Biologic Activity of Tamoxifen at Low Doses in Healthy Women

DeCensi, Andrea; Bonanni, Bernardo; Guerrieri-Gonzaga, Aliana; Gandini, Sara; Robertson, Chris; Johansson, Harriet; Travaglini, Roberto; Sandri, Maria Teresa; Tessadrelli, A.; Farante, G.; Salinaro, F.; Bettega, Donato; Barreca, Antonina; Boyle, Peter; Costa, Alberto; Veronesi, Umberto

doi:10.1093/jnci/90.19.1461

Cited by 95 publications

(61 citation statements)

References 45 publications

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“…Briefly, data from the following phase II trials were analyzed: (1) trial IEO-095 in unaffected hysterectomized women (n ¼ 103) aged 35-70 years allocated to tamoxifen at 2 different low doses [20]; (2) trial IEO-007, a two-by-two trial of low-dose tamoxifen and fenretinide (4-HPR) in premenopausal women (n ¼ 223). Subjects with a history of excised IEN (n ¼ 152) or microinvasive breast cancer (n ¼ 20) and healthy status women with increased risk for breast cancer according to the Gail model (n ¼ 51) were eligible; (3) trial IEO-167, a two-by-two trial of oral coniugated equine estrogens (CEE) or transdermal 17 b-estradiol (E2) and 4-HPR or placebo in unaffected postmenopausal women (n ¼ 222) [21]; (4) trial IEO-137, a trial of two-weeks of raloxifene or placebo given pre-operatively in postmenopausal women (n ¼ 37) with early stage breast cancer [22]; (5) trial IEO-183, a three arm trial of three doses of tamoxifen given for four weeks pre-operatively in women (n ¼ 155) over 45 years old with early stage breast cancer [23].…”

Section: Study Populationmentioning

confidence: 99%

Factors associated with circulating levels of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in 740 women at risk for breast cancer

Johansson

Baglietto

Guerrieri-Gonzaga

et al. 2004

Breast Cancer Res Treat

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Prospective studies have shown an association between elevated plasma levels of insulin-like growth factor-I (IGF-I) and/or decreased levels of its major circulating carrier protein insulin-like growth factor binding protein-3 (IGFBP-3) and increased risk of major cancers. Identifying the factors which affect these biomarkers is of particular interest as subjects at increased risk could benefit from lifestyle changes, and/or chemoprevention intervention. We evaluated the association between constitutional, hormonal and clinical factors and IGF-I and IGFBP-3 in 740 women, including 376 unaffected women and 364 women with intraepithelial neoplasia (IEN) or early invasive breast cancer enrolled in breast cancer chemoprevention trials, conducted at a single institution. Age, body mass index (BMI), height, waist to hip girth ratio (WHR), parity, menopausal status, age at menarche, number of affected first degree relatives, number of biopsies and breast cancer status were considered in the analysis. Women with early breast cancer had 21% higher IGF-I levels (p = 0.033) and 19% higher IGF-I/IGFBP-3 molar ratio (p = 0.047) than unaffected women. In unaffected women, age was negatively associated with IGF-I (p = 0.002) and IGF-I/IGFBP-3 (p = 0.001), while age at menarche was negatively associated with IGFBP-3 levels (p = 0.043). In women with IEN or early breast cancer, IGF-I levels were negatively associated with age (p < 0.001), and positively associated with prior biopsies for benign disease (p = 0.013), while age, parity and menopausal status were significant predictors of IGF-I/IGFBP-3 molar ratio. We conclude that circulating IGF-I levels are higher in women with prior breast cancer compared to unaffected women, and that IGF-I and/or IGFBP-3 levels are influenced by age and by reproductive and hormonal factors. These findings support their putative role as breast cancer risk biomarker.

