Quiroga, Dionisia

Background Breast cancer-related lymphedema (BCRL) is a common and life-long adverse event affecting ~20% of breast cancer survivors. As existing non-pharmacologic management is burdensome, expensive, and variably effective, this systematic scoping review aims to identify pharmacologic and herbal agents for prevention and treatment for BCRL. Methods PubMED, Embase, Web of Science Core collection, and the Cumulative Index to Nursing and Allied Health Literature were searched for studies published in English between 1993 and 2025 that investigated the preventative or therapeutic effect of pharmacologic or herbal agents on BCRL among adult stage I-III breast cancer patients. Studies describing interventions with systemically absorbed anti-inflammatories, anti-thrombotics, anti-coagulants, and blood product components were included. Systematic reviews, protocols for ongoing clinical trials, preclinical and non-human studies, editorials, and studies not exclusive to BCRL were excluded. Three reviewers screened and extracted data between June and August 2025. The primary outcomes of interest were reduction in BCRL incidence or severity. Results Of the 217 articles screened, 37 were included in the final review. After full text review, 13 were excluded for repetitive data, non-English language, or irrelevant outcomes. The 24 studies included in the analysis investigated anti-diabetic, herbal, anti-inflammatory, anti-hypertensive, immunomodulatory, and microbiome modifying agents, and venoactive flavinoid derivates. Three studies explored the role of pharmacologic/herbal agents in BCRL prevention. While thiazolidinediones, anti-hypertensives, and non-steroidal anti-inflammatory drugs (NSAIDs) had no effect on BCRL incidence, glucagon-like peptide-1 receptor agonists (GLP-1 RA) were associated with BCRL prevention. In the 21 studies that assessed the effect of pharmacologic/herbal agents in BCRL treatment, NSAIDs/steroids, anti-hypertensives, microbiome/synbiotic supplements, and doxycycline showed no benefit and data for flavonoid-derived venoactive agents and herbal products were inconsistent. Immune-modulating therapies were associated with improved BCRL signs/symptoms in three studies. Conclusion This systematic scoping review found limited evidence suggesting that GLP-1 RAs may reduce the risk of BCRL and that immunomodulatory agents may improve signs/symptoms of BCRL. Rigorous prospective trials using standardized limb volume/edema, quality-of-life (QoL), and symptom measures and longer follow-up are needed to inform clinical practice aimed at preventing and treating BCRL. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD420251055134.

Abstract Background: DNA methyltransferase (DNMT) isoforms 1, 3A and 3B are enzymes that regulate DNA methylation, controlling gene expression, chromatin stability and genetic imprinting. We have previously shown that DNMT3A protein expression in early triple negative breast cancer (TNBC) is associated with more aggressive clinicopathologic features (higher tumor grade, tumor proliferation and frequency of nodal metastases) and worse clinical outcomes in the absence of chemotherapy (Leon-Ferre et al, SABCS 2024). Pre-clinically, we have shown that DNMT3A protein expression predicts sensitivity to DNMT inhibitors (Yu J et al., J Clin Invest 2018), and that DNMT inhibitor treatment leads to downregulation of DNMT3A, enhanced expression of immune-related pathways, and halted tumor growth, particularly in combination with immunotherapy and paclitaxel. Methods: This is a phase 1, open-label, multicenter study evaluating the safety and recommended phase 2 dose (RP2D) of the oral DNMT inhibitor ASTX727 + paclitaxel + pembrolizumab in metastatic TNBC. ASTX727 is an oral fixed dose combination (FDC) tablet of 35 mg decitabine (active agent) and 100 mg cedazuridine (a cytidine deaminase inhibitor that prevents decitabine degradation in the bowel and liver, allowing oral delivery). The study consists of two parts: Part 1 is a dose-finding cohort, using a 3+3 design, with 5 dose levels (Table), and its primary objective is to determine the RP2D. Part 2 is an expansion cohort (n=6), with the primary objective to confirm tolerability of the regimen at the RP2D. Secondary objectives are to record the antitumor activity of the regimen, describe the AE profile, explore the association of baseline gene expression profiles with clinical benefit, and to evaluate impact of treatment on tumor and ctDNA methylation. Exploratory objectives will evaluate the association of baseline DNMT3A protein expression and antitumor activity, and the impact of treatment on the tumor and peripheral blood immune phenotype. Eligible patients are adults 18 years or older with metastatic TNBC (ER/PR ≤10%, and HER2-negative per ASCO/CAP guidelines), independent of PD-L1 expression. Patients are allowed to have received 0-3 prior lines of systemic therapy in the metastatic setting, including prior immune checkpoint inhibitors in the early and/or metastatic settings. Patients must be eligible for taxanes and have adequate organ and bone marrow function. Patients with treated brain metastases are eligible if previously treated without evidence of progression after 4 weeks. Leptomeningeal carcinomatosis is not allowed. Patients must have an ECOG performance status of ≤2 and have no gastrointestinal disorders impacting absorption of oral medications. As of June 20, 2025, the study is enrolling patients, with 10 patients dosed in the dose-finding phase. Citation Format: R. Leon-Ferre, D. M. Zahrieh, P. P. Advani, D. Quiroga, K. V. Giridhar, P. J. Dizona, D. Stover, X. Wang, A. J. Tevaarwerk, G. M. Choong, S. Yasir, K. R. Kalari, J. Foldi, R. Parajuli, M. H. Hackney, H. K. Chew, R. Wajeeha, H. Bear, E. Sharon, B. Ko, G. I. Shapiro, S. Gore, L. Pelosof, L. Wang, M. P. Goetz. Trial in progress: Phase 1 Study Targeting DNA Methyltransferases in Metastatic Triple-Negative Breast Cancer (NCI Protocol #10546) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-20.