Table 2Randomized controlled trials of primary prevention for breast cancer

TrialIncluded PublicationsNSubjectsPrimary OutcomeDurationStudy Quality/Applicability
Tamoxifen (20 mg/day) vs. Raloxifene (60 mg/day)
Study of Tamoxifen and Raloxifene (STAR)Vogel, 200612;
Land, 200618
9872 tamoxifen
9875 raloxifene
Postmenopausal women with a 5-year predicted breast cancer risk of ≥1.66% based on the modified Gail model.* Age ≥35 years, mean age 58.5 years; 94% white; 52% post hysterectomy; none using estrogen. US based with nearly 200 clinical sites in North AmericaInvasive breast cancerMean follow-up 3.9 years with mean exposure 3.1 to 3.2 years.Good/Good
Tamoxifen (20 mg/day) vs. Placebo
National Surgical
Adjuvant Breast and Bowel Project
P-1 Study
(NSABP-1)
Fisher, 199824;
Fisher, 200523;
Day, 2001a21;
Day, 2001b22
6576 tamoxifen 6599 placeboAge ≥60 years or age 35 to 59 years with a 5-year predicted risk of breast cancer ≥1.66% based on the modified Gail model,* or a history of lobular carcinoma in situ. 39% of women were <50 years old; 97% white; 38% post hysterectomy; none using estrogen. US based with multiple clinical sites in North America.Invasive and noninvasive breast cancerMedian follow-up 4.6 years with median exposure 4.0 years for initial results; median follow-up 7.0 years for long-term results.Good/Good
International
Breast Cancer
Intervention Study
(IBIS-I)
Cuzick, 200219;
Cuzick, 200720
3573 tamoxifen3566 placeboIncreased breast cancer risk based on family history and other factors. Age 35 to 70 years, mean age 50.8 years; 35% post hysterectomy; 40% using estrogen. UK, Australia, NZ, Europe.Invasive and noninvasive breast cancerMedian follow-up 4.2 years for initial results; 8.0 years for long-term results.Fair/Good
Royal Marsden
Hospital Trial
Powles, 199825;
Powles, 200726
1238 tamoxifen 1233 placeboFamily history of breast cancer. Age 30 to 70 years; median age 47 years; 15% of tamoxifen and 27% of placebo group using estrogen at the beginning of trial; UK.Invasive breast cancerMedian follow-up 5.8 years for initial results; 13.2 years for long-term results.Fair/Good
Italian Tamoxifen
Prevention Study
Veronesi, 199828;
Veronesi, 200330;
Veronesi, 200729;
Decensi, 200527
2700 tamoxifen
2708 placebo
Women with hysterectomy for reasons other than cancer.
Age 35 to 70 years; median age 51 years; 14% using estrogen; Italy based with 55 clinical centers in Europe and South America.
Breast cancer incidence and mortalityMedian follow-up 3.8 years for intial results; 11.2 years follow-up and 4.0 years exposure for long-term results.Fair/Fair
Raloxifene (60 or 120 mg/day) vs. Placebo
Multiple Outcomes of Raloxifene
Evaluation (MORE) and Continuing Outcomes Relevant to Evista (CORE)
Ettinger, 199938;
Cummings, 199934;
Cauley, 200133;
Barrett- Connor, 200232;
Delmas, 200235;
Delmas, 200336;
Grady, 200439;
Barrett-Connor, 200431;
Silverman, 200444;
Johnell, 200440;
Martino, 200543;
Duvernoy, 200537;
Keech, 200541;
Siris, 200545;
Lippman, 200642
MORE:
5129 raloxifene
(60 or 120 mg/day)
2576 placebo

CORE:
2725 raloxifene
(60 mg/day)
1286 placebo
Postmenopausal women with osteoporosis.§ Age 31 to 80 years; median age 66.9 years; 96% white; 23% post hysterectomy; none using systemic estrogen. US based with 180 clinical centers in 25 countries. CORE is comprised of a subset of MORE participants to further examine raloxifene’s effect on breast cancer incidence.MORE: Incident radiographic vertebral fractures and verified clinical nonvertebral fractures excluding pathologic, traumatic, and nonosteoporosis-related fractures (i.e., face, skull, finger, toe).
CORE: Breast cancer.
Follow-up time varies with publications and outcomes MORE; results reported at 3 and 4 years and CORE at 4 and 8 years (combines the MORE and CORE data).Good/Good
Raloxifene Use for the Heart (RUTH)Barrett-Connor, 200646; Grady, 2008475044 raloxifene
(60 mg/day)
5057 placebo
Postmenopausal women with coronary heart disease or multiple risk factors for heart disease.|| Age ≥55 years; median age 67.5 years; 84% white; 23% post hysterectomy; none on estrogen; US based with 177 clinical sites in 26 countries.Coronary events (death from coronary causes, nonfatal myocardial infarction, acute coronary syndrome) and invasive breast cancer.Median duration 5.6 years;
median exposure 5.1 years.
Good/Good
Tibolone (1.25 mg/day) vs. Placebo
Long-Term
Intervention on Fractures with Tibolone (LIFT)
Cummings, 2008102267 tibolone
2267 placebo
Women with bone mineral density T-score ≤−2.5 at the hip or spine or T-score ≤−2.0 and radiologic evidence of a vertebral fracture Age 60 to 85 years; mean 68 years; 22% post hysterectomy; none on estrogen. US based with 80 clinical sites in 22 countries.Incident radiographic vertebral fractures and verified clinical nonvertebral fractures excluding pathologic, traumatic, and nonosteoporosis- related fractures (i.e., face, skull, finger, toe).Median exposure 2.8 yearsGood/Good
*

STAR & NSABP-1: The Gail model includes age, number of first-degree relatives with breast cancer, nulliparity or age at first live birth, number of benign breast biopsies, pathologic diagnosis of atypical hyperplasia, and age at menarche. The original model was further modified to predict expected rates of invasive breast cancer only (not invasive and noninvasive as originally designed) and to allow for race-specific determinations of risk.

