Genomic and Immune Profiling of Breast Cancer Brain Metastases

Previous work has shown that breast cancer brain metastases (BCBrM) can have unique molecular profiles compared to extracranial tumors (ECTs), resulting in some patients demonstrating subtype switching between primary/extracranial tumors and brain metastases. Description of the biology of BCBrM and associations between biological features and clinical outcomes, particularly between molecular intrinsic subtypes, will facilitate the design of rational therapies for patients with BCBrM. To better characterize the molecular profiles of BCBrM, we conducted whole exome sequencing (WES) and total RNA sequencing (RNA-Seq) on BCBrM tissues, regardless of clinical or molecular subtype, obtained from a cohort of 42 patients from Duke University Medical Center. This cohort adds valuable patient samples to the field and enables strengthened investigation of somatic mutations, copy number alterations, gene expression profiles, and immune populations within and between BCBrM patients and other similar cohorts. The Duke BCBrM cohort includes clinical and molecular annotation of the 42 patient specimens and their associated WES and RNA-Seq data. Clinical and molecular (PAM50) intrinsic subtypes in ECTs and brain metastases were largely concordant within patients. There were observed differences in intrinsic subtype calls between frozen and FFPE specimens of the same tissue, with discordance mostly observed with LumB calls. Copy number alterations in chromosomal regions included clinically relevant genes, and somatic alterations were largely conserved within patients across matched samples, with few genes, including TP53, being recurrently altered in the majority of patient specimens. In matched FFPE brain metastasis and ECT samples, we observed differentially expressed genes and pathways that had increased or decreased expression in brain metastasis, including in oxidative phosphorylation and DNA repair. Survival outcomes for patients differed by intrinsic molecular subtypes, with some association between expression of select gene pathways and survival. Data available through dbGaP will be the sequencing data and sample attributes from BCBrM tissues obtained from 42 patients from Duke University Medical Center. ]]>
The study cohort includes 42 patients with metastatic breast cancer who underwent craniotomy at Duke University Hospital for breast cancer brain metastases (BCBrM) resection and had available consented frozen and/or FFPE BCBrM tissue for sequencing through the Duke Brain Tumor Center Biorepository (BTBR, IRB Pro00007434) at Duke University. All patients were included, regardless of clinical biomarkers or clinical history or diagnosis dates, so long as they had a consented BCBrM banked at some point in the BTBR. All remaining viable intracranial tissues containing at least 50% tumor cells, and any matched fresh-frozen blood DNA from the same patients, were obtained from the BTBR. Matched extracranial tumors (ECT) for the same patients were FFPE tissue blocks pulled from the surgical pathology archives at Duke or outside hospitals. Collection of tissue samples and clinical information was approved by the Duke University Institutional Review Board (Pro00104321). ]]>