A comparison of two doses of tamoxifen (Nolvadex) in postmenopausal women with advanced breast cancer: 10 mg bd versus 20 mg bd

Bratherton, D. G.; Brown, C. B.; Buchanan, R. B.; Hall, Victoria M.; Pillers, E. M. Kingsley; Wheeler, T.K.; Williams, Carmen J.

doi:10.1038/bjc.1984.163

Cited by 90 publications

(32 citation statements)

References 11 publications

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“…Tamoxifen metabolism shows considerable interindividual variation (10,11). Its side effects may be dose and concentration dependent (12), and an increased risk of endometrial cancer has been associated with duration of treatment and accumulated dose (13)(14)(15).…”

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

178

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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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

178

124

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“…It follows that variations in endoxifen concentrations that result from CYP2D6 polymorphisms and drug interactions may influence antitumoral efficacy and side effects of TAM. It is interesting to note that plasma TAM concentrations have been reported to be poor predictors of therapeutic outcome (Bratherton et al, 1984), but that they are also poor predictors of endoxifen concentrations in breast cancer patients (Y. Jin, Z. Desta, V. Stearns, B. Ward, H. Ho, J.…”

mentioning

confidence: 99%

Comprehensive Evaluation of Tamoxifen Sequential Biotransformation by the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6

Desta

Ward

Soukhova

et al. 2004

J Pharmacol Exp Ther

576

484

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We performed comprehensive kinetic, inhibition, and correlation analyses in human liver microsomes and experiments in expressed human cytochromes P450 (P450s) to identify primary and secondary metabolic routes of tamoxifen (TAM) and the P450s catalyzing these reactions at therapeutically relevant concentrations. N-Desmethyl-TAM formation catalyzed by CYP3A4/5 was quantitatively the major primary metabolite of TAM; 4-hydroxy-TAM formation catalyzed by CYP2D6 (and other P450s) represents a minor route. Other minor primary metabolites include ␣ -, 3-, and 4Ј-hydroxyTAM and one unidentified metabolite (M-I) and were primarily catalyzed by CYP3A4, CYP3A5, CYP2B6/2C19, and CYP3A4, respectively. TAM secondary metabolism was examined using N-desmethyland 4-hydroxy-TAM as intermediate substrates. N-Desmethyl-TAM was predominantly biotransformed to ␣-hydroxy N-desmethyl-, N-didesmethyl-, and 4-hydroxy N-desmethyl-TAM (endoxifen), whereas 4-hydroxy-TAM was converted to 3,4-dihydroxyTAM and endoxifen. Except for the biotransformation of N-desmethyl-TAM to endoxifen, which was exclusively catalyzed by CYP2D6, all other routes of N-desmethyl-and 4-hydroxy-TAM biotransformation were catalyzed predominantly by the CYP3A subfamily. TAM and its primary metabolites undergo extensive oxidation, principally by CYP3A and CYP2D6 to metabolites that exhibit a range of pharmacological effects. Variable activity of these P450s, brought about by genetic polymorphisms and drug interactions, may alter the balance of TAM effects in vivo.

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“…Indeed, it has been suggested that in some cases of apparently static bone disease, there may actually be some tumour response, in spite of the absence of discernable radiological evidence of healing (Coleman & Rubens, 1987). Although there does appear to be a change in the rate of progression of disease in some patients after dose increases, in our patients, as in the series of Bratherton et al (1984), there was no correlation between serum levels and clinical benefit.…”

mentioning

confidence: 57%

“…Results of attempts to increase response rates by using higher initial doses have been disappointing, (Bratherton et al, 1984;Ortiz de Taranco et al, 1979;Rose et al, 1982) although in one series (Ortiz de Taranco et al, 1979) there were substantially higher rates of stable disease and lower rates of progressive disease in patients receiving 40 mg compared with those on 20 mg daily. Furthermore, there have been occasional case reports of initially responding patients who subsequently relapsed on standard doses of tamoxifen, then going into a second remission when the dose was doubled (Manni & Arafah, 1981;Westerberg et al, 1976).…”

mentioning

confidence: 99%

The value of high dose tamoxifen in postmenopausal breast cancer patients progressing on standard doses: A pilot study

1988

Br J Cancer

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A comparison of two doses of tamoxifen (Nolvadex) in postmenopausal women with advanced breast cancer: 10 mg bd versus 20 mg bd

Cited by 90 publications

References 11 publications

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

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

Comprehensive Evaluation of Tamoxifen Sequential Biotransformation by the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6

The value of high dose tamoxifen in postmenopausal breast cancer patients progressing on standard doses: A pilot study

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