Abstract P4-09-06: Brain metastases (BM) in patients with metastatic breast cancer (MBC) and circulating cell-free DNA (cfDNA) somatic BRCA mutations

Abstract

Abstract Background: BM in MBC patients cause significant morbidity and mortality. BRCA1 germline mutations have previously been shown to be associated with an increased risk of developing BM (Lee et al, 2011), with an incidence as high as 15% (Zavitsanos et al, 2016). We previously reported that a subset of MBC patients may have somatic BRCA mutations in the absence of germline BRCA mutations (Vidula N, SABCS, 2017). In this study, we evaluated the incidence and clinical characteristics of BM in MBC patients with somatic BRCA mutations detected by cfDNA. Methods: MBC patients with somatic BRCA1 or 2 mutations detected by cfDNA (Guardant360TM, next generation sequencing, 73 gene panel; mutations classified as somatic by Guardant360TM) with at least 4 months of follow-up post-testing at an academic institution were identified. From this cohort, we identified patients who developed BM post cfDNA testing. A retrospective review of medical records and Guardant360TM reports was conducted to identify demographics, tumor subtype, type of cfDNA BRCA mutation, whether the BRCA mutation was known to be pathogenic, germline BRCA mutation status, mutant allele fraction (MAF), clonality (MAF ratio of BRCA mutation/gene mutation with highest MAF ≥ 0.25 for clonal, and <0.25 for subclonal) and the coexisting genomic environment. Clinical and genomic features of BM and non-BM patients (patients without BM) were compared using a chi-squared test for categorical variables and Wilcoxon rank-sum test for continuous variables. Brain tumor tissue from available cases of BM patients was used to evaluate somatic BRCA mutation status on the tumor tissue and correlated with cfDNA results. Results: Of 36 MBC patients with somatic BRCA mutations, 9 (25%) developed BM and 27 (75%) did not have BM (non-BM). The median time to development of BM was 6.7 months after cfDNA testing. Of the BM patients, 5 (56%) had triple-negative (TN) and 4 (44%) had hormone receptor positive (HR+)/HER2- MBC in comparison with the non-BM cases where 5 (19%) had TN, 19 (70%) had HR+/HER2-, and 3 (11%) had HER2+ MBC. Very few patients (1 BM and 2 non-BM) had known co-existing separate germline BRCA mutations (rest not known BRCA carriers confirmed by negative germline testing and/or absence of family history suggestive of a germline BRCA phenotype). The median age at MBC diagnosis was similar for BM and non-BM patients (57 years). PIK3CA and TP53 mutations were commonly seen in both BM and non-BM cases. Additionally, MYC, EGFR, and CCNE1 mutations were commonly seen in BM cases. As outlined in Table 1, among patients with BM, the somatic BRCA mutations were commonly BRCA1, clonal, known to be pathogenic (56%), and present at a higher MAF, but these findings did not reach statistical significance possibly due to the small sample size. Brain tumor tissue mutation status in BM patients and correlation with cfDNA results will be presented at the meeting. Conclusions: We observed a relatively high incidence (25%) of BM in MBC patients with somatic BRCA mutations detectable by cfDNA, which were often known to be pathogenic mutations (56%), and often associated with co-existing MYC, EGFR, and CCNE1 mutations. Further research using a larger cohort with adequate statistical power is needed to validate these findings, and may help identify MBC patients at risk for BM using a liquid biopsy. Table 1.Characteristic BMNon-BMPrior anthracycline and/or platinum6 (67%)16 (59%)Type of somatic BRCA mutationBRCA16 (67%)11 (41%)BRCA22 (22%)15 (56%)BRCA1 and 21 (11%)1 (4%)Median BRCA MAF0.40.17ClonalityClonal6 (67%)13 (48%)Subclonal3 (33%)14 (52%)Mutation known to be pathogenic5 (56%)7 (26%)Common co-existing mutationsPIK3CA5 (56%)12 (44%)TP535 (56%)15 (56%)MYC5 (56%)8 (30%)EGFR5 (56%)8 (30%)CCNE15 (56%)6 (22%)KIT3 (33%)5 (19%) Citation Format: Neelima Vidula, Andrzej Niemierko, Giuliana Malvarosa, Priscilla Brastianos, Erica Blouch, Kristen Shannon, Steven Isakoff, Seth Wander, Laura Spring, Jerry Younger, Kristin Price, Beverly Moy, Dejan Juric, Leif Ellisen, Aditya Bardia. Brain metastases (BM) in patients with metastatic breast cancer (MBC) and circulating cell-free DNA (cfDNA) somatic BRCA mutations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-09-06.