Influence of endoxifen on mammographic density—results from the KARISMA trial

Purpose Monitoring metabolites of tamoxifen, such as endoxifen, has been suggested as a strategy to ascertain therapeutic effect of tamoxifen therapy but clinical guidelines are missing. Herein we aim to investigate the outcome of endoxifen concentrations of low dose tamoxifen, using change in mammographic breast density (MBD) as a proxy for therapy response. Material and Methods In the randomized KARISMA trial, including five doses of tamoxifen, measurements of plasma endoxifen concentrations, determination of CYP2D6 metabolizer status and MBD change over the trial period, were carried out. Association between endoxifen concentrations and relative MBD change after 6 months treatment was analysed using linear regression in a spline model. Results A total of 824 women (335 premenopausal, 489 postmenopausal) were included. In analyses of premenopausal women, a spline model described a MBD decrease, equivalent to the mean (-18.5%) seen in women exposed to 20 mg tamoxifen, at endoxifen concentrations of 2–3 ng/mL. The MBD decrease reached a nadir at endoxifen levels of 3 ng/mL and did not decrease further at higher endoxifen concentrations. Most intermediate and normal tamoxifen-metabolizers (≈ 90% of all participants) reached an endoxifen concentration of > 2 ng/mL at tamoxifen doses of 5 and 10 mg. No MBD decrease was seen in the postmenopausal group. Conclusion We have identified a possible window of effect on MBD at endoxifen concentrations of 2–3 ng/mL in premenopausal women, which corresponds to the doses of 5 and 10 mg tamoxifen. Since MBD change was used as a surrogate marker for therapy response, results should be confirmed using clinically established outcomes measures. Trial Registration ClinicalTrials.gov ID: NCT03346200