Obesity and metabolic syndrome are associated with short-term endocrine therapy resistance in early ER + breast cancer.

PURPOSE: Increased body mass index (BMI) and metabolic syndrome (MS) are associated with increased breast cancer recurrence risk. Whether this is due to intrinsic tumor biology or modifiable factors of the obese state remains incompletely understood. METHODS: Oncotype DX Recurrence Scores of 751 patients were stratified by BMI to assess association with tumor-intrinsic recurrence risk. Cellular proliferation by Ki67 after 10-21 days of presurgical letrozole treatment was used to stratify endocrine therapy response (sensitive-ln(Ki67) < 1; intermediate-ln(Ki67)1-2; resistant-ln(Ki67) > = 2). BMI at the time of surgery and MS variables were collected retrospectively for 143 patients to analyze association between therapy response and BMI/MS. Additionally, PI3K pathway signaling was evaluated by immunohistochemistry of phosphorylated Akt and S6. RESULTS: There was no significant association between BMI and recurrence score (p = 0.99), and risk score distribution was similar across BMI groups. However, BMI was associated with short-term endocrine therapy resistance, with a significant enrichment of intermediate and resistant tumors in patients with obesity (55%, p = 0.0392). Similarly, the relative risk of an endocrine therapy-resistant tumor was 1.4-fold greater for patients with MS (p = 0.0197). In evaluating PI3K pathway mediators, we found patients with 3 or more MS criteria had more tumors with pAkt scores above the median (p = 0.0436). There were no significant differences in S6 activation. CONCLUSION: Our findings suggest the association between obesity/metabolic syndrome and breast cancer recurrence is better reflected by response to treatment than tumor-intrinsic properties, suggesting interventions to reverse obesity and/or MS may improve outcomes for breast cancer recurrence.

Computer Optimization of Stealth Biodegradable Polymeric Dual-loaded Nanoparticles for Cancer Therapy Using Central Composite Face-centered Design.

BACKGROUND: Combination chemotherapy capable of overcoming cancer drug resistance can be facilitated by nanotechnology. OBJECTIVE: Synthesis, characterization, statistical experimental design, analysis and optimization of stealth pH-sensitive polymeric nanoparticles suitable as a platform for simultaneous delivery of paclitaxel and 17-AAG in breast cancer therapy were investigated. METHODS: An acetal crosslinker and a poly(ɛ)caprolactone macromonomer were synthesized and characterized. The statistical experimental design used was the response surface method (RSM). We used the central composite face-centered design (CCF) in three independent factors and seventeen runs. Nanoparticles were fabricated by dispersion polymerization techniques. Response variables evaluated were: particle size, drug loading, encapsulation efficiency, and in vitro availability. RESULTS: Scanning electron micrographs showed the formation of spherical nanoparticles. Computer software was used for the analysis of variance with a 95% confidence level and Q2 (goodness of prediction) to select an appropriate model for each of the response variables. Each term in each of the models was tested for the significance of the regression coefficients. The computer software optimizer was used for optimization to select factor combination to minimize particle size, time (h) for maximum release of paclitaxel and 17-AAG, to maximize paclitaxel and 17-AAG loading efficiency and to maximize paclitaxel and 17-AAG encapsulation efficiency. CONCLUSION: The optimization was successful, as shown by the validation data which lie within the confidence intervals of predicted values of the response variables. The selected factor combination is suitable for the in vivo evaluation of the nanoparticles loaded with paclitaxel and 17-AAG.