Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic interaction in postmenopausal women with metastatic breast cancer

The goals of this clinical trial involving postmenopausal women with metast atic breast cancer were to: (a) examine the effects of letrozole on tamoxif en (TAM) pharmacokinetics; (b) examine estrogen suppression in patients rec eiving TAM plus letrozole; and (c) evaluate tolerability, toxicity, objecti ve response, and time to progression for the combination. Postmenopausal wo men with measurable or evaluable metastatic breast cancer received TAM (20 mg daily) for 6 weeks, and then letrozole (2.5 mg daily) was added. To exam ine for any effect of letrozole on the levels of TAM and two metabolites [N -desmethyl-TAM and cl-hydroxy-TAM], serum samples were obtained at 6, 12, 1 8, and 24 weeks. To examine for aromatase inhibition, serum samples were ob tained before treatment and at 6, 12, 18, and 24 weeks for estradiol, estro ne (E-1) E-1 sulfate, and sex hormone-binding globulin, A total of 34 patie nts were entered on this trial, and 23 patients were still on study at week 24, 18 of whom had blood samples available at both week 6 and week 24. The 95% confidence interval for the mean difference between levels at week 24 and levels at week 6 was -34 to 15 ng/ml for TAM, -35 to 45 ng/ml for N-des methyl-TAM, and -1 to 2 for 4-hydroxy-TAM. For estradiol, a significant dec rease (median, 88.5%; range, 73.7-95.2%) was identified after 6 weeks of le trozole, which was maintained for an additional 12 weeks. Similar significa nt reductions were identified for E-1. E-1 sulfate levels increased after 6 weeks of TAM alone but then decreased significantly after the addition of letrozole. Sex hormone-binding globulin levels were significantly elevated after 6 weeks of TAM alone and remained elevated after the addition of letr ozole. Six of the 34 patients (17.6%) achieved an objective response (95% c onfidence interval, 6.8-34.5%), with a median time to disease progression o f 7.6 months. There was no indication of a systematic decrease in TAM, N-de smethyl-TAM, or 4-hydroxy-TAM after the additional of letrozole, Estrogen s uppression induced by letrozole was substantial despite the concomitant adm inistration of TAM, The antitumor effect of TAM plus letrozole was less tha n expected.