Over 70% of women with breast cancer are with hormone receptor positive disease [1], and most of them are treated with an adjuvant endocrine therapy. Five years tamoxifen used to be a standard adjuvant endocrine treatment of breast cancer. It was shown by a metaanalysis that tamoxifen reduced about 40% of recurrence rates in both premenopausal and postmenopausal women with breast cancer [2].

Third generation Aromatase Inhibitors (AIs), exemestane (steroidal), anastrozole (non-steroidal), and letrozole (non-steroidal) began to be used in late 90’s as an adjuvant endocrine therapy in postmenopausal women with breast cancer. A randomized controlled trial showed that 5 years adjuvant anastrozole was superior to 5 years adjuvant tamoxifen in terms of disease-free survival (DFS) rates [3]. In addition another randomized controlled trial showed that 5 years of adjuvant letrozole was superior to 5 years adjuvant tamoxifen in terms of DFS rates and overall survival (OS) rates [4]. On the other hand, randomized controlled trials showed that 5 years adjuvant therapy of letrozole or exemestane was not superior to 2 to 3 years of adjuvant tamoxifen followed by 2 to 3 years of letrozole or exemestane [4,5]. In addition, 5 years adjuvant letrozole was not superior to 2 years of adjuvant letrozole followed by tamoxifen [4]. Three AIs seemed to have a similar efficacy in the neoadjuvant setting [6]. All these results suggest that there are two standard options of adjuvant endocrine therapy for postmenopausal women with breast cancer. First is an upfront use of AIs that is intended to be treated for 5 years. Second is an upfront use of tamoxifen that is intended to be treated for 2 to 3 years followed by AIs for a total of 5 years.

The efficacy of AIs and tamoxifen partly depends on patients’ characteristics. It was reported that adjuvant anastrozole was less effective in patients with higher levels of Body Mass Index (BMI) [7]. Levels of estrogen in patients receiving anastrozole or letrozole were greater at higher levels of BMI [8]. However, a steroidal AI, exemestane showed no difference in the efficacy between patients with different levels of BMI as the adjuvant setting [9]. In addition, exemestane was more effective in patients with higher levels of BMI when used as a neoadjuvant setting [10]. These results suggest that the efficacy might be different between the steroidal AI and non-steroidal AIs if patients were stratified by levels of BMI. Anyway, Asian women have lower levels of BMI than Caucasian women [7,8,10]. The efficacy and side effects of non-steroidal AIs may differ between races. In fact, side effects were different between ethnic minorities and Caucasians who took letrozole after 5 years adjuvant tamoxifen [11]. Furthermore, letrozole improved DFS in Caucasians but a definite benefit in minority women was not demonstrated [11].

Tamoxifen is converted to endoxifen by the metabolizing enzymes cytochrome P450 (CYP) 3A4 and CYP2D6 to exert its maximal effect [12]. There are genetic variant forms of CYP2D6 known to have different enzymatic activities and these variant forms of CYP2D6 distribute differently among races [13,14]. For instance, a variant allele of CYP2D6*10 having a decreased activity is found in 51% of Asians; however, it is rare in Caucasians [13]. All these results suggest that the efficacy of tamoxifen may differ between races.

Health-related Quality of Life (HRQOL) scores were higher in Japanese women with breast cancer who took adjuvant tamoxifen compared with adjuvant anastrozole or exemestane [15]. On the other hand, HRQOL scores were similar between Caucasian patients treated with adjuvant tamoxifen and adjuvant AIs [16,17]. A better HRQOL observed in Japanese patients taking tamoxifen may be due to the fact that a fatigue was significantly less frequent in Japanese patients taking tamoxifen than Caucasian patients [15]. One of the reasons for this might be due to the different metabolism of tamoxifen between Japanese patients and Caucasian patients.

From these results, the efficacy of AIs or tamoxifen may be different between patients’ ethnicities. However, there have been no studies that directly compare the efficacy of these drugs between different patients’ ethnicities. Therefore, in order to determine which regimen is better, the efficacy, side effects, and cost should be estimated in each patient who needs to be treated with adjuvant endocrine therapy.

As the superior efficacy of AIs to tamoxifen was shown in clinical trials, an upfront use of AIs is more preferable in breast cancer patients having higher recurrence risks. In Japanese women with breast cancer whose levels of BMI are low, non-steroidal AIs might be effective. On the other hand, an upfront use of tamoxifen is suitable in patients having low recurrence risks. In Japanese women with breast cancer, HRQOL was significantly better in patients treated with adjuvant tamoxifen than adjuvant AIs. Therefore, the upfront use of tamoxifen followed by AIs is considered appropriate in these patients.