CORRESPONDENCE

RESPONSE: Re: Playing the Old Piano: Another Tune for Endocrine Therapy

V. Craig Jordan, Clodia Osipo, Dong Cheng, Joan S. Lewis

Affiliation of authors: Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL.

Correspondence to: V. Craig Jordan, OBE, PhD, DSc, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 303 East Chicago Ave., Olson Pavilion Rm. 8258, Chicago, IL 60611 (e-mail: vcjordan{at}northwestern.edu)

The estrogen receptor (ER) has proved to be an excellent target in breast cancer therapeutics (1); however, examination of the simple mathematics of response rates of ER-positive disease to endocrine therapy illustrates that about two-thirds of the patients ultimately benefit from successful target acquisition (Fig. 1). Nevertheless, endocrine therapy through the ER yields diminishing returns. Indeed, Koeberle et al. state that only one in three patients respond to fulvestrant as a third-line therapy with either a partial response or stable disease. So overall, if we focus on the endocrine nonresponsive disease alone through the treatment cascade, only about 10% of the nonresponsive population gets to third-line therapy with stable disease (Fig. 1).



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Fig. 1. Hypothetical response rates of 1000 patients with estrogen receptor (ER)-rich breast cancer. Adjuvant tamoxifen results in a 50% decrease in recurrence-free survival at 15 years. If the recurrent patients are treated with a second-line antihormone therapy, there will be a 40% response rate. When these tumors no longer respond to second-line antihormone therapy, Koeberle et al. note a partial response or stable disease response rate of 30% with fulvestrant. Ultimately, the majority of patients for whom the initial treatment fails are unresponsive to antihormone therapies.

 
Stable disease control is also noted with fulvestrant in laboratory models of phase I and II tamoxifen resistance (2,3), but we suggest that the new complex pharmacology with estrogen and fulvestrant has broader therapeutic implications. We seek to address a series of questions in a systematic manner through a conversation between laboratory and clinical investigators. What can be done to help the patients with ER-rich tumors who fail antihormone therapy? Why does the ER target become subverted (4)? Is the finding that estrogen can reverse the action of fulvestrant in phase II tamoxifen resistance unique? Or is a new principle emerging for all antihormone therapies?

We recently described an ER-rich breast cancer cell line that grows spontaneously in vitro and in athymic mice after years of estrogen deprivation (5). The tumors could be a model for aromatase inhibitor resistance. The cells respond to fulvestrant with growth arrest but not apoptosis (5), and this response could be described as stable disease. In contrast, estradiol causes complete apoptosis within 5 days (5). Remarkably, fulvestrant prevents estrogen-stimulated apoptosis, but rather than producing growth arrest, it returns the cells to vigorous growth. It may be time to consider these laboratory data in a clinical context.

For 30 years, the clinical community has faithfully followed the doctrine of antiestrogenic therapy in breast cancer. Despite the excellent improvements in survivorship noted with adjuvant antihormone therapy (6), we have now probably attained maximal benefit from yesterday's treatment strategy. Laboratory studies illustrate a new understanding of the weaknesses and susceptibilities of antihormone-resistant cancer cells that could be modulated by the ER (4). The knowledge could be harnessed to benefit the majority of patients who do not respond to antiestrogenic treatments. Koeberle et al. state that a 34% stable disease and partial response rate is observed with fulvestrant. As a first step, we suggest a new approach to the treatment of antihormone refractory disease because, after estrogen induces apoptosis, antihormones are once again effective in controlling the growth of residual disease (7). Could a month (or two at the most) of estrogen therapy be used to destroy vulnerable antihormone-resistant breast cancer cells before long-term fulvestrant with perhaps an aromatase inhibitor? A head-to-head comparison with fulvestrant alone seems to be an ideal undertaking for the Swiss Group for Clinical Cancer Research (SAKK). The strategic application of estrogen-induced apoptosis in the antihormone treatment plan might be used to benefit more patients.

REFERENCES

1 Jensen EV, Jordan VC. The estrogen receptor: a model for molecular medicine. Clin Cancer Res 2003;9:1980–9.[Abstract/Free Full Text]

2 Osborne CK, Coronado-Heinsohn EB, Hilsenbeck SG, McCue BL, Wakeling AE, McClelland RA, et al. Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl Cancer Inst 1995;87:746–50.[Abstract]

3 Osipo C, Gajdos C, Liu H, Chen B, Jordan VC. Paradoxical action of fulvestrant on estradiol-induced regression of tamoxifen-stimulated breast cancer. J Natl Cancer Inst 2003;95:1597–607.[Abstract/Free Full Text]

4 Lewis JS, Cheng D, Jordan VC. Targeting oestrogen to kill the cancer but not the patient. British J Cancer. In press 2004.

5 Lewis JS, Cryns V, Jordan VC. Estradiol but not fulvestrant induces apoptosis in a long-term estrogen deprived variant clone of MCF-7 breast cancer cells [abstract 3034]. Proceedings of the 95th Annual Meeting of the American Association for Cancer Research; 2004 Mar 27–31; Orlando, Florida.

6 Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 1998;351:1451–67.[CrossRef][ISI][Medline]

7 Yao K, Lee ES, Bentrem DJ, England G, Schafer JI, O'Regan RM, et al. Antitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res 2000;6:2028–36.[Abstract/Free Full Text]



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