AR splice variants in circulating tumor cells of patients with castration-resistant prostate cancer: relation with outcome to cabazitaxel.

The androgen receptor splice variant (AR-V) 7 in circulating tumor cells (CTCs) is a predictor for resistance to anti-AR-targeted treatment, but not to taxane-based chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). In this study, we investigated whether the presence of two constitutively active variants (AR-V3, AR-V7) and two other conditionally activated variants (AR-V1, AR-V9) vs full-length androgen receptor (AR-FL) measured in CTCs from patients with mCRPC were associated with outcome to therapy with the taxane cabazitaxel. Blood was collected at baseline and after two cycles of cabazitaxel from 118 mCRPC patients starting cabazitaxel in a prospective phase II trial.

Association between Paclitaxel Clearance and Tumor Response in Patients with Esophageal Cancer.

Inter-individual variability in paclitaxel pharmacokinetics may play a role in the response to chemotherapy. Therefore, we studied the association between paclitaxel clearance and treatment response in patients with esophageal cancer. All patients who received paclitaxel (plus carboplatin) treatment for esophageal cancer between 2007 and 2013 were included.

Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer.

Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood sampling is required to adequately define drug disposition, limiting patient recruitment.

Prognostic factors in men with metastatic castration-resistant prostate cancer treated with cabazitaxel.

Background: Treatment selection for men with metastatic castration-resistant prostate cancer (mCRPC) has become increasingly challenging with the introduction of novel therapies at earlier disease stages. The purpose of this study was to identify prognostic factors for overall survival (OS) and PSA response in patients with mCRPC treated with cabazitaxel.

Results: 224 mCRPC patients were included in the current analysis.

Effects of Budesonide on Cabazitaxel Pharmacokinetics and Cabazitaxel-Induced Diarrhea: A Randomized, Open-Label Multicenter Phase II Study.

Forty-seven percent of patients in the pivotal trial of cabazitaxel reported diarrhea of any grade. Aiming to reduce the incidence of diarrhea, we studied the effects of budesonide on the grade of cabazitaxel-induced diarrhea during the first two treatment cycles. Between December 2011 and October 2015, 246 metastatic castration-resistant prostate cancer patients were randomized to receive standard-of-care cabazitaxel 25 mg/m every 3 weeks plus prednisone 10 mg/day (group CABA) or same dose/schedule of cabazitaxel with concomitant budesonide 9 mg daily during the first two treatment cycles (group BUD).

Predicting paclitaxel-induced neutropenia using the DMET platform.

Aim: The use of paclitaxel in cancer treatment is limited by paclitaxel-induced neutropenia. We investigated the ability of genetic variation in drug-metabolizing enzymes and transporters to predict hematological toxicity.

Patients & Methods: Using a discovery and validation approach, we identified a pharmacogenetic predictive model for neutropenia.

Efficacy of Cabazitaxel in Castration-resistant Prostate Cancer Is Independent of the Presence of AR-V7 in Circulating Tumor Cells.

Background: Androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from patients with metastatic castration-resistant prostate cancer (mCRPC) was recently demonstrated to be associated with resistance to abiraterone and enzalutamide. Cabazitaxel might, however, remain effective in AR-V7-positive patients.

Objective: To investigate the association between AR-V7 expression in CTCs and resistance to cabazitaxel.

Inter-patient variability in docetaxel pharmacokinetics: A review.

Docetaxel is a frequently used chemotherapeutic agent in the treatment of solid cancers. Because of the large inter-individual variability (IIV) in the pharmacokinetics (PK) of docetaxel, it is challenging to determine the optimal dose in individual patients in order to achieve optimal efficacy and acceptable toxicity. Despite the established correlation between systemic docetaxel exposure and efficacy, the precise factors influencing docetaxel PK are not yet completely understood.

Pharmacokinetically based dosing of weekly paclitaxel to reduce drug-related neurotoxicity based on a single sample strategy.

Purpose: The present simulation study was initiated to develop a limited sampling strategy and pharmacokinetically based dosing algorithm of weekly paclitaxel based on pharmacokinetic (PK) and chemotherapy-induced peripheral neuropathy (CIPN) data from a large database.

