Background
Phase III, double-blind, placebo-controlled RCT. 4560 postmenopausal women at elevated breast cancer risk (≥1.66% 5-yr Gail model risk, age ≥60, or prior atypical hyperplasia/LCIS/DCIS). Exemestane — an irreversible steroidal aromatase inactivator — tested as BC chemoprevention. Ran concurrently with IBIS-II (anastrozole), together establishing the AI class in prevention.
Interventions and follow up
Arm A: Exemestane 25mg daily for 5 years
Arm B: Placebo for 5 years
Primary endpoint: Invasive breast cancer incidence
mFollow up: 35 months (primary)
Arm B: Placebo for 5 years
Primary endpoint: Invasive breast cancer incidence
mFollow up: 35 months (primary)
Results
Annual invasive BC rate: 0.19% vs 0.55% (exemestane vs placebo), HR 0.35, 95% CI 0.18–0.70, P=.002 — 65% relative risk reduction
All BC (invasive + DCIS): HR 0.47, 95% CI 0.27–0.79, P=.004
OS: No difference
All BC (invasive + DCIS): HR 0.47, 95% CI 0.27–0.79, P=.004
OS: No difference
Adverse events
Vasomotor/constitutional: Hot flashes 40.1% vs 32.0% (P<.0001); fatigue 27.0% vs 23.0%.
Musculoskeletal: Arthritis/arthralgias 39.5% vs 33.2%; bone mineral density numerically lower with exemestane (not powered for fractures).
Other: No significant increase in cardiovascular events or fractures at median 35 months.
Musculoskeletal: Arthritis/arthralgias 39.5% vs 33.2%; bone mineral density numerically lower with exemestane (not powered for fractures).
Other: No significant increase in cardiovascular events or fractures at median 35 months.
Conclusions
Exemestane reduced invasive breast cancer incidence by 65% vs placebo in postmenopausal high-risk women, with a 53% reduction in all BC. MAP.3, alongside IBIS-II, established AIs as highly effective BC chemoprevention agents with a favorable safety profile in postmenopausal women.
Key Limitations
Short median follow-up (35 months) at primary analysis — long-term safety (fractures, cardiovascular events) with 5-year AI exposure in healthy women is not fully characterized. The placebo-arm annual BC rate (0.55%) reflects a specific elevated-risk population; absolute risk reduction (~0.36%/yr) must be individualized. No mortality benefit. Real-world adherence to 5-year preventive AI is likely lower than in trials. Not applicable to premenopausal women.
Clinical Context
MAP.3 and IBIS-II together established AI chemoprevention as the preferred approach in postmenopausal high-risk women. Exemestane and anastrozole are both endorsed by ASCO for postmenopausal women with elevated BC risk. The choice between them is not evidence-based — both reduce BC incidence by ~50–65% with similar tolerability. Bone density monitoring and counseling about musculoskeletal effects are essential. ESMO-MCBS: not applicable (prevention trial).
References