Background
Phase III, open-label RCT (NSABP P-2). 19747 postmenopausal women with increased BC risk (Gail model ≥1.66% 5-yr risk, or history of LCIS). Direct head-to-head comparison of two SERMs: tamoxifen (established prevention agent from P-1/BCPT) vs raloxifene (osteoporosis agent with potential BC prevention activity). The largest BC prevention trial ever conducted.
Interventions and follow up
Arm A: Tamoxifen 20mg oral daily for 5 years
Arm B: Raloxifene 60mg oral daily for 5 years
Primary endpoint: Invasive breast cancer incidence
mFollow up: 81 months (updated analysis)
Arm B: Raloxifene 60mg oral daily for 5 years
Primary endpoint: Invasive breast cancer incidence
mFollow up: 81 months (updated analysis)
Results
Invasive BC (updated): RR 1.24, 95% CI 1.05–1.47 — tamoxifen slightly more effective than raloxifene
Non-invasive BC (DCIS/LCIS): Tamoxifen more effective
Endometrial cancer: Raloxifene safer — RR 0.55 vs tamoxifen
VTE: Raloxifene safer — RR 0.75 vs tamoxifen
Cataracts: Raloxifene safer; fractures and cardiovascular events similar
Non-invasive BC (DCIS/LCIS): Tamoxifen more effective
Endometrial cancer: Raloxifene safer — RR 0.55 vs tamoxifen
VTE: Raloxifene safer — RR 0.75 vs tamoxifen
Cataracts: Raloxifene safer; fractures and cardiovascular events similar
Adverse events
Gynecologic: Uterine cancer significantly higher with tamoxifen (RR 1.82 vs raloxifene).
Thromboembolic: DVT significantly higher with tamoxifen.
Ocular/vasomotor: Cataract surgery significantly higher with tamoxifen; hot flashes similar between arms; overall quality of life similar.
Thromboembolic: DVT significantly higher with tamoxifen.
Ocular/vasomotor: Cataract surgery significantly higher with tamoxifen; hot flashes similar between arms; overall quality of life similar.
Conclusions
Tamoxifen and raloxifene have broadly similar efficacy for invasive BC prevention, though tamoxifen is more effective for DCIS/non-invasive BC. Raloxifene has a significantly better safety profile: lower uterine cancer, VTE, and cataract risk. STAR established raloxifene as an alternative to tamoxifen for postmenopausal high-risk women.
Key Limitations
Open-label design may introduce bias in adherence and outcome reporting. Postmenopausal women only — tamoxifen remains the only SERM option for premenopausal chemoprevention. Raloxifene's slightly lower invasive BC efficacy (updated RR 1.24 favoring tamoxifen) means tamoxifen may still be preferred in very high-risk patients. AIs (anastrozole, exemestane) now demonstrate superior prevention efficacy (~50–65% RRR) vs both SERMs in postmenopausal women. No OS benefit in either arm.
Clinical Context
STAR established raloxifene as a guideline-endorsed BC prevention option for postmenopausal women (FDA-approved 2007 for risk reduction). Current ASCO guidelines recommend AIs (anastrozole, exemestane) over SERMs as first-line chemoprevention in postmenopausal women due to superior efficacy; tamoxifen remains first-line for premenopausal women; raloxifene is an alternative for postmenopausal women already taking it for osteoporosis. ESMO-MCBS: not applicable (prevention trial).