© 2004 by Oxford University Press
© 2004 Oxford University Press
CORRESPONDENCE |
Re: Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine
Affiliation of authors: Academic Department of Gynecological Oncology, Mauriziano Umberto I° Hospital and Institute for Cancer Research and Treatment of Candiolo, Turin, Italy
Correspondence to: Riccardo Ponzone, MD, PhD, Mauriziano Umberto I° Hospital, Largo Turati 62, 10128 Turin, Italy (e-mail: rponzone{at}mauriziano.it)
Stearns et al. (1) provide convincing evidence on the influence of paroxetine, a selective serotonin reuptake inhibitor (SSRI), in the metabolic pathway of tamoxifen when administered to patients with breast cancer. In particular, they found that paroxetine decreased the plasma concentration of a metabolite they termed endoxifen (4-hydroxy-N-desmethyl-tamoxifen) by inhibiting cytochrome CYP2D6 activity. The authors suggest that endoxifen could be at least as active as 4-hydroxy-tamoxifen, another metabolite that is believed to play a major role in mediating the effects of tamoxifen. Indeed, they found that both metabolites had comparable in vitro anti-estrogenic activity but that endoxifen concentrations were 14-fold higher in the plasma of patients receiving tamoxifen. Paroxetine led to a more pronounced reduction in endoxifen levels in women with a wild-type CYP2D6 genotype than in women with a variant genotype, who had lower endoxifen concentrations irrespective of paroxetine coadministration. Therefore, the authors concluded that pharmacologic (i.e., paroxetine) and genetic (i.e., CYP2D6 variants) factors may influence therapeutic outcomes from tamoxifen treatment.
We fully agree with their cautious final statement that until further data become available, the results of this small study should not alter treatment recommendations. The minimal active dose of tamoxifen is unknown, and although an overview of clinical trials revealed that the conventional dose of 20 mg/day has comparable activity to higher doses of the drug (2), clinical data on the efficacy of lower doses are lacking. It has been shown that, in healthy volunteers, reducing the conventional tamoxifen dose by up to 75% does not affect the concentration of insulin-like growth factor 1, a putative surrogate marker of breast cancer risk (3). Furthermore, tumor expression of Ki-67, a marker of cell proliferation, was reduced in patients with breast cancer who received tamoxifen doses of 1 and 5 mg/day (4). The magnitude of the reduction was not statistically significantly different from that achieved with the conventional dose of 20 mg/day (4). The control of menopause-associated symptoms in breast cancer survivors is important and is an issue that has been greatly understudied. Hormonal remedies have not traditionally been used for breast cancer survivors with menopause-associated symptoms because of the possible risk of inducing cancer recurrence. It is reassuring that clinical data to support such a possible risk are rare (5). Several nonhormonal remedies, including SSRIs, have proven effective in clinical controlled trials, but according to a survey we conducted in Italy, their use is still hampered by disinformation and unjustified concerns expressed by the patients and their doctors (6). Good experimental data, such as those provided by Stearns et al. (1), are essential to understanding the pitfalls of endocrine therapy for breast cancer, but they should not be used to prevent patients from taking drugs that may substantially improve their quality of life.
REFERENCES
1 Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst2003;95:1758–64.
2 Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet1998;351:1451–67.[CrossRef][Web of Science][Medline]
3 Decensi A, Bonanni B, Guerrieri-Gonzaga A, Gandini S, Robertson C, Johansson H, et al. Biologic activity of tamoxifen at low doses in healthy women. J Natl Cancer Inst1998;90:1461–7.
4 Decensi A, Robertson C, Viale G, Pigatto F, Johansson H, Kisanga ER, et al. A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers. J Natl Cancer Inst2003;95:779–90.
5 Biglia N, Gadducci A, Ponzone R, Roagna R, Sismondi P. Hormone replacement therapy in cancer survivors. Maturitas, in press.
6 Biglia N, Cozzarella M, Cacciari F, Ponzone R, Roagna R, Maggiorotto F, et al.. Menopause after breast cancer: a survey on breast cancer survivors. Maturitas2003;45:29–38.[CrossRef][Medline]
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J Natl Cancer Inst 2004 96: 883.
J Natl Cancer Inst 2004 96: 884.
J Natl Cancer Inst 2004 96: 884-885.
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