What are the recommendations for using tamoxifen (Tamoxifen) and raloxifene (Raloxifene) for breast cancer risk reduction in postmenopausal women?

STAR Trial (Study of Tamoxifen and Raloxifene)

Overview and Key Findings

The STAR trial demonstrated that raloxifene is 76% as effective as tamoxifen in preventing invasive breast cancer in postmenopausal women at increased risk, while causing significantly less toxicity, particularly regarding endometrial cancer, thromboembolic events, and cataracts. 1, 2

Trial Design and Population

The STAR trial (NSABP P-2) randomized 19,747 postmenopausal women at increased breast cancer risk to receive either:

• Tamoxifen 20 mg daily for 5 years, or
• Raloxifene 60 mg daily for 5 years 1, 2

Eligibility Criteria

• Postmenopausal women aged ≥35 years 1, 2
• 5-year breast cancer risk ≥1.67% by modified Gail model, OR 1, 2
• History of lobular carcinoma in situ (LCIS) 1, 2
• Excluded: women on hormone therapy, uncontrolled diabetes, hypertension, or history of stroke 1

Population Characteristics (Higher Risk Than Prior Trials)

• Mean age: 58.5 years 1
• 58.7% had ≥3% 5-year projected breast cancer risk 1
• 51% had prior hysterectomy 1
• 32% had history of LCIS or atypical hyperplasia 1

Efficacy Results at 81-Month Follow-Up

Invasive Breast Cancer

• Risk Ratio (raloxifene vs. tamoxifen): 1.24 (95% CI, 1.05-1.47) 1, 2
• Raloxifene: 4.41 per 1,000 women per year 1
• Tamoxifen: 4.30 per 1,000 women per year 1
• Interpretation: Raloxifene retained 76% of tamoxifen's effectiveness 2

Subgroup Analysis by Patient Characteristics

• Women with atypical hyperplasia: RR 1.48 (95% CI, 1.06-2.09) - raloxifene less effective 1
• Women with LCIS: RR 1.13 (95% CI, 0.76-1.69) 1
• Age ≥60 years: RR 1.22 (95% CI, 0.95-1.58) 1
• Age 50-59 years: RR 1.23 (95% CI, 0.97-1.57) 1

Noninvasive Breast Cancer

• Risk Ratio: 1.22 (95% CI, 0.95-1.59) - not statistically significant 1, 2
• The gap between raloxifene and tamoxifen narrowed over time for noninvasive disease 2

Safety and Toxicity Profile

Endometrial Cancer (Major Advantage for Raloxifene)

• Risk Ratio: 0.55 (95% CI, 0.36-0.83; P=0.003) 1, 2
• Raloxifene: 1.23% vs. Tamoxifen: 2.25% 1
• This difference became statistically significant only at long-term follow-up 1, 2

Endometrial Hyperplasia

• Risk Ratio: 0.19 (95% CI, 0.12-0.29) - dramatically lower with raloxifene 1, 2
• Raloxifene: 0.84% vs. Tamoxifen: 4.40% 1

Hysterectomy During Follow-Up

• Risk Ratio: 0.45 (95% CI, 0.37-0.54) 1
• Raloxifene: 5.41% vs. Tamoxifen: 12.08% 1

Thromboembolic Events

• Risk Ratio: 0.75 (95% CI, 0.60-0.93) 1, 2
• Raloxifene: 2.47% vs. Tamoxifen: 3.30% 1
• Deep vein thrombosis RR: 0.55 (95% CI, 0.54-0.95) 1

Cataracts

• Cataracts developed: RR 0.80 (95% CI, 0.72-0.89) 1
• Cataracts requiring surgery: RR 0.79 (95% CI, 0.70-0.90) 1
• Raloxifene: 11.69% vs. Tamoxifen: 14.58% 1

Similar Outcomes Between Groups

• No significant mortality differences 1, 2
• Stroke incidence similar 1
• Ischemic heart disease similar 1
• Bone fracture rates similar 1

