Abstract B028: Pan-cancer landscape of somatic BRCA1 and BRCA2 mutations detected in circulating tumor DNA

Abstract

Abstract Background: Frequencies of germline mutations in BRCA1 and BRCA2 (BRCA1/2) are well-described; however, existing data are incomplete regarding the cancer specific spectrum of somatic BRCA1/2 (sBRCA) mutations and co-occurrence of microsatellite instability (MSI), particularly when detected in circulating tumor DNA (ctDNA). To better elucidate potential target populations for PARP inhibitor (PARPi) monotherapy and combination PARPi-immunotherapy trials and provide data on the frequency of sBRCA mutations detected in ctDNA, we conducted a retrospective, IRB approved analysis of de-identified genomic results of advanced solid tumor patients (pts) who had clinical liquid biopsy testing (Guardant360) from 06-2018 to 05-2019. METHODS Cancer specific sBRCA inactivating mutation frequencies were calculated for cancer types with >50 patients tested; histological sub-types were compared to available TCGA inactivating sBRCA frequencies using Fisher’s exact or Chi-square test as appropriate. RESULTS Overall, 3388 pts were found to have one or more variant of uncertain significance (n=2338) and/or inactivating mutation (n=1050) in BRCA1/2. Of the 1050, 352 (33.5%) had only germline mutation(s) (gBRCA), 24 (2.3%) had both gBRCA and sBRCA, and 674 (64.2%) had sBRCA mutations only. Further analyses were limited to the 674 pts with sBRCA mutations only. Cancer specific sBRCA frequencies in uterine (5.1%), ovarian (5.0%), colorectal (CRC, 3.3%), lung squamous (3.1%), head and neck (2.9%), gastroesophageal (2.6%), melanoma (2.4%), urothelial (2.3%), breast (2.3%), lung adenocarcinoma (2.1%), and pancreatic (2.1%) cancers were not significantly different from TCGA while frequencies in prostate (3.7%, p=0.004) and renal cell (2.1%, p=0.02) cancers were significantly higher than TCGA. The mean (median) number of sBRCA mutations per pt was 1.1 (1) with 47 pts having >1 sBRCA mutation. Multiple sBRCA mutations were seen in pts with CRC (n=14), prostate (n=9), non-small cell lung (n=7), breast (n=6), uterine (n=3), ovarian (n=2), and other (n=5) cancers. Co-occurring MSI was detected in 44/468 (9.4%) pts with sBRCA inactivating mutation(s) tested. CONCLUSIONS ctDNA detected sBRCA mutations at frequencies consistent with, or above TCGA, indicating it is an effective method for identifying pts eligible for PARPi trials. Additional studies are ongoing to assess the clonality of the sBRCA mutations which may further impact PARPi trial considerations. Our cohort consists of advanced cancer pts, so the identification of sBRCA mutations in prostate cancer at a higher frequency than TCGA supports what is known about the association between gBRCA mutations and more aggressive, advanced stage cancer and suggests the possibility of a similar association for sBRCA in prostate and renal cell cancers. The co-occurrence of defective homologous recombination and mismatch repair has previously been reported in tissue sequencing studies, but numbers in those and the current study are small. Still, this co-occurrence sub-population may represent a unique molecular subtype in which to investigate combination PARPi-immunotherapy. In a one year period, standard of care ctDNA testing identified 1050 advanced cancer pts with BRCA mutations, two-thirds of which were somatic, occurring in over 30 cancer types, suggesting that PARPi therapies may have relevance in a broad range of cancers. Citation Format: Carin R Espenschied, Jennifer L Yen, Tracy Nance, Richard B Lanman, Kimberly C Banks. Pan-cancer landscape of somatic BRCA1 and BRCA2 mutations detected in circulating tumor DNA [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B028. doi:10.1158/1535-7163.TARG-19-B028