EDITORIAL

Tamoxifen: Dr. Jekyll and Mr. Hyde?

Daniel F. Hayes

Correspondence to: Daniel F. Hayes, MD, CCGC 6203, 1500 E. Medical Center Dr., Ann Arbor, MI 48109 (e-mail: hayesdf{at}umich.edu)

Without regard to patient selection, other than the eligibility requirements for entry into the studies, worldwide overviews of prospective clinical trials demonstrate that adjuvant tamoxifen reduces the annual odds of death for women with invasive breast cancer by approximately 15% over 10–15 years (1). These data raise the provocative question: Should all patients with invasive breast cancer receive tamoxifen? Application of tamoxifen, irrespective of selection factors, would result in overtreatment of an enormous number of women who would not benefit to ensure the benefits for those who do. Although acceptance of tamoxifen treatment is very high, the ability to measure its target, the estrogen receptor (ER), has permitted application of this drug to those most likely to benefit: patients whose tumors express ER (1,2). Thus, ER is one of the few tumor markers that is recommended for routine clinical use by the American Society of Clinical Oncology (3).

However, tamoxifen is not ideal. Even among women with ER-positive breast cancer, only 40–50% of patients benefit, suggesting that a substantial fraction of ER-positive cancers are resistant to this drug. Moreover, tamoxifen causes both common side effects and occasional life-threatening toxicities (1,4). These observations raise a second question: Why does tamoxifen not seem to work in nearly one-half of women whose tumors appear, at least by ER measurement, to be estrogen dependent?

The answer to this question may be found in an emerging understanding of the biology of the ER and other steroid hormone receptors (5). Preclinical and clinical data over the last 20 years have demonstrated that tamoxifen is not, as originally designated, an "anti-estrogen" (6). Rather, tamoxifen has been designated a "selective estrogen receptor modulator" (SERM). This class of drugs has variable agonistic and/or antagonistic activities, depending on the type of ER (alpha versus beta) and on the coactivator and corepressor milieu in which they bind to the ER (7). Thus, it is possible that, by acting as an agonist within certain hormone-dependent breast cancers, tamoxifen, like Dr. Jekyll, might become a "Mr. Hyde." This hypothesis is supported by in vitro. studies that demonstrate that estrogen- dependent breast cancer cell lines, which are initially growth inhibited by tamoxifen and other SERMs, can become growth dependent on these same agents after long-term exposure to low concentrations (8,9). If these results hold true clinically, then it may be that a major form of resistance to tamoxifen in certain ER-positive cancers occurs because this agent acts as an estrogen, as it does in bone and liver tissue, rather than an anti-estrogen (10).

What is the mechanism of this strange transformation from Jekyll to Hyde? Once again, we turn to emerging biology. Recently published results suggest that breast cancer cell lines may become SERM dependent, in part, by modifying NF-{kappa}B activity and the Fas/Fas ligand system, thus increasing proliferation and decreasing apoptosis (9). In this issue of the Journal, Shou et al. report a series of intriguing laboratory studies that may provide further insight into the phenomenon of tamoxifen duality in hormone-dependent breast cancers (11). They have compared the biology of a HER-2–transfected variant of the most widely used estrogen-dependent human breast cancer cell line, MCF-7, with its HER-2–negative parent, in the setting of estrogen, estrogen depletion, and tamoxifen. HER-2 is one of four transmembrane proteins that belong to the epidermal growth factor receptor (EGFR) family. Three of these four proteins (HER-1, -3, and -4) bind extracellular peptide ligands, all four form homo- or heterodimers, and three of the four (HER-1, -2, and -4) transmit signals through an intra-cytoplasmic tyrosine kinase domain (12). Several retrospective clinical studies have suggested that patients with ER-positive, HER-2–positive breast cancers are less likely to benefit from endocrine therapy than patients with ER-positive, HER-2–negative tumors (13). Embedded within these studies was an observation from one investigation that has often been overlooked or dismissed as artifact: patients with HER-2–overexpressing tumors who were assigned to adjuvant tamoxifen had higher rates of recurrence and mortality than those who did not receive the agent (14,15).

In this regard, Shou et al. (11). have confirmed previously demonstrated phosphorylation "cross-talk" between these very disparate steroid hormone receptor (ER) and peptide growth factor receptor (EGFR) systems (16). [See figure 6 in Shou et al. (11). for a diagrammatic model of current understanding of this cross-talk.] Among other interesting results within this article, there are two important observations. First, in the HER-2–transfected cells, tamoxifen acted like an estrogen agonist by every measure studied. Second, the EGFR inhibitor gefitinib–presumably by inhibiting HER-2–to–ER crosstalk–restored the ER antagonistic properties of tamoxifen. These results are consistent with those of other investigators who have reported enhancement of tamoxifen activity in ER-positive, HER-2–positive cultured cells by treatment with trastuzumab, a monoclonal antibody that binds the extracellular domain of HER-2 (17).

