Table 2.
Raloxifene (RLX): characteristics of the reviewed studies (n = 9).
| Authors/year | Endpoint | Design | High risk definition | Population/number of cases | Age | Method of breast density measurement/time | Mammograms readers | Reproducibility | BD baseline |
|---|---|---|---|---|---|---|---|---|---|
| Jackson et al. 2003 [42] | Effect of raloxifene and HRT on breast density | Randomized, open-label, parallel designed trial | NA | 356 postmenopausal women with osteopenia or osteoporosis/280 assigned randomly/193 included in the final analysis: RLX: 109; ccHT: 841 | Mean 66.7 y; average y postmenopause: 17.9; RLX (mean ± SD): 66.9 y ± 5.3; ccHT: 66.4 y ± 4.5 | Visually according to BI-RADs classification at baseline and after 12 months of therapy | Three radiologists blinded to treatment assignment | Weighted Kappa for interrater reliability at baseline: 0.57 to 0.70; after 12 months: 0.51 to 0.66 | BI-RADs I: 16.6–22.8%; II: 65.3–75.6%; III: 7.8–10.9%; IV: 0-1% |
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| Eilertsen et al. 2008 [43] | Effect of raloxifene and different regimens of HT on breast density | Open-label, randomized, comparative clinical trial | NA | 358 postmenopausal women/202 assigned randomly/178 included in the final analysis: low-dose combined HT: n = 44, conventional-dose combined HT: n = 45, tibolone: n = 45, and RLX: n = 442 | 45–65 yrs: low-dose combined HT (mean ± SD): 54.8 y ± 5.0; conventional-dose combined HT: 56.1 y ± 3.6; tibolone: 54.9 y ± 4.7; RLX: 56.3 y ± 4.9 | Volumetric breast density by a fully automated technique in full-field digital mammograms at baseline and after 12 weeks | NA | NA | Low-dose HT: 8.6 (5.1–17.1); conventional-dose HT: 8.3 (5.5–11.4); tibolone: 7.5 (5.3–12.3); RLX: 7.7 (5.7–11.1)3 |
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| Eng-Wong et al. 2008 [44] | Effect of raloxifene on breast density | Retrospective analysis of a phase II prospective trial | Gail 5-year risk ≥ 1.7%, or a family history of BC, or previous LCIS, ADH, DCIS | 37 high risk premenopausal | 43 y (35–47) | On digitized mammograms using a semiquantitative technique and using MRI T1-weighted images to determine breast MRI volume using a semiautomatic method at baseline, after 1 and 2 years, and 1 year posttreatment | Two radiologists | Previously tested in another validation study for MRIV (94.95% agreement). For mammograms: interradiologist correlation: 1 y: 0.63; 2 y: 0.62; 3 y (one year off RLX): 0.39 | Mean BD (range) 39% (7–78) |
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| Freedman et al. 2001 [45] | Effect of raloxifene (at one of two doses) and HRT on breast density | Subgroup analysis of a prospective double-blind, randomized, placebo-controlled trial | NA | 619 postmenopausal women with previous hysterectomy/168 included in the final analysis: placebo (n = 45); RLX 60 mg/day (n = 45); 150 mg/day (n = 42); estrogen 0.625 mg/day (n = 36) | Mean 53 y (45–60); mean y after menopause: 6. Placebo (mean ± SD): 52.2 y ± 5.1; RLX 60 mg/day: 54.1 y ± 4.2; 150 mg/day: 53.3 y ± 4.8; estrogen: 52.1 y ± 4.6 |
Digital scanning and computer-assisted segmentation of mammograms at baseline and 2 years | One radiologist blinded to treatment | Previously tested in another validation study | Placebo: 9.8% ± 9.6%; RLX 60 mg/day: 9.3% ± 9.1%; 150 mg/day: 8.1% ± 6.6%; estrogen: 13.5% ± 11.5% |
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| Harvey et al. 2009 [46] | Effect of bazedoxifene compared with raloxifene or placebo on breast density | Retrospective analysis of a phase III randomized placebo- and active-controlled trial | NA | 7 609 postmenopausal women with osteoporosis/1 243 eligible for participation; 622 eligible for digitization and 442 included in the final analysis: bazedoxifene 20 mg (n = 92); bazedoxifene 40 mg (n = 106); RLX 60 mg (n = 119); placebo (n = 125) | ≤62 y; mean age: 58.7 y. Mean ± SD: bazedoxifene 20 mg/day: 58.3 y ± 2.5; 40 mg/day: 58.8 y ± 2.4; RLX 60 mg/day: 58.8 y ± 2.6; placebo: 58.8 y ± 2.5 | On digitized mammograms using an interactive thresholding software at baseline and at 2 years | One radiologist blinded to time sequence and treatment arm | NA | Bazedoxifene 20 mg: 26.4% (SD 18.7%); bazedoxifene 40 mg: 25.8% (SD 19.1%); RLX 60 mg: 27.6% (SD 19.3%); placebo: 27.2% (SD 18.1%) |
