Abstract S1-05: A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy (tx) with letrozole (L) in postmenopausal women with hormone-receptor (+) breast cancer (BC) who have completed previous adjuvant tx with an aromatase inhibitor (AI): Results from NRG Oncology/NSABP B-42
Authors: Mamounas EP , Bandos H , Lembersky BC , Geyer CE , Fehrenbacher L , Graham ML , Chia SL , Brufsky AM , Hennessy BT , Soori GS , Dakil SR , Seay TE , Wade JL , McCarron EC , Paik S , Swain SM , Wickerham DL , Wolmark N 
Published: March 2017

Background: Extending adjuvant endocrine therapy (tx) after 5 yrs of tamoxifen (Tam) with either Tam or an AI improves disease-free survival (DFS) in early-stage breast cancer (BC). However, optimal duration of adjuvant AI tx beyond 5 yrs is unknown. NSABP B-42 aimed to determine whether 5 yrs of letrozole (L) v placebo (P) improves DFS in patients (pts) who have completed 5 yrs of hormonal tx (with either AI or TAM→AI).

Methods: Postmenopausal pts with stage I-III, hormone-receptor (+) BC, disease-free after 5 yrs of either AI or Tam for ≤3 years→AI for the remainder of 5 yrs, were randomized to L 2.5 mg or P daily for an additional 5 yrs. Stratification was by pathological nodal status, prior adjuvant Tam or not, and baseline dexa T scores (&gt;-2.0, ≤-2.0 SD). Primary endpoint was DFS including local, regional, distant recurrence (DR), second primary cancers, and deaths from any cause as first event. Secondary endpoints included overall survival (OS), BC-free interval (BCFI including recurrence or contralateral BC as first event), DR, osteoporotic fractures (OF), and arterial thrombotic (AT) events. Differences in DFS, OS, BCFI, DR, OF, and AT between L and P were assessed by the stratified log-rank tests and Cox proportional hazards models. Statistical significance level for DFS was set at 0.0418 as per statistical plan.

Results: From 9/06-1/10, 3966 pts were randomized (34% were &lt;60 yrs, 57% were node-negative, 39% received prior TAM, 14% were HER-2 neu positive). Median follow-up for 3923 pts included in efficacy analyses was 6.9 years. As of 8/16, 631 DFS events occurred (L=292, P=339); L did not result in statistically significant increase in DFS v P (HR=0.85; 95% CI 0.73, 0.999; P=0.048), even after adjusting for age or surgery type; 7-yr DFS was L=84.7% and P=81.3%. There were no significant interactions between treatment and stratification variables. 310 deaths occurred (L=164, P=146); there was no statistically significant difference in OS with L v P (HR=1.15, 95% CI 0.92, 1.44; P=0.22); 7-yr OS was L=91.8% and P=92.3%; 306 BCFI events occurred (L=127, P=179); L v P resulted in a statistically significant 29% decrease in BCFI events (HR=0.71, 95% CI 0.56, 0.89; P=0.003); 7-yr cumulative incidence (CIn) of BCFI was L=6.7% v P=10%; 175 DRs occurred (L=73, P=102); L v P resulted in a statistically significant 28% reduction in DR (HR=0.72, 95% CI 0.53, 0.97; P=0.03). There were 169 OF (L=91, P=78). There were no significant differences in time to OF with L v P (P=0.27). CIn of OF through 7 yrs was L=5.4% v P=4.8%. There were 127 AT events (L=69, P=58). Treatment with L did not result in an overall statistically significant increase in AT events compared to P (P=0.33). CIn of AT through 7 yrs was L=3.9% v P=3.3%.

Conclusions: After 5 yrs of an AI or TAM→AI, the beneficial effect of extended tx with 5 yrs of L on DFS did not reach statistical significance. There was no significant improvement in OS with L but L provided a significant improvement in BCFI and DR.

Support: U10CA180868, -180822; UG1CA189867; Novartis.

Citation Format: Mamounas EP, Bandos H, Lembersky BC, Geyer, Jr CE, Fehrenbacher L, Graham ML, Chia SL, Brufsky AM, Hennessy BT, Soori GS, Dakil SR, Seay TE, Wade, III JL, McCarron EC, Paik S, Swain SM, Wickerham DL, Wolmark N. A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy (tx) with letrozole (L) in postmenopausal women with hormone-receptor (+) breast cancer (BC) who have completed previous adjuvant tx with an aromatase inhibitor (AI): Results from NRG Oncology/NSABP B-42 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-05.