Prediction of Late Breast Cancer-Specific Mortality in Recurrence-Free Breast Cancer Survivors Treated for Five Years with Tamoxifen.

PURPOSE: The extension of endocrine therapy beyond 5 years for recurrence-free survivors of breast cancer improves survival; however, the issue on how to clinically identify appropriate candidates remains controversial. This study aimed to identify prognostic factors for breast-cancer-specific mortality in patients who have had 5 years of tamoxifen treatment and categorize subgroups based on the risk of death using combinations of these prognostic factors to assist in the clinical decision to perform further endocrine therapy. METHODS: In total, 3,158 patients with breast cancer were enrolled. Breast cancer-specific survival rates after 5 years of tamoxifen treatment were calculated, and associated prognostic factors were analyzed using a Cox proportional-hazards model. RESULTS: An age extreme at diagnosis (i.e., < 40 or ≥ 60 years), tumor size > 2 cm, and positive lymphovascular invasion were robust independent prognostic factors for late breast cancer-specific death in tamoxifen-treated patients (hazard ratio [HR] = 2.162, 1.739, and 1.993; p = 0.001, 0.047, and 0.011, respectively). Lymph node metastasis and progesterone receptor negativity had borderline significance in this regard (HR = 1.741 and 1.638, p = 0.099 and 0.061). The study patients were classified into four groups according to the number of prognostic indicators, i.e., low, intermediate, high, and extremely high risk. The additional 5- and 10-year cumulative risks of breast cancer-specific death were 0.8% and 1.5% in the low-risk group, 0.9% and 3.9% in the intermediate-risk group, 1.3% and 7.3% in the high-risk group, and 4.8% and 13.8% in the extremely high-risk group, respectively. CONCLUSION: This new risk stratification system for late mortality in breast cancer can be used to identify the right candidates for extended endocrine therapy after 5 years of tamoxifen treatment.

Cisplatin-Encapsulated Polymeric Nanoparticles with Molecular Geometry-Regulated Colloidal Properties and Controlled Drug Release.

Encapsulation of chemotherapeutic agents inside a nanoscale delivery platform can provide an attractive therapeutic strategy with many pharmaceutical benefits, such as increased plasma solubility, prolonged in vivo circulation, and reduced acute toxicity. Given that the biological activities of polymeric nanoparticles are highly dependent on their colloidal structures, the molecular geometry-regulated programming of self-assembled nanoscale architecture is of great interest for chemical design of an ideal delivery platform. In this report, we demonstrate that the molecular geometry of block-copolymer excipients can govern the level of drug-loading capacity and core hydrophobicity of polymeric nanoparticles, which can eventually control the pH-sensitive drug-release property. Atom-transfer radical polymerization was employed as a controlled synthetic method for the copolymer excipients, which contain the metal-chelating poly(acrylic acid) block linked to either a small mPEG-grafted poly(methacrylate) to generate a bulky brush-like chains or a simple linear mPEG segment. During the coordination of cis-diammineplatinum(II) as an active pharmacophore of cisplatin, aqueous-phase size-exclusion chromatography analyses exhibited highly different self-association kinetic regimes prompted by versatile molecular geometry of copolymer excipients, which further allows us to explore the molecular geometry-colloidal property relationship.

Cisplatin-Mediated Formation of Polyampholytic Chitosan Nanoparticles with Attenuated Viscosity and pH-Sensitive Drug Release.

Chitosan is a biocompatible natural polysaccharide, which has been employed as a polymeric scaffold for versatile, systemic delivery platforms and for locally injectable gels with temperature-sensitive viscosity modulation. Despite the extensive investigation on the chemical modification strategies, however, most of the chitosan-based delivery platforms have been focused on the encapsulation of hydrophobic drugs, which can be simply adsorbed on the chitosan scaffolds by hydrophobic interaction via the postparticle-formation drug-loading process. Herein, we present the facile formation of a cisplatin-coordinated chitosan nanoplatform by exploiting the divalent metal (PtII)-mediated conformational changes of chitosan chains, which allows for the simultaneous drug-loading and nanoparticle formation. To this end, the native chitosan has been chemically modified with short polyethylene glycol and malonic acid as a colloidal stabilizer and a bidentate chelating ligand for PtII coordination, respectively. The resulting PtII-modified polyampholytic chitosan (PtII-MPC) has been self-associated in aqueous media by hydrophobic segregation into a compact nanostructure, which exhibited an attenuated viscosity and pH-sensitive release of PtII compounds. Once the cationic drug molecules have been released under mild acidic conditions, the neutralized PtII-free MPC undergoes interchain flocculation near the isoelectric point because of the polyampholytic property, possibly allowing for the facilitated endosomal escape during the cellular endocytosis by the known membrane perturbation property of chitosan.