Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction in healthy women

被引:70
作者
Decensi, A
Gandini, S
Guerrieri-Gonzaga, A
Johansson, H
Manetti, L
Bonanni, B
Sandri, MT
Barreca, A
Costa, A
Robertson, C
Lien, EA
机构
[1] Ist Europeo Oncol, Chemoprevent Unit, Div Epidemiol & Biostat, I-20141 Milan, Italy
[2] Ist Europeo Oncol, Div Lab Med, I-20141 Milan, Italy
[3] Univ Genoa, Dept Endocrinol, Genoa, Italy
[4] Univ Bergen, Dept Pharmacol, Bergen, Norway
关键词
D O I
10.1200/JCO.1999.17.9.2633
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Tamoxifen administered at 20 mg/d has been shown to decrease breast cancer incidence in at-risk women by 50%, but toxicity may limit its broad use, particularly in postmenopausal women. Because toxicity may be dose-dependent, we studied the biologic activity of low concentrations of tamoxifen to determine the plausibility of a dose reduction. Patients and Methods: We measured the blood concentrations of tamoxifen and its main metabolites in a dose titration study in 105 healthy women (placebo, tamoxifen 10 me on alternate days, tamoxifen 10 mg/d, and tamoxifen 20 mg/d). Drug levels measured after 2 months of treatment were correlated with the changes in surrogate biomarkers of different diseases, including lipid profile, brood cell count, fibrinogen, antithrombin ill, osteocalcin, and insulin-like growth factor I, a promising surrogate biomarker of breast cancer. Results: The means (+/- SD) for tamoxifen and N-desmethyltamoxifen (metabolite X) concentrations (ng/mt) were dose-related, being, respectively, 0 and 0 with placebo, 26.8 +/- 15.1 and 43.7 +/- 22.5 with 10 me every other day, 51.2 +/- 24.1 and 90.7 +/- 48.0 with 10 mg/d, and 136.0 +/- 52.7 and 230.6 +/- 75.0 with 20 mg/d of tamoxifen. At variance, the biomarker changes were of comparable magnitude at any drug concentration except for platelet count and triglycerides levels, the latter showing a trend to an increase with increasing tamoxifen concentrations. Conclusion: An 80% reduction in blood concentrations does not seem to affect the activity of tamoxifen on biomarkers of cardiovascular or breast cancer risk and may in fact have a more favorable safety profile. Additional studies are warranted to determine the most appropriate dose of this agent. (C) 1999 by American Society of Clinical Oncology.
引用
收藏
页码:2633 / 2638
页数:6
相关论文
共 30 条
  • [1] [Anonymous], 1998, LANCET, V351, P1451
  • [2] BIOEQUIVALENCE OF 20-MG ONCE-DAILY TAMOXIFEN RELATIVE TO 10-MG TWICE-DAILY TAMOXIFEN REGIMENS FOR BREAST-CANCER
    BUZDAR, AU
    HORTOBAGYI, GN
    FRYE, D
    HO, D
    BOOSER, DJ
    VALERO, V
    HOLMES, FA
    BIRMINGHAM, BK
    BUI, K
    YEH, C
    PLOURDE, PV
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 1994, 12 (01) : 50 - 54
  • [3] COEZY E, 1982, CANCER RES, V42, P317
  • [4] Biologic activity of tamoxifen at low doses in healthy women
    Decensi, A
    Bonanni, BD
    Guerrieri-Gonzaga, A
    Gandini, S
    Robertson, C
    Johansson, H
    Travaglini, R
    Sandri, MT
    Tessadrelli, A
    Farante, G
    Salinaro, F
    Bettega, D
    Barreca, A
    Boyle, P
    Costa, A
    Veronesi, U
    [J]. JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1998, 90 (19) : 1461 - 1467
  • [5] Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study
    Fisher, B
    Costantino, JP
    Wickerham, DL
    Redmond, CK
    Kavanah, M
    Cronin, WM
    Vogel, V
    Robidoux, A
    Dimitrov, N
    Atkins, J
    Daly, M
    Wieand, S
    Tan-Chiu, E
    Ford, L
    Wolmark, N
    [J]. JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1998, 90 (18) : 1371 - 1388
  • [6] ENDOMETRIAL CANCER IN TAMOXIFEN-TREATED BREAST-CANCER PATIENTS - FINDINGS FROM THE NATIONAL SURGICAL ADJUVANT BREAST AND BOWEL PROJECT (NSABP) B-14
    FISHER, B
    COSTANTINO, JP
    REDMOND, CK
    FISHER, ER
    WICKERHAM, DL
    CRONIN, WM
    BOWMAN, D
    COUTURE, J
    DIMITROV, NV
    EVANS, J
    FARRAR, W
    KAVANAH, M
    LICKLEY, HL
    MARGOLESE, R
    PATERSON, AHG
    ROBIDOUX, A
    SHIBATA, H
    TERZ, J
    [J]. JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1994, 86 (07): : 527 - 537
  • [7] Circulating concentrations of insulin-like growth factor-I and risk of breast cancer
    Hankinson, SE
    Willett, WC
    Colditz, GA
    Hunter, DJ
    Michaud, DS
    Deroo, B
    Rosner, B
    Speizer, FE
    Pollak, M
    [J]. LANCET, 1998, 351 (9113) : 1393 - 1396
  • [8] Hemminki K, 1996, CANCER RES, V56, P4374
  • [9] AN ANALYSIS OF RANDOMIZED TRIALS EVALUATING THE EFFECT OF CHOLESTEROL REDUCTION ON TOTAL MORTALITY AND CORONARY HEART-DISEASE INCIDENCE
    HOLME, I
    [J]. CIRCULATION, 1990, 82 (06) : 1916 - 1924
  • [10] EFFECT OF ESTROGEN-RECEPTOR STATUS AND TIME ON THE INTRA-TUMORAL ACCUMULATION OF TAMOXIFEN AND N-DESMETHYLTAMOXIFEN FOLLOWING SHORT-TERM THERAPY IN HUMAN PRIMARY BREAST-CANCER
    JOHNSTON, SRD
    HAYNES, BP
    SACKS, NPM
    MCKINNA, JA
    GRIGGS, LJ
    JARMAN, M
    BAUM, M
    SMITH, IE
    DOWSETT, M
    [J]. BREAST CANCER RESEARCH AND TREATMENT, 1993, 28 (03) : 241 - 250