Optimal Duration of Extended Adjuvant Endocrine Therapy for Early Breast Cancer

Results of the IDEAL Trial (BOOG 2006-05)

Erik J. Blok; Judith R. Kroep; Elma Meershoek-Klein Kranenbarg; Marjolijn Duijm-de Carpentier; Hein Putter; Joan van den Bosch; Eduard Maartense; A. Elise van Leeuwen-Stok; Gerrit-Jan Liefers; Johan W. R. Nortier; Emiel J. Th. Rutgers; Cornelis J. H. van de Velde

Disclosures

J Natl Cancer Inst. 2018;110(1):40-48. 

In This Article

Abstract and Introduction

Abstract

Background The optimal duration of extended endocrine therapy beyond five years after initial aromatase inhibitor–based adjuvant therapy for postmenopausal women with hormone receptor–positive breast cancer is still unknown. Therefore, we conducted a clinical trial to compare two different extended endocrine therapy durations.

Methods In the randomized phase III IDEAL trial, postmenopausal patients with hormone receptor–positive breast cancer were randomly allocated to either 2.5 or five years of letrozole after the initial five years of any endocrine therapy. The primary end point was disease free survival (DFS), and secondary end points were overall survival (OS), distant metastasis–free interval (DMFi), new primary breast cancer, and safety. Hazard ratios (HRs) were determined using Cox regression analysis. All analyses were by intention-to-treat principle.

Results A total of 1824 patients were assigned to either 2.5 years (n = 909) or five years (n = 915) of letrozole, with a median follow-up of 6.6 years. A DFS event occurred in 152 patients in the five-year group, compared with 163 patients in the 2.5-year group (HR = 0.92, 95% confidence interval [CI] = 0.74 to 1.16). OS (HR = 1.04, 95% CI = 0.78 to 1.38) and DMFi (HR = 1.06, 95% CI = 0.78 to 1.45) were not different between both groups. A reduction in occurrence of second primary breast cancer was observed with five years of treatment (HR = 0.39, 95% CI = 0.19 to 0.81). Subgroup analysis did not identify patients who benefit from five-year extended therapy.

Conclusion This study showed no superiority of five years over 2.5 years of extended adjuvant letrozole after an initial five years of adjuvant endocrine therapy.

Introduction

Multiple large clinical trials showed superiority of aromatase inhibitor (AI)–based adjuvant therapy (either upfront or after two to three years of tamoxifen) over five years of tamoxifen monotherapy.[1–4] Just recently, an EBCTCG meta-analysis showed the superiority of AI monotherapy for five years over the sequential therapy of tamoxifen followed by an AI, although the absolute benefit was marginal.[5]

Despite the success of adjuvant endocrine therapy, still 50% of all recurrences occur after the first five years, especially in hormone receptor–positive breast cancer.[6] Randomized trials showed that a period 10 years of adjuvant tamoxifen was superior over five years, although a benefit on overall survival (OS) was not observed.[7–9] The MA.17 study investigated extended endocrine therapy with an AI after five years of tamoxifen by randomly assigning patients to five years of letrozole or placebo. At interim-analysis after 2.4 years, it was observed that letrozole was superior, leading to early closure and crossover, which hampered the power for long-term follow-up.[10] Although this trial was broadly interpreted as evidence for five years' therapy extension, the actual evidence before crossover is only until 2.4 years. The actual benefit of five years vs placebo, or the difference in effect between 2.5 and five years, has never been shown, except in extrapolated subgroup analyses.[10–13]

Until now, all evidence for extended endocrine therapy was obtained in clinical trials that included patients who received tamoxifen monotherapy during the first five years of adjuvant therapy. As shown recently in the EBCTCG meta-analysis, adjuvant therapy containing AIs in the first five years of adjuvant therapy is superior to tamoxifen monotherapy.[5] However, limited evidence is available for extending AI-based adjuvant therapy beyond five years of AI-containing therapy, in particular for the optimal duration of therapy.[14]

We report the results of the phase III open label multicenter Investigation on the Duration of Extended Adjuvant Letrozole treatment (IDEAL) trial, which randomly assigned patients to either 2.5 or five years of letrozole after receiving any adjuvant endocrine therapy for five years. The aim of this trial was to determine the optimal duration of extended endocrine therapy, in particular after receiving AI-based adjuvant therapy.

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