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Section: Study Populationmentioning

confidence: 99%

Factors associated with circulating levels of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in 740 women at risk for breast cancer

Johansson

Baglietto

Guerrieri-Gonzaga

et al. 2004

Breast Cancer Res Treat

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“…Sex hormone replacement therapy in postmenopausal women has been shown to decrease colorectal cancer risk as well as the development of colorectal adenomas (2)(3)(4). Both sex hormone replacement therapy (5,6) and selective estrogen receptor modulators, e.g., tamoxifen (7,8), have been shown to reduce serum insulin-like growth factor-I (IGF-I) concentrations.…”

Section: Introductionmentioning

confidence: 99%

No Effect of Red Clover–Derived Isoflavone Intervention on the Insulin-Like Growth Factor System in Women at Increased Risk of Colorectal Cancer

Vrieling¹,

Rookus²,

Kampman

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Increased insulin-like growth factor (IGF)-I and IGF-II concentrations are related to increased colorectal cancer risk. Isoflavones have been associated with reduced colorectal cancer risk, and may affect the IGF system because of their weak estrogenic activity. The aim of the study was to investigate the effect of isolated isoflavones on serum concentrations of IGF system components. Materials and Methods: We conducted a randomized, placebo-controlled, double-blinded, crossover trial in four hospitals in the Netherlands to investigate the effect of an 8-week supplementation with red clover -derived isoflavones (84 mg/d) on serum IGF-I concentrations. In addition, serum concentrations of IGF-IIand IGF binding proteins (IGFBP)-1, IGFBP-2, and IGFBP-3 were assessed. Normal colorectal tissue biopsies were obtained after the first intervention period and mRNA expression of IGF-I, IGF-II, IGFBP-3, and IGF-IR was evaluated. Our study population consisted of 34 postmenopausal women with

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“…Furthermore, the activity and side effects of tamoxifen may be attributed not only to concentrations of the parent drug but also to its biologically active metabolites and their accumulation in target tissues. Moreover, doses lower than the conventional 20 mg/day may have a more favorable safety profile on serum biomarkers of cardiovascular disease (16), suggesting that a dose reduction may decrease side effects of tamoxifen.…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen and Metabolite Concentrations in Serum and Breast Cancer Tissue during Three Dose Regimens in a Randomized Preoperative Trial

Kisanga

Gjerde

Guerrieri-Gonzaga

et al. 2004

Clinical Cancer Research

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124

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Purpose: Both therapeutic and adverse effects of tamoxifen may be related to its tissue concentrations. We investigated concentrations of tamoxifen, 4-hydroxytamoxifen, Ndesmethyltamoxifen, and N-didesmethyltamoxifen in serum, normal breast, and breast cancer tissues during conventional dosage and two low-dose regimens. Furthermore we studied tamoxifen effects on the cancer proliferation marker Ki-67, and on sex hormone-binding globulin (SHBG).Experimental Design: From September 1999 to August 2001, 120 breast cancer patients were randomized to 20-, 5-, or 1-mg tamoxifen daily. We measured serum and tissue concentrations of tamoxifen and three metabolites after 28 days of treatment, and the changes between baseline and post-treatment levels of SHBG and Ki-67.Results: The median (range) tamoxifen concentrations (ng/ml) at doses of 1, 5, and 20 mg daily (n ‫؍‬ 38, 37, and 36) were 7.5 (2.9 -120.9), 25.2 (1.9 -180.9), and 83.6 (8.7-134.4) in serum, and 78.2 (35.9 -184), 272.3 (122-641), and 744.4 (208.6 -2556) in breast cancer tissue, respectively. Tamoxifen levels followed a dose-concentration relationship. The concentrations of tamoxifen and metabolites were related to each other. Serum and tissue concentrations of tamoxifen were associated with corresponding changes of SHBG levels, whereas changes of Ki-67 levels were not related. Conclusions:Estrogen agonistic effects of tamoxifen on SHBG decreased with lower dosage, whereas tamoxifen effects on Ki-67 expression did not change. This together with a >10-fold variation in serum tamoxifen concentrations and a serum to tissue concentration relationship suggest that tamoxifen treatment may be improved by administration of lower doses and therapeutic drug monitoring.

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Biologic Activity of Tamoxifen at Low Doses in Healthy Women

Cited by 95 publications

References 45 publications

Factors associated with circulating levels of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in 740 women at risk for breast cancer

Factors associated with circulating levels of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in 740 women at risk for breast cancer

No Effect of Red Clover–Derived Isoflavone Intervention on the Insulin-Like Growth Factor System in Women at Increased Risk of Colorectal Cancer

Tamoxifen and Metabolite Concentrations in Serum and Breast Cancer Tissue during Three Dose Regimens in a Randomized Preoperative Trial

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