IBIS: 2-fold relative risk for ages 45 to 70, 4-fold relative risk for ages 40 to 44, 10-fold relative risk for ages 35 to 39 based on family history criteria. All criteria permit entry to trial at age 45 years.

1. First-degree relative who developed breast cancer at or before age 50.

2. First-degree relative with bilateral breast cancer (permits entry from age 40; if relative diagnosed before age 40, permits entry at age 35).

3. Two or more first-degree or second-degree relatives with breast cancer (permits entry from age 40 if both developed breast cancer before age 50, permits entry at age 35 if both relatives are first-degree and both developed breast cancer before age 50).

4. Benign breast biopsy and first-degree relative with breast cancer.

5. Lobular carcinoma in situ (permits entry from age 35).

6. Atypical hyperplasia (permits entry from age 40).

7. Nulliparous and a first-degree relative who developed breast cancer.

8. Risk equivalent (strong family history, not fitting specific categories, but judged to be at higher risk than eligibility category by the study chairman).

Family history criteria for Royal Marsden Hospital Trial:

1. One first-degree relative under 50 years old with breast cancer, or

2. One first-degree relative with bilateral breast cancer, or

3. One affected first-degree of any age plus another affected first-degree or second-degree relative

4. Benign breast biopsy and a first-degree relative with breast cancer

§

MORE:

Study Group 1: Femoral neck or lumbar spine bone mineral density (BMD) T-score <−2.5.

Study Group 2: Low BMD and one or more moderate or severe vertebral fractures or 2 or more milder vertebral fractures (20% to 25% reduction in height); or at least 2 moderate fractures (25% to 40% reduction from expected vertebral height), regardless of BMD.

||

Participants were required to have a cardiovascular risk score of 4 or more according to a point system: established coronary heart disease (4 points), arterial disease of the leg (4 points), at least 70 years old (2 points), diabetes mellitus (3 points), cigarette smoking (1 point), hypertension (1 point), and hyperlipidemia (1 point).

STAR & NSABP-1: The Gail model includes age, number of first-degree relatives with breast cancer, nulliparity or age at first live birth, number of benign breast biopsies, pathologic diagnosis of atypical hyperplasia, and age at menarche. The original model was further modified to predict expected rates of invasive breast cancer only (not invasive and noninvasive as originally designed) and to allow for race-specific determinations of risk.

IBIS: 2-fold relative risk for ages 45 to 70, 4-fold relative risk for ages 40 to 44, 10-fold relative risk for ages 35 to 39 based on family history criteria. All criteria permit entry to trial at age 45 years.

1. First-degree relative who developed breast cancer at or before age 50.

2. First-degree relative with bilateral breast cancer (permits entry from age 40; if relative diagnosed before age 40, permits entry at age 35).

3. Two or more first-degree or second-degree relatives with breast cancer (permits entry from age 40 if both developed breast cancer before age 50, permits entry at age 35 if both relatives are first-degree and both developed breast cancer before age 50).

4. Benign breast biopsy and first-degree relative with breast cancer.

5. Lobular carcinoma in situ (permits entry from age 35).

6. Atypical hyperplasia (permits entry from age 40).

7. Nulliparous and a first-degree relative who developed breast cancer.

8. Risk equivalent (strong family history, not fitting specific categories, but judged to be at higher risk than eligibility category by the study chairman).

Family history criteria for Royal Marsden Hospital Trial:

1. One first-degree relative under 50 years old with breast cancer, or

2. One first-degree relative with bilateral breast cancer, or

3. One affected first-degree of any age plus another affected first-degree or second-degree relative

4. Benign breast biopsy and a first-degree relative with breast cancer

MORE:

Study Group 1: Femoral neck or lumbar spine bone mineral density (BMD) T-score <−2.5.

Study Group 2: Low BMD and one or more moderate or severe vertebral fractures or 2 or more milder vertebral fractures (20% to 25% reduction in height); or at least 2 moderate fractures (25% to 40% reduction from expected vertebral height), regardless of BMD.

Participants were required to have a cardiovascular risk score of 4 or more according to a point system: established coronary heart disease (4 points), arterial disease of the leg (4 points), at least 70 years old (2 points), diabetes mellitus (3 points), cigarette smoking (1 point), hypertension (1 point), and hyperlipidemia (1 point).

From: Results

Cover of Comparative Effectiveness of Medications To Reduce Risk of Primary Breast Cancer in Women
Comparative Effectiveness of Medications To Reduce Risk of Primary Breast Cancer in Women [Internet].
AHRQ Comparative Effectiveness Reviews, No. 17.
Nelson HD, Fu R, Humphrey L, et al.

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