Effect modifiers of low dose tamoxifen in a randomized trial in breast non-invasive disease.

Purpose: Low-dose tamoxifen halved recurrence after surgery in a phase-III trial in breast non-invasive disease without increasing adverse events. We explored the effect of low dose tamoxifen in clinically relevant subgroups, including menopausal status, estradiol levels, smoking, body mass index and proliferation of baseline lesion. Experimental Design: Incidence of invasive breast cancer or DCIS was the primary endpoint. Hazard ratios and interactions terms were estimated using Cox models. Results: A favorable hazard ratio and 95% CI could be demonstrated for postmenopausal status (HR=0.30, 95% CI, 0.11, 0.82 versus HR=0.73, 95% CI, 0.30, 1.76 in premenopausal women, p-interaction=0.13), women with estradiol less than 15.8 pg/ml, presence of menopausal symptoms at baseline, and never smoking (p-interaction=0.07), although the interaction p-value was >0.05 for all characteristics. Efficacy was similar in all body mass index categories. Tumors with Ki-67 above the median level of 10% had a greater benefit (HR=0.27, 95% CI, 0.09, 0.81) than those with Ki-67 {less than or equal to}10% (HR=1.58, 95% CI, 0.45, 5.60, p-interaction=0.04). Conclusions: The efficacy of low-dose tamoxifen seems to be greater in postmenopausal women and in women with lower estradiol levels. Benefits appear to be larger also in women with menopausal symptoms, never smokers and tumors with Ki-67>10%. Our results by menopausal status provide important insight into low-dose tamoxifen personalized treatment, although caution is necessary given their exploratory nature. Observation of an improved response in tumors with Ki-67>10% is consistent but the use of the marker in this setting is investigational.