Due to cessation of hormone production by the ovaries, the level of circulating estrogen after the menopause is substantially lower than in the premenopausal women. For therapeutic purposes, the effect of estrogen on hormone-sensitive breast cancer cells can be additionally reduced with selective estrogen receptor modulators (SERMs) like tamoxifen [30] or with selective estrogen receptor downregulators (SERDs) like fulvestrant [31]. Alternatively the level of circulating estrogen can be lowered with the use of aromatase inhibitors (AIs) [32]. These drugs block the extragonadal transformation of androgen to estrogen, in particular in the adrenal glands and in several other tissues. In postmenopausal women, this aromatization is the primary source of estrogen.

Tamoxifen is a SERM with a predominantly antagonistic effect on the ERs in breast tissue, a partial agonistic effect in bone, the cardiovascular system and the CNS and an agonistic effect on the uterus, liver and vaginal mucosa. For more than 30 years, tamoxifen has been the drug of choice in the treatment of hormone-sensitive breast cancer, leading to a reduction in disease recurrence and in contralateral breast cancer of about 50% and of mortality by around 30% [12, 16]. In early breast cancer, treatment with tamoxifen for 5 years reduces the recurrence rate by about half during treatment and by about one-third in the subsequent 5 years and reduces breast cancer mortality by almost one-third throughout the first 15 years [15]. Extending tamoxifen treatment to 10 years induces a further mortality reduction during years 10 to 14 [18, 33] by about 20%.

In the concomitant administration of tamoxifen and chemotherapy in postmenopausal women, tamoxifen seems to diminish the efficacy of anthracycline-based chemotherapy [34, 35], and it should be avoided. Few or no data are available for the interaction of tamoxifen with other treatments like taxanes, trastuzumab or radiotherapy [36].

The conversion of tamoxifen to the active metabolite endoxifen is dependent on the activity of cytochrome P450 2D6 (CYP2D6). During the last decades, several studies have reported on the potential association between CYP2D6 polymorphism and tamoxifen treatment outcomes, with highly inconsistent results [37, 38]. The recently published ASCO Guidelines about the use of biomarkers to guide decisions on adjuvant systemic therapy couldn’t support the use of CYP2D6 polymorphism to decide which patients may benefit from tamoxifen [39]. Association between vasomotor or musculoskeletal symptoms, metabolism and outcome has been extensively reported. Poor or intermediate metabolism phenotypes seem to be associated with tamoxifen-induced hot flushes but not with inferior outcomes in term of disease-free survival [40]. On the other hand, patients reporting arthralgia/myalgia symptoms may have favourable disease-free survival and breast cancer-free interval [41].

A recently published meta-analysis using individual data from almost 32000 postmenopausal women with hormone-sensitive early breast cancer participating in clinical trials showed that 5 years of aromatase inhibitor treatment reduces the relative recurrence rates by about 30% compared with 5 years of tamoxifen during the treatment phase, but not thereafter. Five years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% if compared with 5 years of tamoxifen and by about 40% (proportionately) if compared with no endocrine treatment at all [44]. In particular in trials comparing 5 years of tamoxifen versus AI treatment (n = 9885), AIs reduced breast cancer recurrence during years 0 to 1 (RR 0.64, 95% CI 0.52–0.78) and years 2 to 4 (RR 0.80, 95% CI 0.68–0.93) and lowered breast cancer mortality (RR 0.85, 95% CI 0.75–0.96). Five years of AI also reduce the incidence of contralateral breast by about 1.5% in ten years if compared with 5 years of tamoxifen (incidence rate of 2.1% for AI versus 4.7% for tamoxifen). In trials comparing a five-year course of tamoxifen versus 2–3 years of tamoxifen followed by an AI to complete 5 years of endocrine treatment (n = 11,798), the switch to an AI resulted in a reduced breast cancer recurrence rate during years 2–4 (RR 0.56, 95% CI 0.46–0.67) and fewer deaths from breast cancer (RR 0.84, 95% CI 0.72–0.96) as well as an absolute reduction of contralateral breast cancer incidence by 0.8%. Finally, in trials, which compared 5 years of AI alone versus 2–3 years of tamoxifen followed by an AI, the treatment with an AI alone resulted in a lower recurrence rate during years 0 to 1 (RR 0.74, 95% CI 0.62–0.89) and similar recurrence rates in years 2 to 4 (RR 0.99, 95% CI 0.85–1.15) as well as a trend towards reduced breast cancer mortality (RR 0.89, 95% CI 0.78–1.03) but no relevant reduction in contralateral breast cancer (0.3%) .

In the same meta-analysis, the sequence of AI followed by tamoxifen as investigated in the BIG 1–98 trial [45–47] was not included. In the BIG 1–98 trial, 8000 women were randomized to receive 5 years of tamoxifen or letrozole or a sequential treatment with 2.5 years of tamoxifen followed by 2.5 years of letrozole or vice versa. Monotherapy with letrozole showed a better outcome compared with tamoxifen alone, but there was no significant difference between sequential therapies with only 2.5 years of AI and letrozole alone for 5 years.

Recently data about extended endocrine treatment with an AI has been published. A total of 1918 patients were randomly assigned to receive letrozole (959 patients) or placebo (959 patients) after 4.5 to 6 years of AI [72]. The 5-year disease-free survival rate was 95% (95% confidence interval [CI], 93 to 96) with letrozole and 91% (95% CI; 89 to 93) with placebo [48] (◘ Table 35.3).