Aromatase Inhibitor as Adjuvant Therapy for Breast Cancer: Is Longer Treatment Better?

Study Overview

Objective. To assess the effect of extending adjuvant therapy with an aromatase inhibitor beyond 5 years in postmenopausal women with breast cancer.

Design. Phase 3, randomized, double-blind, placebo-controlled trial.

Setting and participants. This was a North American Breast Cancer Group trial, coordinated by the Canadian Cancer Trials Group. The trial was originally designed as an extension of the MA.17 trial evaluating the role for 5 years of letrozole versus placebo after 5 years of tamoxifen, with re-randomization of letrozole-assigned patients to an additional 5 years of letrozole versus placebo. The trial was then extended to include additional postmenopausal women with stage I-III breast cancer who had been treated with 4.5 to 6 years of adjuvant therapy with any aromatase inhibitor with or without prior tamoxifen.

Most patients had received adjuvant treatment with tamoxifen before the aromatase inhibitor. Patients were randomized within 2 years after completing treatment with the aromatase inhibitor to either letrozole 2.5 mg or placebo orally once a day, for another 5 years. The criteria for stratification included lymph node status, prior receipt of adjuvant chemotherapy, the interval between the last dose of aromatase inhibitor and randomization, and the duration of prior use of tamoxifen. Eligibility criteria included patients who were disease-free after 4.5 to 6 years of aromatase inhibitor, hormone-positive tumors (and unknown receptor status for participants in the MA.17 trial), ECOG performance status of 0 to 2, and life expectancy of 5 or more years.

Main outcome measures. The primary endpoint was disease-free survival, defined as the time from randomization to recurrence or the development of new primary breast cancer. Secondary endpoints included overall survival, incidence of contralateral breast cancer, quality of life using the Medical Outcomes Study 36-Item Short-Form Heath Survey (SF-36) and the Menopause-Specific Quality of Life (MENQOL) questionnaire, and long-term safety. The investigators calculated that 196 events were required for the study to have 80% power to detect a 33% lower hazard of recurrence with letrozole as compared with placebo. At the 6-year point, only 176 events had been observed, and the study design was amended to have a time-based analysis instead of event-based. On 13 Nov 2015 the final database had 165 events, with 80% power to detect a hazard ratio for disease-free survival of 0.655. The analysis of time-to-event outcomes was performed utilizing a log-rank test with adjustment for stratification factors. Fisher’s exact test was used to assess binary outcomes, and Wilcoxon test, to assess continuous outcomes. Comparisons between the letrozole and the placebo groups were made using a 2-sided test with an alpha level of 5%.

Main results. A total of 1918 patients were randomized to receive either letrozole (n = 959) or placebo (n = 959). The rate of adherence to the study regimen was approximately 62% for both arms. The median duration of prior treatment with tamoxifen was 5 years; 20.7% of patients did not receive tamoxifen. The median duration of prior treatment with aromatase inhibitor was 5 years, and the median time interval between the last dose of aromatase inhibitor and randomization was less than 6 months. The median duration of the study regimen (letrozole or placebo) was 5 years, and the median follow-up was 6.3 years. Approximately 90% of patients had stage T1 or T2 tumors at diagnosis, and 94% of nodal stage were N0 or N1. Estrogen receptor, progesterone receptor or both were known to be positive in 98.8% of patients.

Disease recurrence or contralateral breast cancer occurred in 67 patients (7%) in the letrozole group and 98 patients (10.2%) in the placebo group. The hazard ratio for recurrence or occurrence of contralateral breast cancer was 0.66 (95% confidence interval [CI], 0.48–0.91, P = 0.01). In the letrozole group, 55 patients had disease recurrence and 13 patients had contralateral breast cancer. Among the patients in the placebo group, 68 had recurrence of disease and 31 had contralateral breast cancer. Both disease recurrence and contralateral breast cancer occurred in one patient in each group. Distant disease recurrence was 5.5% in the placebo group and 4.4% in the letrozole group.

Five-year disease-free survival, the primary endpoint of this study, was 95% in the letrozole group (95% CI, 93–96) and 91% in the placebo group (95% CI, 89–93). The rate of 5-year disease free-survival was higher in the letrozole group in all subgroups. A total of 200 deaths were observed, 100 in each group. The rate of 5-year overall survival was not statistically different between the 2 groups (93% in the letrozole group and 94% in the placebo group, HR 0.97, P = 0.83). The annual incidence rate of contralateral breast cancer favored the letrozole group, with a rate of 0.21% in comparison with 0.49% in the placebo group (HR 0.42, P = 0.007).

Discontinuation of treatment occurred in 5.4% of patients in the letrozole group and 3.7% in the placebo group. The majority of toxic effects had a similar incidence in both groups, however bone-related side effects were more common in the letrozole group. Bone fractures occurred in 14% of patients in the letrozole group and 9% in the placebo group (P = 0.001). New-onset osteoporosis was also more common in the letrozole group (11% versus 6%, P < 0.001). Of note, 5 patients developed a hip fracture after discontinuation of letrozole. In regards to quality of life, patients receiving letrozole had a greater reduction in scores in the role-physical subscale of the SF-36 survey, indicating worse quality of life, but the difference was less than the minimum clinically important difference. There were no differences in the MENQOL questionnaire subscales.

Conclusion. Treatment with an aromatase inhibitor for additional 4.5 to 6 years was beneficial in preventing disease recurrence. There was no difference in overall survival.