Tamoxifen

Tamoxifen, a selective ER modulator, has been the historic standard for adjuvant endocrine therapy. Multiple prospective, randomized, clinical trials of adjuvant tamoxifen therapy have been analyzed as part of the Early Breast Cancer Trialists’ Group overview analysis. Five years of tamoxifen therapy lowers the risk of breast cancer recurrence by approximately 40% and lowers the risk of breast cancer mortality by approximately 20%. The benefits of tamoxifen are seen regardless of patient age or menopausal status. The optimal duration of tamoxifen therapy seems to be a total of 5 years. Published studies that have examined continuation of tamoxifen treatment beyond 5 years have not demonstrated a significant clinical benefit for additional therapy. Preliminary studies from the large Adjuvant Tamoxifen Treatment Offers More? (ATTOM) and Adjuvant Tamoxifen—Longer Against Shorter (ATLAS) trials have raised anew questions regarding the optimal duration of tamoxifen treatment; however, at present, 5 years remains the standard for women taking tamoxifen alone.

The side effects of tamoxifen have been well characterized ( Table 1 ). Common side effects include menopausal symptoms, such as hot flashes and night sweats, and in premenopausal women, menstrual irregularities. Tamoxifen is associated with a low but increased risk of uterine cancer and deep venous thrombosis, particularly in postmenopausal women. Quality-of-life studies suggest that most women on tamoxifen have a well-preserved quality of life in all functional domains and that most women are reasonably adherent with treatment.

Adjuvant endocrine therapy for postmenopausal women with hormone receptor–positive early-stage breast cancer

The introduction of aromatase inhibitors (AIs) has defined a new era of adjuvant endocrine treatment for postmenopausal women with hormone receptor–positive breast cancer. AIs function by blocking the conversion of androgens into estrogens through the aromatase enzyme. The consequence of such therapy for postmenopausal women is profound estrogen deprivation—circulating estrogen levels are typically depleted by 90% from baseline. It is presumed that the resultant estrogen deprivation causes the antineoplastic effects of AI therapy. Because premenopausal women have residual ovarian function and the capacity to up-regulate aromatase expression in ovarian tissues in response to estrogen deprivation, AIs are contraindicated in premenopausal women.

AIs have been studied in several contexts as adjuvant endocrine treatment for postmenopausal women. Because the historical standard for adjuvant therapy has been 5 years of tamoxifen, most of the major adjuvant trials have compared AI-based treatment with 5 years of tamoxifen. The development of AIs as adjuvant treatment has included studies of primary endocrine therapy, which used AIs as initial treatment instead of tamoxifen; sequential endocrine therapy, which integrated AIs as adjuvant treatment after several (typically, 2 to 3) years of tamoxifen; and extended adjuvant therapy, which explored AI-based treatment after 5 years of adjuvant tamoxifen. Table 2 identifies the major adjuvant trials that have reported in the past decade on the role of AIs in the adjuvant setting.

Collectively, these trials have demonstrated important observations. First, incorporation of an AI during the first 5 years of adjuvant endocrine treatment, or as extended therapy after 5 years of tamoxifen, is associated with a reduction in the risk of breast cancer recurrence. This reduction in risk is approximately a 15% to 20% proportionate risk reduction compared with tamoxifen alone. Because of the generally favorable prognosis for most postmenopausal women with early-stage breast cancer, the absolute difference in breast cancer events associated with AI-based therapy compared with tamoxifen is approximately 2% to 3%. The improvement in breast cancer outcomes includes reduction in the risk of distant metastatic recurrence as well as reduction in local/in-breast events and contralateral breast cancer. These modest gains are noted in comparing initial use of an AI with tamoxifen or in comparing tamoxifen alone with a sequence of tamoxifen followed by an AI. To date, studies have not reported a significant survival advantage for initial use of an AI compared with a sequential treatment program of tamoxifen and an AI. Compared with treatment with tamoxifen alone, sequential use of an AI may confer a modest survival advantage.

Second, it seems that a variety of treatment strategies yield similar outcomes, provided that an AI is incorporated at some point. Direct comparisons of results between initial use of an AI and a sequential program of a tamoxifen followed by an AI show equivalent rates of tumor recurrence in the Breast International Group (BIG) 1-98 and Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trials. In the Arimidex, Tamoxifen Alone or in Combination (ATAC) study, the combination of an AI with tamoxifen was not superior to tamoxifen alone.

These findings support the recommendation for consideration of an AI at some point during adjuvant endocrine treatment in postmenopausal women. The optimal timing of AI therapy vis-à-vis tamoxifen remains unknown. It is also unknown whether or not a longer total duration of treatment, accomplished with extended therapy using tamoxifen followed by an AI, would differ from initial use of an AI. Another persistent question remains the best duration of AI treatment itself. Different studies used different durations of AI therapy. As primary treatment, data show equivalence for 2.5 or 5 years of AI therapy. Ongoing trials are examining whether or not longer-term use of an AI in excess of 5 years’ total duration is safe and effective. No studies reported to date have directly compared the cancer outcomes for one AI with another as adjuvant treatment. In broad terms, the findings with each of the commercially available AIs (anastrozole, exemestane, and letrozole) seem qualitatively similar; thus, it seems likely that the benefits seen with AI treatment represent a class effect. Ongoing trials are comparing directly one AI with another.

Clinical experience with in the adjuvant setting has identified common side effects of AI treatment (see Table 1 ). Patients taking AIs are at greater risk for musculoskeletal health problems, including accelerated osteoporosis and fractures, than are women taking tamoxifen. Bisphosphonate therapy seems to mitigate AI-associated loss of bone mineral density. AIs are associated with a unique arthralgia syndrome, characterized by muscle and joint stiffness and achiness, which is common although usually of modest intensity. AIs are also associated with a slightly greater risk of hypertension and hypercholesterolemia; the long-term cardiac consequences of these effects are not yet well characterized.

There remains considerable interest in efforts to tailor specific adjuvant endocrine treatment options for individual patients based on tumor characteristics or biomarkers or based on consideration of pharmacogenetic studies. These retrospective efforts remain inconclusive. At present, it does not seem that there are sufficient data for using CYP2D6 genotyping for deciding whether or not tamoxifen is a suitable treatment option for specific women. A variety of pathologic and other biomarker studies confirm prognostic markers for patients treated with AIs. These measures lack sufficient data, however, for predicting which treatment strategy (tamoxifen alone, AI alone, or a sequence of tamoxifen and an AI) would be best for a given woman. Currently, the recommendation for initial treatment choices should be informed by the available data on efficacy, side-effect profiles, and patient preferences in postmenopausal women.