The effect of alternating letrozole and tamoxifen in comparison to sequential treatment with each drug alone or in combination

Using the intratumoral aromatase model for postmenopausal breast cancer studies, we had previously predicted that the aromatase inhibitor letrozole (L) would be more effective than the antiestrogen tamoxifen (T) at slowing tumor growth and prolonging time to progression. This has recently been confirmed in a clinical trial. The aim of the present study was to determine the best treatment strategy for using L and T. We compared sequential treatment with each drug alone to alternating the two drugs and to combining the two drugs. Aromatase-transfected MCF-7Ca human breast cancer cells were inoculated (4 sites) into female ovariectomized athymic nude mice. For the duration of the experiment the animals were supplemented daily with the aromatase substrate androstenedione (Δ4A, 100 μg/day). When tumor volumes were 50 mm³, animals were grouped (n = 20) for treatment with vehicle, L ( 10 μg/day), T (100 μg/day), [L to T] (every 4-weeks), [T to L] (every 4-weeks), and [L plus T]. Tumors in the L-treated animals regressed by 54% over the first 4-weeks of treatment and then started to proliferate slowly. After 12 weeks of treatment, volumes were still 20% lower than pretreatment levels. Volumes of the T-treated tumors increased by 10-15% over the first 2-weeks and remained at this level for an additional 6-weeks. After 8-weeks of T, tumor growth rate started to increase rapidly and by 12-weeks, tumor volumes had increased 1.7-fold. Tumor volumes in the animals treated with [L plus T] also regressed, but by only 28% over the first 3-weeks of treatment. Tumors then started to proliferate slowly and by 12-weeks, tumor volumes had increased 1.5-fold. Tumor volumes in the animals alternated from [L to T] increased to a level similar to the T-treated animals and regressed again when T was alternated to L. By 12-weeks, volumes had increased 1.1-fold from pretreated volumes. This pattern was also observed when the animals were alternated from [T to L]. After 2 alternations and 12-weeks of treatment, tumor volumes in the [T to L) group were similar to T alone and had increased 1.8-fold. Each of the treatments was significantly better than vehicle. However, the results indicate that L alone is the most effective therapy. L is presently being compared to T in patients as adjuvant therapy for early breast cancer. This data suggests that long-term rather than short-term therapy with L may be more beneficial to patients with hormone-dependent breast cancer.