Endoxifen, one of two active metabolites that mediate tamoxifen’s therapeutic effect, is formed through the action of the CYP2D6 enzyme [12–14]. Several polymorphisms of the CYP2D6 gene that influence the enzyme’s activity and, therefore, endoxifen levels have been identified. However, studies designed to uncover the link between patient response to tamoxifen and CYP2D6 enzyme activity (or CYP2D6 genotype) have yielded inconsistent results, perhaps as a result of limited sample sizes. Regan and colleagues [15] studied 4,861 postmenopausal patients with hormone receptor-positive breast cancer who were randomized to receive tamoxifen, letrozole, or both. Extracted DNA was used to genotype CYP2D6 and classify each patient as a poor metabolizer (PM), intermediate metabolizer (IM), or extensive metabolizer (EM). No significant association was observed between CYP2D6 phenotype and disease recurrence in tamoxifen-treated patients. Contrary to an existing hypothesis that high rates of tamoxifen-induced hot flashes are a surrogate for EM phenotype, PM and IM phenotype patients experienced the highest rates of hot flashes.

Rae and colleagues studied 1,203 patients with hormone receptor-positive early-stage breast cancer from the ATAC clinical trial who were available for genotyping of CYP2D6 and for whom 10 years of follow-up data were available [16]. Patients were classified as a PM, IM, or EM based on CYP2D6 genotyping. No significant associations were observed between CYP2D6 genotype and recurrence in tamoxifen-treated patients. These two studies confirm that there is no compelling evidence to support CYP2D6 testing in patients who are being considered for tamoxifen therapy and the NCCN treatment guidelines do not support their use [17].

Antidepressants (selective serotonin reuptake inhibitor (SSRI)) are commonly prescribed to breast cancer patients for depression and to reduce the effects of hot flashes, but there is evidence that the concurrent use of certain antidepressants can reduce the efficacy of tamoxifen via the CYP2D6 pathway. Although clinicians should not stop antidepressants prescribed for a psychiatric disorder, better choices among the SSRIs may be considered with concurrent use of tamoxifen and the patient should be aware of the potential interaction [18].

The use of AIs has increased dramatically over the last decade with the introduction of new, more selective aromatase inhibitors, such as anastrozole, exemestane, and letrozole. Current guidelines by ASCO [19] and NCCN [17] recommend third-generation AIs as a component of adjuvant therapy in postmenopausal women, either as monotherapy or in a sequential strategy with tamoxifen. The guidelines do not distinguish between the AIs, even though individual trials used a specific agent. There is no compelling evidence that one agent is superior to another either from an efficacy or tolerability standpoint.

This class of agents effectively blocks the extra-ovarian sites of estradiol synthesis, decreasing its serum concentration by more than 90 % in postmenopausal women [20, 21]. In contrast to tamoxifen, the newer AIs lack partial agonist activity and thus appear to avoid a concerning toxicity associated with tamoxifen, that is the highest risk for developing endometrial cancer [22]. There also appears to be a reduced risk of thromboembolic disease associated with the use of the AIs [22]. Because of this lack of estrogen agonist activity, AIs can potentially result in the loss of bone density (Table 24.2) [22]. Unlike tamoxifen, the AIs do not appear to be beneficial in premenopausal women. Even the newer aromatase inhibitors are unable to inhibit ovarian aromatase activity and, as a result, are unable to suppress estrogen synthesis in premenopausal women.

Data is available from several randomized clinical trials in the adjuvant setting that show a superior clinical outcome for postmenopausal patients who receive an AI as a component of their adjuvant therapy program. Trial designs compared (1) an aromatase inhibitor to tamoxifen, each for 5 years, (2) a sequence of tamoxifen with an aromatase inhibitor versus either alone as monotherapy for 5 years duration, or (3) 5 years of tamoxifen followed by no additional therapy or 5 years of an AI. Findings from some of the key pivotal trials are summarized below:

Recent reports have also suggested that obese women with early-stage breast cancer, in particular those with body mass index (BMI) ≥35 kg/m², may have a greater risk of disease recurrence when treated with anastrozole compared to their ideal weight counterparts or those treated with tamoxifen. These findings raise a concern that aromatase inhibition in obese women may be a less effective risk reduction strategy and/or the use of the less potent aromatase inhibitors can adversely impact on clinical outcome [37]. To date, the clinical evidence suggesting that one third-generation aromatase inhibitor is more effective than another has been sparse, but preclinical data and clinical surrogates of clinical activity have shown that letrozole is more potent than anastrozole at suppressing estradiol and estrone sulfate [38]. Whether the differences in estrogen suppression with anastrozole or letrozole actually translate into a different clinical outcome cannot be determined from these data. The ALIQUOT study (Anastrozole vs. Letrozole, an Investigation of Quality of Life and Tolerability) compared the ability of anastrozole and letrozole to suppress estrogen in obese postmenopausal women with early-stage breast cancer. Letrozole appeared to be more effective; however, this small study did not demonstrate a differential effect on clinical outcome. Furthermore, the association between obesity and breast cancer is certainly more complicated than suggesting estradiol alone is the culprit. Increased levels in insulin, inflammatory mediators, and other proteins have been implicated as risk factors for breast cancer and breast cancer recurrence in obese patients [37].