Randomized biomarker trial of anastrozole and low-dose tamoxifen in breast intraepithelial neoplasia: Effects on bone turnover and drug concentrations

Abstract

1000 Background: We have shown that low dose tamoxifen (T) has a similar activity compared to the conventional dose, based on the antiproliferative effect (%Ki-67) and breast biomarkers modulation. The long half-life of T provides the basis for a weekly dose regimen. Anastrozole (A), has shown a higher efficacy compared to T in the ATAC trial, while the combination arm (A+T) appears to be detrimental. This may be due to an adverse pharmacokinetic interaction between drugs which reduces by 30% the bioavailability of A. However, A increases bone fractures and the addition of T may counteract A-induced bone loss. Methods: We conducted a phase IIb trial in postmenopausal ER+ve DCIS or LCIS patients who were randomized to low dose T (10 mg/week), or A (1 mg/day), or A+T and treated for 1 year. The main endpoint is the study of the plasma drug concentrations. Secondary endpoints include effects on biomarkers of breast cancer (SHBG, E2, E1, E1-S, IGF-I, IGFBP3), bone turnover (CTX, osteocalcin) and cardiovascular risk (lipids, coagulation, C-reactive protein, homocisteine). Results: 25 patients have been randomized in each arm. Sixtyeight subjects (91%) completed treatment and 7 dropped-out. No major toxicity was observed. After 1 year, mean A concentrations were 31.5±15.0 and 37.7±17.0 ng/ml in the A and in the A+T arm, respectively and no statistical difference has been observed. Results on some biomarkers are reported in the table below. Conclusions: The combination of low dose T and A does not affect A concentration and these results differ from the ATAC trial. Low dose T reduces IGF-I and osteocalcin concentrations. A increases osteocalcin and CTX while the combination has a beneficial effect on these bone formation and resorption biomarkers. These effects may be associated with a safer long-term effect on bone fracture risk in postmenopausal women. Supported by the Italian Foundation for Cancer Research (FIRC) No significant financial relationships to disclose.