Tamoxifen Metabolism and Efficacy in Breast Cancer: A Prospective Multicenter Trial.

Purpose: Levels of endoxifen, the most active metabolite of tamoxifen, vary by the highly polymorphic cytochrome P450 (CYP) 2D6 enzyme. We prospectively investigated tamoxifen efficacy by serum endoxifen levels and the tamoxifen activity score (TAS).Experimental Design: A prospective observational multicenter study included postmenopausal women with an estrogen receptor-positive breast cancer receiving first-line tamoxifen, 20 mg daily in the neoadjuvant or metastatic setting, recruited between February 2009 and May 2014. The primary endpoint was the objective response rate (ORR) using RECIST criteria 1.0. Secondary endpoints were clinical benefit (CB), progression-free survival (PFS), and tolerability of tamoxifen. The main analysis used logistic regression to relate ORR to serum endoxifen levels after 3 months. Endpoints were also related to other tamoxifen metabolites and to TAS.Results: Endoxifen levels were available for 247 of all 297 patients (83%), of which 209 with target lesions (85%). Median follow-up time for PFS was 32.5 months, and 62% progressed. ORR and CB were 45% and 84%, respectively. ORR was not related to endoxifen, and the OR of ORR was 1.008 per µg/L increase in endoxifen (95% confidence interval, 0.971-1.046; P = 0.56). In general, none of the endpoints was associated with endoxifen levels, tamoxifen metabolites, or TAS.Conclusions: Under the prespecified assumptions, the results from this prospective clinical trial do not suggest therapeutic drug monitoring of endoxifen to be of clinical value in postmenopausal women treated with tamoxifen for breast cancer in the neoadjuvant or metastatic setting. Clin Cancer Res; 24(10); 2312-8. ©2018 AACR.

Uterine and quality of life changes in postmenopausal women with an asymptomatic tamoxifen-thickened endometrium randomized to continuation of tamoxifen or switching to anastrozole.

OBJECTIVE: Before the knowledge that 5 years of adjuvant tamoxifen is less efficacious than 2 to 3 years of tamoxifen followed by 2 to 3 years of anastrozole/exemestane, we designed a multicenter double-blind randomized controlled trial in women taking tamoxifen with a thickened endometrium to compare uterine and quality-of-life parameters between those switching to anastrozole and those continuing tamoxifen. METHODS: Asymptomatic postmenopausal women who took adjuvant tamoxifen for 2 to 3 years for operable breast cancer with a double endometrial thickness greater than 7 mm were randomized to 20 mg tamoxifen or 1 mg anastrozole for the remaining duration, totaling 5 years. Tablets were unrecognizable for drug assignment. The primary endpoints were the differences in double endometrial thickness and uterine volume after 1 year. Uterine and quality-of-life data were analyzed using regression methods, and missing values were handled using multiple imputation. RESULTS: Seventy-two women (median age, 60 y) were randomized in five hospitals. Relative to women continuing tamoxifen, women switching to anastrozole experienced a decrease of 53% (95% CI, 41%-63%) in double endometrial thickness and a decrease of 51% (95% CI, 39%-60%) in uterine volume. Vaginal dryness (b = 0.064; 95% CI, 0.016-0.112) and sexual problems (b = 0.054; 95% CI, 0.007-0.102) increased in women taking anastrozole compared with women taking tamoxifen. Treatment arms did not differ regarding withdrawal rate and the experience of (serious) adverse events. CONCLUSIONS: Despite premature trial closure, our data provided valuable insights. Switching to anastrozole strongly decreased the endometrial thickness and uterine volume but increased sexual disturbances. Safe and effective interventions are needed to alleviate sexual dysfunction.