Methods: We used paclitaxel plasma concentrations from 200 patients with solid tumors receiving weekly paclitaxel infusions to build a population PK model and a proportional odds model on CIPN. Different limited sampling strategies were tested on their accuracy to estimate the individual paclitaxel time-above-threshold-concentration of 0.

Influence of drug formulation on OATP1B-mediated transport of paclitaxel.

Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters before metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by the choice of drug delivery system. Transport of paclitaxel, docetaxel, and cabazitaxel was studied in vitro using various cell lines transfected with OATP1B1, OATP1B3, or the rodent equivalent OATP1B2.

A pharmacogenetic predictive model for paclitaxel clearance based on the DMET platform.

Purpose: Paclitaxel is used in the treatment of solid tumors and displays high interindividual variation in exposure. Low paclitaxel clearance could lead to increased toxicity during treatment. We present a genetic prediction model identifying patients with low paclitaxel clearance, based on the drug-metabolizing enzyme and transporter (DMET)-platform, capable of detecting 1,936 genetic variants in 225 metabolizing enzyme and drug transporter genes.

CYP3A4 intron 6 C>T SNP (CYP3A4*22) encodes lower CYP3A4 activity in cancer patients, as measured with probes midazolam and erythromycin.

Aim: The CYP3A4*22 allele was recently reported to be associated with reduced CYP3A4 activity. We investigated the impact of this allele on the metabolism of the CYP3A-phenotyping probes, midazolam (MDZ) and erythromycin.

Patients & Methods: Genomic DNA from 108 cancer patients receiving intravenous MDZ and 45 undergoing the erythromycin breath test was analyzed for CYP3A4*22 (rs35599367 C>T) and CYP3A5*3.

Impact of POR*28 on the clinical pharmacokinetics of CYP3A phenotyping probes midazolam and erythromycin.

Objective: P450 oxidoreductase (POR) is essential for cytochrome P450 (CYP) activity in humans. The POR*28 allele (A503V) has been shown to impact on in-vitro CYP-mediated metabolism, including CYP3A isoenzymes. The aim of the present study was to determine the in vivo impact of the POR*28 allele on the pharmacokinetics of the classic CYP3A phenotyping probes midazolam and erythromycin.

Combinations of urinary biomarkers for surveillance of patients with incident nonmuscle invasive bladder cancer: the European FP7 UROMOL project.

Purpose: We determined a combination of markers with optimal sensitivity to detect recurrence in voided urine after resection of an incident low grade, nonmuscle invasive bladder tumor.

Materials And Methods: A total of 136 patients with G1/G2 nonmuscle invasive bladder tumor were included in the study at transurethral resection of the incident tumor. At least 3 followup urine samples were required for patient selection.

Quantification of cabazitaxel in human plasma by liquid chromatography/triple-quadrupole mass spectrometry: a practical solution for non-specific binding.

A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the quantitative determination of cabazitaxel, a novel tubulin-binding taxane, in 100 μl aliquots of human lithium heparinized plasma with deuterated cabazitaxel as internal standard. The sample extraction and cleaning-up involved a simple liquid-liquid extraction with 20 μl aliquots of 4% ammonium hydroxide, 100 μl aliquots of acetonitrile and 1 ml aliquots of n-butylchloride. Chromatographic separations were achieved on a reversed phase C₁₈ column eluted at a flow-rate of 0.

Markers predicting response to bacillus Calmette-Guérin immunotherapy in high-risk bladder cancer patients: a systematic review.

Context: Currently, bacillus Calmette-Guérin (BCG) intravesical instillations are standard treatment for patients with high-grade non-muscle-invasive bladder cancer; however, no markers are available to predict BCG response.

Objective: To review the contemporary literature on markers predicting BCG response, to discuss the key issues concerning the identification of predictive markers, and to provide recommendations for further research studies.

Evidence Acquisition: We performed a systematic review of the literature using PubMed and Embase databases in the period 1996-2010.