Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Local and Contralateral Recurrence in Breast Intraepithelial Neoplasia

Abstract

Purpose: Tamoxifen administered for 5 years at 20 mg/d is effective in breast cancer treatment and prevention, but toxicity has limited its broad use. Biomarker trials showed that 5 mg/d is not inferior to 20 mg/d in decreasing breast cancer proliferation. We hypothesized that a lower dose given for a shorter period could be as effective in preventing recurrence from breast intraepithelial neoplasia but have a lower toxicity than the standard dose.

Patients and methods: We conducted a multicenter randomized trial of tamoxifen, 5 mg/d or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ. The primary end point was the incidence of invasive breast cancer or ductal carcinoma in situ.

Results: Five hundred women 75 years of age or younger were included. After a median follow-up of 5.1 years (interquartile range, 3.9-6.3 years), there were 14 neoplastic events with tamoxifen and 28 with placebo (11.6 v 23.9 per 1,000 person-years; hazard ratio, 0.48; 95% CI, 0.26 to 0.92; P = .02), which resulted in a 5-year number needed to treat of 22 (95% CI, 20 to 27). Tamoxifen decreased contralateral breast events by 75% (three v 12 events; hazard ratio, 0.25; 95% CI, 0.07 to 0.88; P = .02). Patient-reported outcomes were not different between arms except for a slight increase in frequency of daily hot flashes with tamoxifen (P = .02). There were 12 serious adverse events with tamoxifen and 16 with placebo, including one deep vein thrombosis and one stage I endometrial cancer with tamoxifen and one pulmonary embolism with placebo.

Conclusion: Tamoxifen at 5 mg/d for 3 years can halve the recurrence of breast intraepithelial neoplasia with a limited toxicity, which provides a new treatment option in these disorders.

Trial registration: ClinicalTrials.gov NCT01357772.

FIG 1.

Participant flow diagram. The intention-to-treat population included all patients who underwent random assignment (n = 253 in the tamoxifen arm; n = 247 in the placebo arm). The safety population included all patients who received at least one dose of trial agent (n = 249 in the tamoxifen arm; n = 246 in the placebo arm). Completion of the study is defined as having completed the 36-month double-blind treatment phase. ADH, atypical ductal hyperplasia; AE, adverse event; DCIS, ductal carcinoma in situ; ER, estrogen receptor; IEN, intraepithelial neoplasia; LCIS, lobular carcinoma in situ.

FIG 2.

Kaplan-Meier estimates of (A) cumulative incidence of breast cancer events (invasive breast cancer or ductal carcinoma in situ and of (B) contralateral breast cancer events in the overall intention-to-treat population (ITT) by allocated arm. Numbers in parentheses represent the number of events that occurred within each time interval by treatment arm. The log-rank test was used to draw inferences. The estimate of the hazard ratio (HR) was based on a univariable Cox proportional hazards regression model (ie, with only the treatment arm variable). In the overall ITT population, there were 42 breast cancer events (14 in the tamoxifen arm and 28 in the placebo arm) of which there were 15 contralateral breast cancer events (three in the tamoxifen arm and 12 in the placebo arm). The 3-year cumulative incidence rate of breast cancer events was 2.3% (95% CI, 1.7% to 6.6%) in the tamoxifen arm and 7.6% (95% CI, 4.8% to 11.8%) in the placebo arm, and the 5-year cumulative incidence rate was 6.4% (95% CI, 3.7% to 10.9%) and 11.0% (95% CI, 7.4% to 16.0%), respectively. The 3-year cumulative incidence rate of contralateral breast cancer was 0.4% (95% CI, 0.1% to 3.1%) in the tamoxifen arm and 2.5% (95% CI, 5.5% to 1.1%) in the placebo arm, and the 5-year cumulative incidence rate was 1.1% (95% CI, 0.3% to 4.5%) and 4.2% (95% CI, 2.2% to 8.0%), respectively.

FIG 3.

Marginal predicted means of daily (A) hot flash frequency and (B) score (frequency × intensity), (C) vaginal dryness or pain with intercourse, and (D) musculoskeletal pain or arthralgia during the double-blind treatment phase. Values at baseline (month 0) are observed mean. Daily frequency but not daily score of hot flashes in the tamoxifen arm increased significantly relative to the placebo arm (P for treatment effect = .02 and .16, respectively). There was no difference between arms on vaginal dryness or pain with intercourse and musculoskeletal pain or arthralgia (P for treatment effect = .40 and .41, respectively).

FIG A1.

Kaplan-Meier estimates of cumulative breast cancer incidence by histologic type (atypical ductal hyperplasia [ADH], lobular carcinoma in situ [LCIS], ductal carcinoma in situ [DCIS]) regardless of treatment with tamoxifen. Numbers in parentheses represent the number of events that occurred within each time interval by treatment arm. The log-rank test was used to draw inferences. The hazard ratios (HRs) for LCIS versus ADH and DCIS versus ADH were estimated from a Cox proportional hazards regression model adjusted for treatment arm; the HR of the treatment effect (data not shown), adjusted for the histologic type, was 0.48 (95% CI, 0.25 to 0.91). In the overall intention-to-treat population, there were 42 breast cancer events (three in the ADH group, 31 in the DCIS group, and eight in the LCIS group). The 5-year cumulative incidence rate of breast cancer was 3.2% (95% CI, 1.0% to 9.5%) in the ADH group, 9.0% (95% CI, 6.1% to 13.0%) in the DCIS group, and 18.0% (95% CI, 9.2% to 33.4%) in the LCIS group. The HRs compared with ADH are adjusted for treatment arm.

FIG A2.

Estimated marginal means of endometrial thickness (in millimeters) change in postmenopausal women during the double-blind treatment phase by allocated arm. Endometrial thickness in the tamoxifen arm was significantly increased compared with the placebo arm.

FIG A3.

Kaplan-Meier curve for time to first nonadherent study visit according to treatment arm. Numbers in parentheses represent the number of events that occurred within each time interval by treatment arm. The log-rank test was used to draw inferences. Overall, 62.8% of women were adherent for at least 2.5 years. The mean time on treatment was 2.3 years (standard deviation, 1.1). Kaplan-Meier estimate for adherence was not significantly different in women who took tamoxifen (64.8%) compared with those who took placebo (60.7%). Overall, dropout rates were highest within the first 6 months since randomization (10.3% in the tamoxifen arm; 12.2% in the placebo arm) and decreased thereafter. HR, hazard ratio.