Current Guideline Recommendations

For Postmenopausal Women

Both tamoxifen and raloxifene are Category 1 recommendations for breast cancer risk reduction in postmenopausal women aged ≥35 years with:

• ≥1.7% 5-year breast cancer risk by modified Gail model, OR 1
• History of LCIS, OR 1
• History of atypical hyperplasia 1

Choosing Between Tamoxifen and Raloxifene

For postmenopausal women WITH an intact uterus: Raloxifene is preferred due to significantly lower endometrial cancer risk (RR 0.55) and lower hysterectomy rates (RR 0.45), while maintaining 76% of tamoxifen's efficacy. 1, 2, 3

For postmenopausal women WITHOUT a uterus (prior hysterectomy): Either agent is appropriate as the benefit/risk ratio is similar when endometrial cancer risk is eliminated. 3

Avoid raloxifene in women with atypical hyperplasia: The risk ratio of 1.48 (95% CI, 1.06-2.09) suggests raloxifene is significantly less effective than tamoxifen in this subgroup. 1

Special Populations

BRCA1/2 mutation carriers: Raloxifene use is Category 2A (lower evidence) as no specific data exist for this population. 1, 4

Prior thoracic radiation: Raloxifene use is Category 2A recommendation. 1

Premenopausal women: Raloxifene is inappropriate outside clinical trials. 1

Clinical Decision-Making Algorithm

Step 1: Confirm Eligibility

• Postmenopausal status 1
• Age ≥35 years 1
• Life expectancy ≥10 years 1
• Calculate 5-year breast cancer risk using modified Gail model 1

Step 2: Assess Contraindications

Absolute contraindications for both agents:

• Active or history of venous thromboembolism 4
• History of stroke or TIA 5
• Concurrent hormone replacement therapy 5

Step 3: Risk Stratification

If 5-year risk ≥1.7% or history of LCIS/atypical hyperplasia, proceed to Step 4 1

Step 4: Choose Agent Based on Uterine Status and Risk Factors

Intact uterus → Raloxifene preferred 3

• 45% lower endometrial cancer risk 1
• 81% lower endometrial hyperplasia risk 1
• 55% lower hysterectomy rate 1
• 25% lower thromboembolic events 1
• 20% lower cataract development 1

Prior hysterectomy → Either agent acceptable 3

• Consider tamoxifen if atypical hyperplasia present 1
• Consider raloxifene if thromboembolic risk factors present 1

Atypical hyperplasia → Tamoxifen preferred 1

• Raloxifene 48% less effective in this subgroup 1

Step 5: Dosing and Duration

• Raloxifene: 60 mg daily for 5 years 1, 4
• Tamoxifen: 20 mg daily for 5 years 1, 5
• Optimal duration beyond 5 years unknown 4

Step 6: Monitoring Requirements

For raloxifene:

• Baseline and ongoing breast exams and mammograms 4
• Monitor for thromboembolic symptoms 4
• Gynecologic examination if uterus present 4

For tamoxifen:

• Regular gynecologic examinations (endometrial cancer surveillance) 5
• Monitor for thromboembolic events 5
• Avoid CYP2D6 inhibitors 5

Important Clinical Caveats

The benefit/risk ratio is influenced by age and comorbidities - older women with cardiovascular risk factors may have less favorable outcomes. 1, 5

Neither agent eliminates breast cancer risk - continued surveillance with breast exams and mammography is mandatory. 4

Quality of life considerations: Overall quality of life was similar between groups, though tamoxifen users reported better sexual function. 1

The STAR trial population was higher risk than general prevention populations - 58.7% had ≥3% 5-year risk and 32% had LCIS/atypical hyperplasia, which may limit generalizability to lower-risk women. 1

Long-term effects beyond 5 years are unknown - only 27% of STAR participants completed the full 5-year treatment course. 4