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| Nielsen et al. 2009 [47] | Effect of transdermal estradiol compared with raloxifene on breast density or heterogeneity | Post hoc analysis of a prospective randomized study | NA | 500 women at least 5 y postmenopausal/270 included in the final analysis: RLX 60 mg/day (n = 135); low-dose estradiol (n = 135)4 | 66 years (55–80) mean ± SD: RLX: 66.7 y ± 0.5; estradiol: 66.3 y ± 0.5 |
Visually according to BI-RADs classification, area percentage and computer-based (E2-specific) heterogeneity examination of digitized mammograms at baseline and at 2 years | One radiologist blinded to treatment | Previously tested in another validation study: intraobserver variability between baseline and 2-year assessments = 0.79 (range 0.70–0.86) | RLX 60 mg: 16% (5–31); low-dose estradiol: 16% (7–24) |
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| Lasco et al. 2006 [48] | Effects of long-term raloxifene on breast density | Prospective case control study | NA | 70 postmenopausal women with normal body weight/cases: women with osteoporosis receiving RLX 60 mg/day (n = 50); controls: women without osteoporosis (n = 20) | Cases: 52.4 ± 4.1 y, menopausal age: 42.1 ± 3.9 y; controls: 53.6 ± 3.5 y, menopausal age: 43.1 ± 3.6 y | Digital scanning and computer-assisted segmentation of mammograms at baseline and 2 years | NA | NA | Image mean index (IMI)5: ~3.35 for both groups |
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| Christodoulakos et al. 2002 [49] | Effect of raloxifene compared with tibolone on breast density | Randomized, comparative clinical trial | NA | 131 postmenopausal women/tibolone 2.5 mg/day (n = 56), RLX 60 mg/day (n = 48) and controls: no risk factors of osteoporosis or denied treatment: (n = 27) | Mean age ± SD: tibolone: 52.6 y ± 4.8, RLX: 53.9 y ± 3.9, controls: 51.4 y ± 7.6, mean months since menopause: range 69.8–88.3 | Visually according to Wolfe 6classification at baseline and 12 months | Two radiologists blinded to treatment arm | In case of discrepancies (9.2–13%), films were reevaluated by the 2 radiologists together for consensus | N1: tibolone: 19 (36.5%), RLX: 23 (47.9%), controls: 6 (22.2%); P1: tibolone: 16 (30.8%), RLX: 10 (20.8%), controls: 7 (25.9%); P2: tibolone: 15 (28.8%), RLX: 12 (25%), controls: 11 (40.7%); DY: tibolone: 2 (3.8%), RLX: 3 (6.3%), controls: 3 (11.1%)7 |
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| Cirpan et al. 2006 [50] | Effect of raloxifene on breast density | Retrospective study | NA | 55 postmenopausal women with osteopenia or osteoporosis | Mean age ± SD: 50.4 y ± 3.6 (43–58) | Visually according to BI-RADs classification at baseline and after 12 to 16 months of therapy | NA | NA | BI-RADs category I: n = 8 (14.5%); II: n = 28 (50.9%); III: n = 17 (30.9%); IV: n = 2 (3.6%) |
1ccHT: continuous-combined HT: conjugated equine estrogen 0.625 mg/day + medroxyprogesterone acetate 2.5 mg/day. 2Conventional-dose HT = 2 mg 17 β-estradiol and 1 mg norethisterone acetate, low-dose HT = 1 mg 17 β-estradiol and 0.5 mg norethisterone acetate. NA: not available or not applicable. 3Values are represented as median (25th–75th percentile of interquartile range). LCIS: lobular carcinoma in situ, ADH: atypical ductal hyperplasia, and DCIS: ductal carcinoma in situ. 4Weekly patch delivering 0.014 mg estradiol/day. 5Image Mean Index (IMI): computer-assisted algorithm calculation including identification and delimitation of the same region of interest for each image and the differentiation of gray levels into 10 classes. 6Wolfe classification: N1: parenchymal pattern composed almost entirely of fat with trabeculae but no visible ducts, P1: pattern composed mainly of fat with fibroglandular tissue that constitutes 25% of the breast, P2: pattern composed of fibroglandular tissue appearing as a heterogeneously dense breast that occupies more than 25% of the breast, and DY: extremely dense tissue. 7Tibolone versus controls: P = 0.32 or RLX versus controls: P = 0.18.