ABSTRACT
BACKGROUND: Breast cancer-related leptomeningeal disease (BC-LMD) is a dire diagnosis for 5-8% of patients with breast cancer (BC). We conducted a retrospective review of BC-LMD patients diagnosed at Moffitt Cancer Center from 2011 to 2020, to determine the changing incidence of BC-LMD, factors which are associated with the progression of BC CNS metastasis to BC-LMD, and factors which are associated with OS for patients with BC-LMD. METHODS: Patients with BC and brain/spinal metastatic disease were identified. For those who eventually developed BC-LMD, we used Kaplan-Meier survival curve, log-rank test, univariable, and multivariate Cox proportional hazards regression model to identify factors affecting time from CNS metastasis to BC-LMD and OS. RESULTS: 128 cases of BC-LMD were identified. The proportion of BC-LMD to total BC patients was higher between 2016 and 2020 when compared to 2011-2015. Patients with HR+ or HER2 + BC experienced longer times between CNS metastasis and LMD than patients with triple-negative breast cancer (TNBC). Systemic therapy and whole-brain radiation therapy (WBRT) was associated with prolonged progression to LMD in all patients. Hormone therapy in patients with HR + BC were associated with a delayed BC-CNS metastasis to LMD progression. Lapatinib treatment was associated with a delayed progression to LMD in patients with HER2 + BC. Patients with TNBC-LMD had shorter OS compared to those with HR + and HER2 + BC-LMD. Systemic therapy, intrathecal (IT) therapy, and WBRT was associated with prolonged survival for all patients. Lapatinib and trastuzumab therapy was associated with improved OS in patients with HER2 + BC-LMD. CONCLUSIONS: Increasing rates of BC-LMD provide treatment challenges and opportunities for clinical trials. Prospective trials testing lapatinib and/or similar tyrosine kinase inhibitors, IT therapies, and combination treatments are urgently needed.
Subject(s)
Brain Neoplasms , Breast Diseases , Breast Neoplasms , Central Nervous System Neoplasms , Triple Negative Breast Neoplasms , Humans , Female , Breast Neoplasms/complications , Breast Neoplasms/epidemiology , Breast Neoplasms/therapy , Brain Neoplasms/secondary , Lapatinib , Retrospective Studies , Prospective Studies , Cranial Irradiation , Breast Diseases/complications , Receptor, ErbB-2ABSTRACT
Polyphenon E (Poly E) is a standardized, caffeine-free green tea extract with defined polyphenol content. Poly E is reported to confer chemoprotective activity against prostate cancer (PCa) progression in the TRAMP model of human PCa, and has shown limited activity against human PCa in human trials. The molecular mechanisms of the observed Poly E chemopreventive activity against PCa are not fully understood. We hypothesized that Poly E treatment of PCa cells induces gene expression changes, which could underpin the molecular mechanisms of the limited Poly E chemoprevention activity against PCa. PC-3 cells were cultured in complete growth media supplemented with varied Poly E concentrations for 24 h, then RNA was isolated for comparative DNA microarray (0 vs. 200 mg/L Poly E) and subsequent TaqMan qRT-PCR analyses. Microarray data for 54,613 genes were filtered for >2-fold expression level changes, with 8319 genes increased and 6176 genes decreased. Eight genes involved in key signaling or regulatory pathways were selected for qRT-PCR. Two genes increased expression significantly, MXD1 (13.98-fold; p = 0.0003) and RGS4 (21.98-fold; p = 0.0011), by qRT-PCR. MXD1 and RGS4 significantly increased gene expression in Poly E-treated PC-3 cells, and the MXD1 gene expression increases were Poly E dose-dependent.
