Journal of the National Cancer Institute Advance Access originally published online on October 30, 2007
JNCI Journal of the National Cancer Institute 2007 99(21):1645-1646; doi:10.1093/jnci/djm178
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© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Responses: Re: Treatment of Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer Xenografts With Multiagent Human Epidermal Growth Factor Receptor-Targeted Therapy
Affiliations of authors: Parkside Oncology Clinic, London, U.K. (TJP); Royal Marsden Hospital, London, U.K. (SA, IES, MD); Institute of Cancer Research, London, U.K. (TJP, IES, MD)
Correspondence to: Trevor J. Powles, PhD, Parkside Oncology Clinic, 49 Parkside, Wimbledon, London SW19 5NB, U.K. (e-mail: hdummer{at}parkside-hospital.co.uk).
The correspondence by Ferretti et al. referring to the paper by Arpino et al. raises important issues related to breast cancer, tamoxifen, and hormone replacement therapy (HRT). The observation in the discussion of Arpino et al. (no data provided) "that the antitumor effect of tamoxifen was lower when estrogen was present than when estrogen was absent" may not be clinically relevant because of the near-complete saturation of the estrogen receptor by tamoxifen and its metabolites (1). This lack of relevance is supported by the clinical evidence. The response of advanced breast cancer to tamoxifen (2) and the relapse and survival for adjuvant tamoxifen (in patients not also receiving chemotherapy) are similar in pre- and postmenopausal women in spite of the very different estrogen levels between these women (3). The reference in Ferretti et al. to the observed increased response by adding tamoxifen to ovarian suppression probably relates to the residual levels of estrogen after ovarian suppression.
In the tamoxifen breast cancer risk reduction setting, HRT used before, at the same time, or after tamoxifen prophylaxis could influence the efficacy of treatment in many ways. When used before tamoxifen, HRT could increase the risk of endocrine-sensitive cancers. When HRT and tamoxifen are used at the same time, there could be a mechanistic interaction between the two. After treatment, HRT could compromise any risk-reduction benefit by tamoxifen. Early risk reduction could for the most part represent treatment of occult disease in which a treatment interaction could be important. The period after treatment may be more important because of the risk that HRT could compromise a true prevention effect of tamoxifen.
In the Royal Marsden trial, we failed to observe a statistically significant breast cancer risk reduction with tamoxifen during the 8-year treatment period but did observe a statistically significant 50% risk reduction with tamoxifen in the posttreatment period that appeared to increase with longer follow-up, indicating a probable true prevention effect by tamoxifen (4). We have therefore now analyzed the tamoxifen risk reduction efficacy with or without HRT before, during, or after the tamoxifen treatment period (Table 1). During the tamoxifen treatment period, the use of HRT was not a factor in causing the failure of tamoxifen to reduce the risk of breast cancer in our trial; other factors, such as the population characteristics, might be involved. Furthermore, we have previously found (5) no evidence of any interaction between HRT and tamoxifen on lipid levels, clotting factors, or changes in bone density in this study. However, it was reassuring that the posttreatment risk reduction that we observed and that indicated true prevention of breast cancer remained unimpaired by use of HRT during or after the treatment period. There was no evidence that use of HRT before tamoxifen prophylaxis increased this tamoxifen preventative effect. Although these results are reassuring in that the tamoxifen risk reduction effect appears to be similar in pre- and postmenopausal women with or without HRT and therefore independent of estrogen levels, caution is needed in interpretation of the data from this trial and the other tamoxifen trials using these retrospective subgroup analyses.
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NOTES
Written informed consent was obtained from each participant in the Royal Marsden trial, and the trial was approved by the Ethics Committee at the Royal Marsden Hospital in 1985 in accordance with U.K. regulations.
Professor Powles is a consultant to the advisory boards of Pfizer and Eli Lilly.
REFERENCES
(1) Dowsett M, Haynes B. Hormonal effects of aromatase inhibitors: focus on premenopausal effects and interaction with tamoxifen. J Steroid Biochem Mol Biol (2003) 86:255–63.[CrossRef][Web of Science][Medline]
(2) Sunderland M, Osbourne C. Tamoxifen in premenopausal patients with metastatic breast cancer: a review. J Clin Oncol (1991) 9:1283–97.[Abstract]
(3) Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet (1992) 339:1–15.[Web of Science][Medline]
(4) Powles TJ, Ashley S, Tidy A, Smith IE, Dowsett M. Twenty year follow up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst (2007) 99:283–90.
(5) Chang J, Powles TJ, Ashley SE, Gregory RK, Tidy VA, Treleaven JG, et al. The effect of tamoxifen and hormone replacement therapy on serum cholesterol, bone mineral density and coagulation factors in healthy women participating in a randomised, controlled tamoxifen prevention study. Ann Oncol (1996) 7:671–5.
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J Natl Cancer Inst 2007 99: 1644.
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