Background
MA.17R. Phase III, double-blind RCT of 1,918 postmenopausal patients with HR+ breast cancer who had completed ~5 years of an aromatase inhibitor (most after prior tamoxifen). Tested a second 5 years of extended letrozole vs placebo.
Interventions and follow up
Arm A: Letrozole × 5yr after ~5yr of an AI
Arm B: Placebo × 5yr after ~5yr of an AI
Primary endpoint: DFS
mFollow up: 6.3yr
Arm B: Placebo × 5yr after ~5yr of an AI
Primary endpoint: DFS
mFollow up: 6.3yr
Results
5-yr DFS: 95% (letrozole) vs 91% (placebo); HR 0.79, 95%CI 0.63–1.00; P=.05
5-yr OS: 93% vs 94%; HR 0.97, 95%CI 0.73–1.28; P=.83
Annual contralateral breast cancer incidence: 0.21% vs 0.49%; HR 0.42, P=.007
5-yr OS: 93% vs 94%; HR 0.97, 95%CI 0.73–1.28; P=.83
Annual contralateral breast cancer incidence: 0.21% vs 0.49%; HR 0.42, P=.007
Adverse events
Vasomotor: Hot flushes 38% (letrozole) vs 37% (placebo)
Musculoskeletal: New osteoporosis 11% vs 6%; bone fractures 14% vs 9%
Musculoskeletal: New osteoporosis 11% vs 6%; bone fractures 14% vs 9%
Conclusions
Extending letrozole to a total of ~10 years improved DFS (driven largely by reduced contralateral breast cancer) without an OS benefit, at the cost of increased osteoporosis and fractures.
Key Limitations
Borderline primary DFS result (P=.05) driven mainly by contralateral breast cancers rather than distant recurrence. No OS benefit. Largely node-positive, lower-recurrence-risk enriched population that had already tolerated 5 years of an AI (selection toward tolerant patients). Bone toxicity is clinically meaningful.
Clinical Context
First trial to test a second 5 years of AI after an initial AI-containing 5 years. Supports individualized extended endocrine therapy in higher-risk patients tolerating an AI, with attention to bone health. ASCO/ESMO recommend shared decision-making rather than routine 10-year AI for all.