Introduction

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Treatment paradigms for the management of breast cancer are constantly evolving. It is evident that 5 years of tamoxifen alone is no longer the optimal treatment for postmenopausal women with hormone-sensitive breast cancer. The aromatase inhibitors (AIs) are rapidly moving to the forefront, with concerns of AI therapy-induced bone loss leading to specific trials addressing incidence and management strategies. The articles presented in this supplement to Seminars in Oncology highlight some of the recent advances involving the AI letrozole for the treatment of hormone-sensitive breast cancer.

Dr Forbes begins the supplement with a review of the efficacy of letrozole as initial adjuvant therapy in the Breast International Group (BIG) 1-98 trial. Dr Forbes also discusses how these data compare with those of the Arimidex, Tamoxifen Alone or in Combination (ATAC) study, which investigated anastrozole in a similar treatment setting. He also stresses the limitations of subgroup and cross-trial comparisons. The early results from the BIG 1-98 trial indicate that letrozole offers improved disease-free survival when compared with tamoxifen, especially reducing recurrence at distant sites. These data also show that letrozole leads to significant benefit in multiple patient subgroups, including those with node-positive breast cancer and those who have received chemotherapy. Based on these results, letrozole can now be considered part of standard adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer.

Letrozole now has established efficacy for both initial and extended adjuvant therapy. Currently, letrozole is the only AI approved as an extended adjuvant therapy based on the results from the interim analysis of the MA.17 trial. Because there is no proven benefit in extending tamoxifen treatment beyond 5 years, the extended adjuvant letrozole treatment paradigm offers women who have completed 5 years of adjuvant tamoxifen the opportunity to further reduce their risk of recurrence. In this supplement, Dr Goss reviews the published results of the MA.17 final analysis of 30 months’ follow-up. These updated data confirm the results found in the interim analysis, and show a significant survival advantage in the subset of patients with node-positive disease receiving extended adjuvant letrozole.

The next article is on another topic of much interest: the use of bisphosphonates. Postmenopausal women are at increased risk of bone loss caused by age-related estrogen deficiency, but postmenopausal women with cancer face accelerated bone loss with the use of estrogen-depleting therapies such as third-generation AIs. Dr Brufsky reviews the updated 12-month data from the Zometa/Femara Adjuvant Synergy Trial (Z-FAST). A full publication of the data is eagerly awaited, but the results presented thus far indicate that upfront treatment with zoledronic acid can be an effective approach to decreasing bone loss caused by adjuvant AI therapy in patients at increased risk, although longer follow-up is required to determine the most appropriate time to initiate this and other bisphosphonates in this setting.

Fittingly, this supplement ends with an article that describes what is on the horizon for letrozole. The possibility of giving AIs with signal transduction inhibitors is being investigated, and Drs Lane and Lebwohl review the studies of combining RAD001 (everolimus, an mTOR inhibitor) and letrozole in breast cancer. The inhibition of mTOR activity by RAD001 may effectively block the development of estrogen independence that would otherwise occur in tumors treated with letrozole alone. A full publication of the safety and pharmacokinetics of RAD001 in combination with letrozole in patients with advanced breast cancer is expected shortly, but the results thus far indicate that such a combination treatment regimen is a rational, feasible approach as a first-line therapy for advanced breast cancer.

We hope that this supplement is useful in summarizing the most current efficacy and safety information regarding letrozole. The upcoming 42nd Annual American Society of Clinical Oncology conference in Atlanta, Georgia, from June 2–6, 2006, will continue to provide important trial results and keep clinicians abreast of the current progress in and the future prospects for the adjuvant treatment of postmenopausal women with hormone-receptor breast cancer.