Tissue Type Differences in ABCB1 Expression and Paclitaxel Tissue Pharmacokinetics in Patients With Esophageal Cancer

Abstract

Background: Data from previous work suggests that there is no correlation between systemic (plasma) paclitaxel exposure and efficacy in patients treated for esophageal cancer. In this trial, we investigated ATP-binding cassette efflux transporter expression and intratumoral pharmacokinetics of paclitaxel to identify changes which could be a first sign of chemoresistance.Methods: Patients with esophageal cancer treated with paclitaxel and carboplatin (± concomitant radiotherapy) were included. During the first and last cycle of weekly paclitaxel, blood samples and biopsies of esophageal mucosa and tumor tissue were taken. Changes in paclitaxel exposure and expression of ABCB1 (P-glycoprotein) over time were studied in both tumor tissue and normal appearing esophageal mucosa.Results: ABCB1 was significantly higher expressed in tumor tissue compared to esophageal tissue, during both the first and last cycle of paclitaxel (cycle 1: p < 0.01; cycle 5/6: p = 0.01). Interestingly, ABCB1 expression was significantly higher in adenocarcinoma than in squamous cell carcinoma (p < 0.01). During the first cycle, a trend towards a higher intratumoral paclitaxel concentration was observed compared to the esophageal mucosa concentration (RD:43%; 95%CI: −3% to 111% p = 0.07). Intratumoral and plasma paclitaxel concentrations were significantly correlated during the first cycle (AUC0–48 h: r = 0.72; p < 0.01).Conclusion: Higher ABCB1 expression in tumor tissue, and differences between histological tumor types might partly explain why tumors respond differently to systemic treatment. Resistance by altered intratumoral paclitaxel concentrations could not be demonstrated because the majority of the biopsies taken at the last cycle of paclitaxel did contain a low amount of tumor cells or no tumor.

Impact of ABCB1, ABCC1, ABCC2, and ABCG2 variants in predicting prognosis and clinical outcomes of north Indian lung cancer patients undergoing platinum‐based doublet chemotherapy

“…When we stratified our analysis of ABCB1 polymorphism based on histology, we found that adenocarcinoma patients who have homozygous wild‐type alleles ( CC ) for ABCB1 C 1236 T and C 3435 T had better survival compared to their associated carrier alleles ( CT ). This can be supported by the study by Eerden et al, 35 who found that the expression of ABCB1 efflux transporter is higher in the adenocarcinoma than in the other histology subtypes of squamous cell carcinoma. The significantly higher survival in wild‐type patients is associated with the low ABCB1 mRNA levels and prolonged prognosis 14 .…”

CINOVA: a phase II study of CPC634 (nanoparticulate docetaxel) in patients with platinum resistant recurrent ovarian cancer

“…One of the most important mechanisms is through increased drug efflux by transporters, of which the adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) is most important 27–30. Indeed, a direct association between ABCB1 expression, drug resistance, and prognosis has been found in ovarian cancer 31 32.…”

Natural Taxanes: From Plant Composition to Human Pharmacology and Toxicity

“…Total amount of active drug that reaches the systemic circulation (AUC 0–48 h, 1500–10,000 ng·h/mL) and the concentration taken 4 h (50–350 ng/mL) after the dose were positively correlated with the intratumoral concentration (approximately 1.5–7.0 ng/mg). The concentration in the oesophageal mucosa did not correlate with these parameters and was approximately the same at the beginning and at the end of the PTX dosing cycle [ 85 ].…”