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):1644; doi:10.1093/jnci/djm175
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© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Re: Treatment of Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer Xenografts With Multiagent Human Epidermal Growth Factor Receptor–Targeted Therapy
Affiliation of authors: Division of Medical Oncology A, Regina Elena Cancer Institute, Rome, Italy
Correspondence to: Gianluigi Ferretti, MD, PhD, Division of Medical Oncology A, Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy (e-mail: gia.fer{at}flashnet.it).
In the Discussion section of their article, Arpino et al. (1) asserted that the antitumor effect of tamoxifen and human epidermal growth factor receptor (HER) inhibition "was lower when estrogen was present than when estrogen was absent." Estrogen-induced tumor growth is only partially dependent on epidermal growth factor receptor– and HER2-mediated activation of ERK1,2 mitogen-activated protein kinase, whereas that induced by tamoxifen is totally dependent on this pathway (2). With complete HER inhibition, the presence of estrogen may reduce the potency of the estrogen receptor antagonizing activity of tamoxifen in MCF-7/HER2-18 tumors (1). Without HER inhibition, the growth of MCF-7/HER2-18 tumors was completely inhibited by estrogen withdrawal and was stimulated by tamoxifen in the presence of estrogen deprivation (2). Results from several clinical trials (3,4) indicate that, in premenopausal patients, combination treatment with ovarian ablation and tamoxifen may be associated with a better outcome than either treatment alone. However, these findings were observed without any treatment to inhibit HER.
In the same issue of the Journal, Veronesi et al. (5) reported a statistically significant 50%–60% reduction of breast cancers with tamoxifen treatment relative to placebo among women who were using hormone replacement therapy (HRT) at random assignment. In that study, no effect of tamoxifen was observed among women who had had both of their ovaries removed. The findings with HRT must be interpreted with caution, mainly because HRT was not a factor for randomization. In the recent report from the International Breast Cancer Intervention Study I (6), the risk-reducing benefits of tamoxifen prophylaxis were clear only among never and previous users of HRT, with little or no benefit observed among concurrent users. This finding must be regarded as hypothesis generating as well and interpreted with caution. In the Royal Marsden trial (7), concomitant use of HRT had no impact on the benefit of tamoxifen in the posttreatment phase. The effectiveness of combination treatment of HRT and tamoxifen remains open but is currently being addressed in the HRT Opposed to Low-Dose Tamoxifen Study.
Finally, it is not clear why BT474 xenograft tumors, which express estrogen receptor and in which the HER2 gene is naturally amplified, appeared to depend on only the HER pathway for survival, whereas MCF-7/HER2-18 xenograft tumors, which also express estrogen receptors but were stably transfected with HER2 overexpression vector, appeared to depend on both estrogen receptor and HER2 pathways for survival (1). The molecular mechanism of this finding should be the subject of future investigation.
NOTES
Editor's note: The authors of Arpino et al. declined to respond to this Correspondence.
REFERENCES
(1) Arpino G, Gutierrez C, Weiss H, Rimawi M, Massarweh S, Bharwani L, et al. Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J Natl Cancer Inst (2007) 99:694–705.
(2) Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, Schiff R. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER-2/neu crosstalk in ER/HER2-positive breast cancer. J Natl Cancer Inst (2004) 96:926–35.
(3) Klijn JG, Beex LV, Mauriac L, van Zijl JA, Veyret C, Wildiers J, Jassem J, et al. Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst (2000) 92:903–11.
(4) Davidson NE, O'Neill AM, Vukov AM, Osborne CK, Martino S, White DR, et al. Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188). J Clin Oncol (2005) 23:5973–82.
(5) Veronesi U, Maisonneuve P, Rotmensz N, Bonanni B, Boyle P, Viale G, et al. Tamoxifen for the prevention of breast cancer: late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy. In: J Natl Cancer Inst (2007) 99:727–37.
(6) Cuzick J, Forbes JF, Sestak I, Cawthorn S, Hamed H, Holli K, et al. International Breast Cancer Intervention Study (IBIS) I Investigators. Long-term results of tamoxifen prophylaxis for breast cancer—96 month follow-up of the randomized IBIS-I study. J Natl Cancer Inst (2007) 99:272–82.
(7) 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.
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