PHARMACOKINETICS AND CLINICAL IMPACT OF ALL-TRANS-RETINOIC ACID IN METASTATIC BREAST-CANCER - A PHASE-II TRIAL

Purpose: The purpose of this trial was to evaluate tumor cytoreduction by all-trans retinoic acid (ATRA) in patients with metastatic breast cancer and to characterize the initial pharmacokinetics of this agent. Method's: The study was a single institution, phase II study. The tre atment regimen consisted of ATRA administered orally at a dose of 50 m g/m(2) three times a day for 14 consecutive days of a 21-day cycle. Cy cles were repeated until disease progression, unacceptable toxicity or patient withdrawal. Plasma samples were obtained following the first dose of ATRA for pharmacokinetic analysis. Results: A total of 17 pati ents with metastatic breast cancer were enrolled in the study, and 14 completed at least one cycle of therapy and were evaluable for respons e. One patient achieved a partial response in soft tissue of 4 months duration. Three patients had stable disease for 4, 2, and 2 months dur ation. The remainder had progressive disease. ATRA was reasonably well tolerated. Pharmacokinetic analysis revealed a high degree of interpa tient variability in systemic exposure following the initial dose of A TRA. Conclusions: We conclude, that in the dose and schedule tested, A TRA does not have significant activity in patients with hormone-refrac tory, metastatic breast cancer. Future studies should focus on more in tensive investigation of those individuals with very high or low ATRA initial systemic exposure in the hope of expanding our understanding o f ATRA's clinical pharmacology, ultimately leading to improved efficac y.