Optimizing endocrine therapy for estrogen receptor-positive breast cancer: treating the right patients for the right length of time.

Patients with estrogen receptor (ER) –positive tumors are at continued risk of relapse for many years after initial breast cancer diagnosis. Among women treated with tamoxifen for 5 years, more than half of all recurrences occur between 6 to 15 years after diagnosis. Although tamoxifen (and probably the aromatase inhibitors [AIs]) lower the risk of recurrence for several years after they are stopped, late recurrences and deaths remain a major clinical challenge. If we want to reduce morbidity and mortality from ER-positive breast cancer, we must focus on strategies to confront this challenge. The use of a first-line AI for 5 years has been shown to improve disease-free survival (DFS) in patients with early-stage, ER-positive disease, compared with tamoxifen. However, no difference in overall survival has emerged. With 100-month median follow-up, there is no difference in overall survival between women randomly assigned to either 5 years of tamoxifen or anastrozole. Trials comparing a 5-year course of tamoxifen with a 2to 3-year course of tamoxifen followed by either exemestane or anastrozole for a total of 5 years of adjuvant treatment have demonstrated improvements in DFS and improvements in overall survival of borderline statistical significance. Thus, although the incorporation of an AI at some time during the first 5 years represents an advance over the use of tamoxifen alone, it is unlikely that a 5-year course of treatment, no matter which of the available agents is used, will have a substantial impact on either survival or late recurrence. The addition of adjuvant chemotherapy to endocrine treatment does not reduce the risk of late recurrence, and there is increasing doubt about the importance of chemotherapy in subsets of patients with ER-positive disease. In this issue of the Journal of Clinical Oncology, three reports directly address the impact of extended hormonal therapy in postmenopausal women with ERand/or progesterone receptor–positive tumors. Collectively, these analyses indicate that extending the duration of endocrine treatment beyond 5 years reduces the risk of late events, with limited adverse effects on quality of life (QOL). The MA.17 investigators previously reported results from the primary analysis of that trial, which randomly assigned 5,187 women who had completed 5 years of tamoxifen therapy to either letrozole or placebo for an additional 5 years. The use of letrozole was associated with a significant improvement in DFS and, among the node-positive subset, a survival benefit. A strength of the study was the inclusion of a large cohort of older patients, with approximately one fourth of patients older than 70 years on study entry. Muss et al now report that the benefits, as well as the risks, associated with letrozole were similar across all age groups. In older patients, toxicities were similar to rates associated with placebo; though there was an initial decrement in QOL with letrozole, this difference disappeared by 36 months. In 2003, after MA.17 was unblinded, approximately two thirds of patients who had originally been assigned to the placebo arm chose to switch to letrozole. Goss et al now report that both DFS and distant DFS were superior in the group of women who chose to switch to letrozole, even though letrozole was not started until a median of 2.8 years from the completion of tamoxifen, or approximately 8 years from initial diagnosis. Furthermore, this improvement in DFS and distant DFS was seen despite the fact that the group of women who chose not to take letrozole were, by all measures, at lower risk of disease recurrence than those who chose letrozole. Of course, it is unknown if the same result would be observed if the prior treatment had been an AI rather than tamoxifen. In 2008, with a growing number of women now completing a 5-year course of primary AI treatment, this question is becoming more relevant than ever. An unavoidable consequence of the unblinding of MA.17 was the early termination of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33, a trial that initially randomly assigned women who had completed a 5-year course of tamoxifen to a 2-year course of exemestane or placebo. At the time of study closure, 1,598 of a planned 3,000 patients were enrolled, and women enrolled onto both arms were offered exemestane for 5 years. Seventy-two percent of women on the exemestane arm and 44% of those on the placebo arm accepted the offer. As reported by Mamounas et al, after a median follow-up of 30 months, an intent-to-treat analysis demonstrated a nonstatistically significant improvement in DFS for the group of women initially assigned to receive exemestane. The study has major limitations given the unblinding, uneven crossover, and relatively short follow-up. Nevertheless, the findings are consistent with the primary results from the MA.17 trial: the use of an AI after a 5-year course of tamoxifen reduces the risk of disease recurrence. What are the implications of these three related studies, and how do they inform clinical practice in 2008? Clearly, the studies confirm the ongoing risk of late recurrence in women with ER-positive breast cancer. Women initially randomly assigned to placebo in either MA.17 or B-33 had a 2% to 3% annual risk of a breast cancer recurrence or new primary. Similarly, among patients initially randomly assigned to the placebo arm of MA.17, and who chose not to cross JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 12 APRIL 2