The impact of statin use on the efficacy of abiraterone acetate in patients with castration‐resistant prostate cancer

Background

Statins compete with DHEAS for influx through the SLCO2B1 transporter, which may prolong time to progression (TTP) on androgen deprivation therapy. Abiraterone acetate (AA) may also undergo SLCO‐mediated transport. Based on preclinical findings showing antagonism, we hypothesized that statins may compete with AA for influx via SLCO2B1 and could negatively impact drug efficacy.

Methods

We queried two institutional clinical databases (Dana‐Farber Cancer Institute [DFCI], Johns Hopkins University [JHU]) for CRPC patients treated with AA. Treatment duration was a surrogate for TTP. Associations between statin use and AA duration were estimated using the Kaplan‐Meier method. Multivariable Cox regression modeling adjusted for known prognostic factors.

Results

Of the 224 DFCI and 270 JHU patients included, the majority (96%) had metastatic disease. Nearly half (41% and 45%) were statin users. In the DFCI cohort, there was a trend toward longer AA duration in statin users: 14.2 versus 9.2 months (HR 0.79, 95%CI: 0.57‐1.09, P = 0.14). There was no association between statin use and AA duration in the JHU cohort: 8.3 versus 8.0 months (HR 0.89, 95%CI: 0.69‐1.16, P = 0.38) in the statin users versus non‐users, except for a trend in patients that had not previously received docetaxel or enzalutamide (HR 0.79; 95%CI: 0.57‐1.10).

Conclusions

Contrary to our initial hypothesis, there was a trend toward longer (rather than shorter) AA duration in statin users in the entire DFCI cohort and in the enzalutamide‐ and docetaxel‐naïve JHU patients. Together, these results do not support the hypothesis that statins interfere with AA efficacy.     

Charcot Pathogenesis: A Study of In Vivo Gene Expression

Charcot neuroarthropathy is a rare but often difficult to manage disease in the neuropathic patient. Early signs such as unremarkable edema, marginal trauma, or minor infection can activate a cascade of bony destruction and lead to gross prominence or deformity, with dire consequences. The exact molecular mechanism is poorly understood. Current theory states that an inflammatory reaction leads to the activation of osteoclasts mediated by specific cytokines. Our study sought to test the genetic expression of certain biomarkers in diabetic patients with and without Charcot neuroarthropathy compared with patients with and without diabetes or neuropathy. A total of 30 patients participated in the study, 17 (57%) males and 13 (43%) females. Peripheral blood samples were drawn, and gene expression was measured using real-time polymerase chain reaction. The expression levels of receptor activator of nuclear factor kappa-B ligand and osteoprotegerin showed no significant increase in the Charcot neuroarthropathy group compared with the healthy control group. We determined that the levels of receptor activator of nuclear factor kappa-B ligand and osteoprotegerin were not significantly increased in Charcot neuroarthropathy patients compared with healthy control patients. These results demonstrate a need for further investigation into alternative molecular pathways to determine the exact mechanism of the disease process.     

Differences in patellofemoral kinematics between weight‐bearing and non‐weight‐bearing conditions in patients with patellofemoral pain

Patellar maltracking is thought to be one source of patellofemoral pain. Measurements of patellar tracking are frequently obtained during non‐weight‐bearing knee extension; however, pain typically arises during highly loaded activities, such as squatting, stair climbing, and running. It is unclear whether patellofemoral joint kinematics during lightly loaded tasks replicate patellofemoral joint motion during weight‐bearing activities. The purpose of this study was to: evaluate differences between upright, weight‐bearing and supine, non‐weight‐bearing joint kinematics in patients with patellofemoral pain; and evaluate whether the kinematics in subjects with maltracking respond differently to weight‐bearing than those in nonmaltrackers. We used real‐time magnetic resonance imaging to visualize the patellofemoral joint during dynamic knee extension from 30° to 0° of knee flexion during two conditions: upright, weight‐bearing and supine, non‐weight‐bearing. We compared patellofemoral kinematics measured from the images. The patella translated more laterally during the supine task compared to the weight‐bearing task for knee flexion angles between 0° and 5° (p = 0.001). The kinematics of the maltrackers responded differently to joint loading than those of the non‐maltrackers. In subjects with excessive lateral patellar translation, the patella translated more laterally during upright, weight‐bearing knee extension for knee flexion angles between 25° and 30° (p = 0.001). However, in subjects with normal patellar translation, the patella translated more laterally during supine, non‐weight‐bearing knee extension near full extension (p = 0.001). These results suggest that patellofemoral kinematics measured during supine, unloaded tasks do not accurately represent the joint motion during weight‐bearing activities. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:312–317, 2011