologist using online genomic resources (ClinVar, mycancergenome, ARUP, and pubmed). Concordance between cfDNA and TG was assessed. Results: Of 372 patients with MBC who underwent TG, 46 (12.4%) had BRCA1/2 mutations identified on TG (85% on metastatic specimens), 15 (33%) BRCA1 and 31 (67%) BRCA2, with 1 patient having both BRCA1 and BRCA2 mutations. Of these, 26 (57%) were hormone receptor (HR)+/HER2-, 14 (30%) were triple negative (TNBC), 3 (6.5%) were HR-/HER2+, and 3 (6.5%) had HR+/HER2+ MBC. Thirty-four mutations (74%) were pathogenic. Median age at MBC diagnosis was 61 years (range 31-82). Common co-existing mutations found in TG included TP53 (37%), PI3KCA (22%), NF1 (8.6%), ESR1 (8.6%), MAP3K1 (6.5%), ATM (6.5%), and PTEN (6.5%). Of 22 patients with BRCA1/2 mutations on TG who had cfDNA testing results available, 10 (45%) had concordant BRCA1/2 mutations seen in TG and cfDNA. On expert review, 29 (63%) BRCA1/2 mutations were presumed germline mutations, and 17 (37%) were presumed somatic mutations. Eighteen patients with germline genetic testing results available had confirmed germline BRCA1/2 mutations. Fourteen patients with presumed germline BRCA1/2 mutations received a PARP inhibitor with a median duration of response (DOR) of 6 months (range 2-28). Two patients with presumed somatic BRCA1/2 mutations received a PARP inhibitor with median DOR of 13 months (range 10-16). Conclusions: TG can identify both germline and somatic BRCA1/2 mutations in a proportion of patients with MBC, especially HR+/HER2- and TNBC, and in conjunction with TP53 mutations. Some of these mutations in TG are concordant with cfDNA. The identification of BRCA1/2 mutations on TG may lead to consideration of genotype-directed therapy with a PARP inhibitor in germline and somatic BRCA1/2-mutant cancers.

Citation Format: Neelima Vidula, Erica Blouch, Alexander Farahani, Hetal Marble, Andrzej Niemierko, Kathleen Hesler, Elyssa Denault, Dejan Juric, Leif W. Ellisen, Beverly Moy, Steven Isakoff, Jochen Lennerz, Aditya Bardia. Clinical characteristics associated withBRCA1/2mutations identified on routine tumor tissue genotyping in metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-11.