A 5-year extension of letrozole following an initial 5 years of aromatase inhibitor–based adjuvant hormone therapy did not significantly improve disease-free survival (DFS) or overall survival (OS) in postmenopausal women with early-stage hormone receptor (HR)-positive breast cancer.
This finding comes from a new analysis of the NSABP B-42 (NRG Oncology) trial, presented at the 2016 San Antonio Breast Cancer Symposium.
The data showed that extended letrozole therapy resulted in a nonsignificant (15%) reduction in the risk for a DFS event, reported Terry Mamounas, MD, MPH, Medical Director of the Comprehensive Breast Program at UF Health Cancer Center at Orlando Health and Chair of the NRG Oncology Breast Committee.
“Our findings suggest that careful assessment of potential risks and benefits is required before recommending extended letrozole therapy to patients with early-stage breast cancer, including patient and tumor characteristics, existing comorbidities, information on bone mineral density, and tolerance of the aromatase inhibitor in the initial 5 years,” said Dr Mamounas.
Extended adjuvant endocrine therapy with either tamoxifen or an aromatase inhibitor after 5 years of tamoxifen has been shown to improve DFS in early-stage breast cancer, but the optimal duration of adjuvant therapy beyond 5 years was not known.
Results of previous studies have suggested that approximately half of recurrences and approximately two-thirds of deaths in patients with HR-positive, early-stage breast cancer occur after the first 5 years from the time of diagnosis. Therefore, the aim of NSABP B-42 was to assess whether 5 years of letrozole compared with 5 years of placebo would improve DFS in postmenopausal patients with early-stage breast cancer who had already completed 5 years of adjuvant hormonal therapy with either an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor. DFS was defined as local, regional, or distant recurrence; development of contralateral breast cancer; a second nonbreast primary cancer; and death from any cause as first event.
Mamounas and colleagues randomly assigned 3966 patients to 2.5 mg of letrozole or placebo daily, in a 1:1 ratio, for 5 years. The primary end point was DFS, and secondary end points included OS, breast cancer–free interval, distant recurrence, osteoporotic fractures, and arterial thrombotic events.
The median duration of treatment was 59.8 months in both groups. Overall, 60.3% of patients randomized to extended letrozole and 62.5% randomized to placebo completed 5 years of therapy.
The median follow-up from randomization for the 3923 patients included in the efficacy analysis was 6.9 years, at which time the DFS rates were 84.7% in the extended letrozole group and 81.3% in the placebo group, for a hazard ratio of 0.85 (P = .048, which missed the statistically significant level of .0418). The OS rates were 91.8% and 92.3%, respectively.
There were 87 distant recurrent events (4.4%) in the placebo group compared with 61 (3.1%) in the letrozole group.
The rate of breast cancer–free interval was improved with extended letrozole, with a 29% reduction in the risk of breast cancer recurrence or cancer in the opposite breast as a first event (10.0% in placebo group vs 6.7% in letrozole group; P = .003). In addition, a significant 28% reduction in the cumulative risk for disease recurrence was observed with letrozole (5.8% with placebo vs 3.9% with letrozole; P = .03). Most of the benefit with letrozole on distant recurrence occurred after 4.1 years.
The risk for osteoporotic fractures was increased in the letrozole group compared with placebo (91 events vs 78 events) but this difference failed to achieve significance (hazard ratio, 1.19; P = .27). The risk for arterial thrombotic events was not significantly increased but the rate was numerically higher in the letrozole group compared with placebo (4.0% vs 3.4%, respectively; hazard ratio, 1.21; P = .29). The risk for arterial thrombotic events did become elevated for letrozole-treated patients after 2.5 years (hazard ratio, 1.85; P = .007), Dr Mamounas noted.“We hope that genomic classifiers that predict risk of late recurrence and/or benefit from extended endocrine therapy may help to further individualize the recommendation for extended aromatase inhibitor therapy,” he said.