The majority of invasive breast cancer patients present with hormone receptor-positive disease, and modulation of estrogen receptor (ER) activation is an essential component of systemic adjuvant therapy for these women. While tamoxifen has traditionally been the primary adjuvant endocrine therapy for all ER-positive women, recent trials evaluating the use of aromatase inhibitors (AIs) have challenged this standard in postmenopausal women, and ongoing trials are examining the optimal use of endocrine therapy in younger women. Issues regarding the optimal approach to endocrine therapy in both pre- and postmenopausal women are examined in this review.
Approximately three-quarters of invasive breast cancer patients present with hormone receptor-positive disease. As the estrogen receptor (ER) pathway is key to the growth of these cancers, modulation of ER activation is an essential component of systemic adjuvant therapy for these women. While tamoxifen, a selective estrogen receptor modulator, has traditionally been the mainstay of adjuvant endocrine therapy in pre- and postmenopausal women, recent trials evaluating the use of aromatase inhibitors (AIs) have challenged this standard in postmenopausal women (Table 1), and ongoing trials are examining the optimal use of endocrine therapy in younger women (Table 2).
The most recent Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview analysis demonstrated that 5 years of adjuvant tamoxifen reduced the annual death rate by 31% among women with ER-positive disease regardless of age. However, we now recognize that not all patients with ER-positive disease benefit equally from various endocrine therapies. Resistance to endocrine therapy in ER-positive tumors may be intrinsic, occurring at first exposure (de novo), or may develop over time following an initial response to endocrine therapy (acquired). Identification of the key mechanisms involved is essential to predict response or resistance to specific treatments, and to facilitate development of new pharmaceutical agents targeted at the various molecular components of endocrine-resistance pathways.
Individual tumor characteristics as well as host factors likely influence both response and toxicity in an individual patient. Gene-expression profiles have been used to identify at least two subtypes of ER-positive breast cancer-luminal A and B. Furthermore, a commercial assay using formalin-fixed paraffin-embedded tissue has been validated retrospectively to have strong prognostic and predictive value for patients with lymph node-negative, ER-positive breast cancer treated with tamoxifen with or without chemotherapy.[4,5]
Adjuvant Endocrine Therapy in Postmenopausal Women
Aromatase Inhibitors Instead of Tamoxifen
The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared 5 years of therapy with anastrozole (Arimidex) alone, tamoxifen alone, and the combination of both agents in 9,000 postmenopausal women with hormone receptor-positive breast cancer. The primary endpoints were disease-free survival (DFS) and safety/tolerability. The initial analysis, presented at a median follow-up of 33 months, revealed superior DFS for the anastrozole arm compared to the tamoxifen arm (89.4% vs 87.4%, respectively; P = .013). Results from the combination arm were not significantly different from those for tamoxifen alone; this arm was therefore discontinued and not included in subsequent analyses. The incidence of contralateral breast cancer was also significantly lower with anastrozole compared to tamoxifen, with an odds ratio of 0.42 (P = .007) Anastrozole was significantly better tolerated than tamoxifen with respect to cerebrovascular events, venous thromboembolic events, endometrial cancer, vaginal bleeding, and hot flashes, whereas tamoxifen was significantly better tolerated than anastrozole with respect to musculoskeletal disorders and fractures.
The ATAC trial was recently updated with 68 months of follow-up, and the benefit of anastrozole over tamoxifen was maintained. With only 8% of patients remaining on trial, DFS was significantly longer for anastrozole compared to tamoxifen, with a hazard ratio of 0.74 (P = .0002) and an absolute difference of 3.7% between the two arms. At present, there is no significant survival difference between tamoxifen and anastrozole therapy.
The Breast International Group (BIG) 1-98 trial randomized 8,028 postmenopausal women with hormone receptor-positive breast cancer to one of four arms: 5 years of tamoxifen, 5 years of letrozole (Femara), 2 years of tamoxifen followed by 3 years of letrozole, or 2 years of letrozole followed by 3 years of tamoxifen. The first analysis of this trial compared the two groups assigned to initial tamoxifen (4,007 women) to the two groups assigned to initial letrozole (4,003 women). At a median follow-up of 25.8 months, letrozole significantly improved DFS compared to tamoxifen, with a hazard ratio of 0.81 (P = .003). Estimates of 5-year DFS were 84% for the letrozole group and 81.4% for the tamoxifen group, leading to an absolute difference of 2.6% between the two groups—a magnitude of benefit similar to that seen in the ATAC trial.
As compared with tamoxifen, letrozole was associated with more fractures (5.7% vs 4.0%, P < .001) but fewer thromboembolic events (1.5% vs 3.5%, P < .001), a lower rate of vaginal bleeding (3.3% vs 6.6%, P < .001), fewer endometrial biopsies (2.3% vs 9.1%, P < .001) and fewer invasive endometrial cancers (0.1% vs 0.3%, P = .18). At present, there is no significant difference in overall survival. Data from the sequential arms is not currently available.
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