Extended adjuvant letrozole improves DFS among certain postmenopausal women with breast cancer
SAN ANTONIO — Extended adjuvant endocrine therapy with letrozole improved DFS compared with placebo among postmenopausal women with hormone receptor-positive breast cancer who completed previous adjuvant therapy with an aromatase inhibitor, according to 10-year results from the randomized NRG Oncology/NSABP B-42 trial presented at San Antonio Breast Cancer Symposium.
Extended letrozole also provided statistically significant improvements in breast cancer-free interval and distant recurrence. However, researchers reported no significant difference in OS with letrozole.
“Our findings continue to suggest that careful assessment of potential risks and benefits is necessary for selecting appropriate candidates for extended letrozole therapy in ... early-stage breast cancer,” Terry P. Mamounas, MD, medical director of the comprehensive breast program at University of Florida Health Center, said during a presentation.
These include patient and tumor characteristics, such as age and nodal status; existing co-morbidities; information on bone mineral density; and tolerance of the aromatase inhibitor in the initial 5 years.
Extended adjuvant endocrine therapy after 5 years of tamoxifen prolongs DFS among women with early-stage breast cancer. However, the optimal duration of adjuvant aromatase inhibitor therapy has not been established.
In the double-blind, placebo-controlled NSABP B-42 trial, Mamounas and colleagues aimed to evaluate whether 5 years of letrozole improved DFS compared with placebo for patients who completed 5 years of hormonal therapy with either an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor.
The trial included 3,966 postmenopausal women (34% aged younger than 60 years; 93% white, 57% node negative) with ER-positive or PR-positive breast cancer.
All patients had stage I, stage II or stage IIIa invasive disease at diagnosis, and they were disease free after 5 years of endocrine therapy.
Researchers stratified by pathological nodal status, receipt of prior adjuvant tamoxifen and lowest bone mineral density T score (spine, hip or femur).
The majority of patients were HER2-negative (78%) and had undergone prior breast-conserving surgery (61%); 39% received prior tamoxifen and 25% had a lowest bone mineral density score less than 2.
Investigators randomly assigned 1,950 patients to letrozole for 5 years. The other 1,953 patients received placebo.
DFS served as the primary endpoint. Secondary endpoints included OS, breast cancer-free interval, distant recurrence, osteoporotic fractures and arterial thrombotic events.
Patients who had no follow-up and those not at risk for the primary endpoint — such as those with metastases at the time of random assignment and those who experienced a first nondeath event within 30 days of randomization — were excluded.
Seven-year results presented in 2016 at San Antonio Breast Cancer Symposium showed extended letrozole had no statistically significant effect on DFS or OS. However, the regimen appeared associated with a 29% reduction in rate of breast cancer-free interval events (HR = .071; P = .003) and a 28% reduction in rate of distant recurrence events (HR = 0.72; P = .03).
Ten-year results presented at this year’s symposium — based on median follow-up of 9.3 years — showed a small but statistically significant improvement in DFS with extended letrozole (76.1% vs. 72.1%; HR = 0.84; 95% CI, 0.74-0.96).
An analysis of first DFS events by treatment showed women assigned placebo were more likely than those assigned extended letrozole to experience any event (24.5% vs. 21.1%), distant recurrence (5.7% vs. 4.2%) or second primary cancer (11.8% vs. 9.4%), including second primary cancer of the breast (4.1% vs. 2.7%) or outside the breast (7.6% vs. 6.7%). Rates of local recurrence were comparable between groups (2.2% vs. 2.3%).
However, death as first DFS event was more common among those assigned extended letrozole (5.2% vs. 4.9%).
Multivariate analysis showed lowest bone mineral density T score greater than – 2 (HR = 0.86; 95% CI, 0.74-1) and prior tamoxifen (HR = 0.76; 95% CI, 0.66-0.87) were significant predictors of DFS benefit with extended letrozole, whereas older age ( 60 years vs. < 60 years, HR = 1.64; 95% CI, 1.4-1.92) and positive nodal status (HR = 1.38; 95% CI, 1.21-1.58) predicted poorer outcomes.
“When we looked at letrozole’s effect on DFS in subgroups, we saw no significant interactions with any of the factors such as nodal status, prior tamoxifen, age of patients and receipt of prior surgery,” Mamounas said. “However, there was significant interaction with T score, something we did not see in the 7-year results.”
OS did not differ significantly between the letrozole and placebo groups (86.1% vs. 85.5%; HR = 0.97; 95% CI, 0.82-1.16). However, the number of deaths — which had been higher in the letrozole group at the 7-year analysis (164 vs. 146) — were higher in the placebo group at the 10-year mark (252 vs. 243).
Breast cancer-free interval favored extended letrozole at 10 years (13.3% vs. 10.3%; HR = 0.74; 95% CI, 0.81-0.91), as did the rate of distant recurrence (5.7% vs. 7.5%; HR = 0.71; 95% CI, 0.55-0.93).
Extended letrozole did not significantly increase risk for osteoporotic fractures (6.5% vs. 6.4%; HR = 1.11; 95% CI, 0.64-1.45) or arterial thrombotic events (4.7% vs. 4.1%; HR = 1.13; 95% CI, 0.84-1.56).
“We hope that genomic classifiers that predict risk of late recurrence and/or benefit from extended endocrine therapy may further assist with the decision to recommend extended aromatase inhibitor therapy,” Mamounas said. “Such correlative studies are underway.” – by Mark Leiser
Mamounas EP, et al. Abstract GS4-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2019; San Antonio.
Disclosures: Mamounas reports consultant advisory roles with Biotheranostics, Daiichi Sankyo, Genentech/Roche, Genomic Health and Merck, as well as non-CME service fees from commercial interests or agents from Genentech and Genomic Health Inc. Please see the abstract for all other authors’ relevant financial disclosures.