Are these data clinically relevant? All but one of the experiments were performed in a single cultured cell line or its transfected derivative. Thus, the question remains as to whether these results can be extrapolated to other cell lines, and, more important, to the vastly heterogenous clinical situation. Nevertheless, the study has two potential clinical implications. First, recent studies have suggested that newer agents might be more effective than tamoxifen against hormone-dependent breast cancers yet retain (or even improve on) its favorable toxicity profile. Perhaps the most important of these is a class of agents known as aromatase inhibitors (anastrozole, letrozole, and exemestane). These agents prevent the peripheral and tumoral P450 aromatase activity that is required to convert precursors to estradiol, thus depleting estrogen-dependent breast cancers of their required ligand. Clinical investigations have demonstrated that these agents are at least as effective, if not more so, than tamoxifen in both the metastatic and adjuvant settings (1824). Aromatase inhibitors are bereft of toxicities associated with estrogenic activity of tamoxifen and other SERMs, such as increased thrombosis and uterine cancer risk. However, they are clearly associated with problems related to estrogen depletion, including high rates of osteoporosis and bone fracture, which are of major concern in the group of patients most likely to receive them: postmenopausal women (25). Clinicians are therefore faced with the dilemma of choosing between these newer agents and the old standby, tamoxifen, weighing what appears to be modestly higher efficacy and lack of both thrombogenicity and uterine carcinogenesis of the newer agents with the established activity, proven reduction in osteoporosis, and many more women-years of experience of tamoxifen (25).

Given the choice between a SERM or an aromatase inhibitor in the adjuvant setting, the preclinical studies by Shou et al. (11). suggest that one might elect to recommend the latter in patients with ER-positive, HER-2–positive breast cancers to avoid the potential estrogen agonist activity that might be associated with tamoxifen. This concept is far from confirmed. However, it is supported by results from the retrospective clinical study discussed above (14,15). as well as by recently reported preliminary correlative science studies of HER-2 in large randomized clinical trials comparing tamoxifen with anastrozole and tamoxifen with letrozole in both classic and neo-adjuvant settings (26,27).

The second clinical implication of the results of Shou et al. (11). is that clinical trials of the combination of tamoxifen with gefitinib (and perhaps trastuzumab as well) in ER-positive, HER-2–positive breast cancers are justified. If successful, this strategy might provide the antineoplastic benefits of the aromatase inhibitors but retain the bone-sparing effect of the SERMs. Results from three phase II studies of single-agent gefitinib in unselected patients with metastatic breast cancer have been generally disappointing using classic phase II criteria for "success" (2830). However, in each study, a few objective responses or disease stabilizations were observed. Coupled with recent reports that, in non–small-cell lung cancer, responses to gefitinib were seen almost exclusively in patients with apparent activating mutations in EGFR (31,32). the results by Shou et al. (11). suggest that this drug may yet have a role in the treatment of breast cancer, if we can be clever about its use.

Like Dr. Jekyll, tamoxifen has clearly contributed immensely to the well-being of patients. Like Mr. Hyde, cloaked in the disguise of an agonist rather than an antagonist for its receptor, it may also have harmed some. It is imperative that we now take advantage of the advances in understanding of the biology of these two receptor systems to efficiently select optimal treatment and even further reduce mortality of patients with breast cancer. These steps can be taken only by conducting well-designed clinical trials founded in translational science, such as the study reported by Shou et al. (11).

NOTES

See "Notes" following "References."

Supported by a grant from the National Institutes of Health RO1 CA092461 and by Fashion Footwear Foundation/QVC Presents Shoes on Sale. The author receives research funding from AstraZeneca, maker of gefitinib, tamoxifen, and anastrozole. He receives occasional honoraria from Pfizer (maker of exemestane), Novartis (maker of letrozole), and Genentech (maker of trastuzumab).

REFERENCES

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

2 McGuire WL. Estrogen receptors in human breast cancer. J Clin Invest 1973;52:73–7.[ISI][Medline]

3 Bast RC, Jr, Ravdin P, Hayes DF, Bates S, Fritsche H, Jr, Jessup JM, et al. 2000 Update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001;19:1865–78.[Abstract/Free Full Text]

4 Osborne CK. Tamoxifen in the treatment of breast cancer. New Engl J Med 1998;33:1609–18.[CrossRef]

5 Li X, O'Malley BW. Unfolding the action of progesterone receptors. J Biol Chem 2003;278:39261–4.[Free Full Text]

6 Tormey DC, Simon RM, Lippman ME. Evaluation of tamoxifen dose in advanced breast cancer: a progress report. Cancer Treat Rep 1976;60:1451.[ISI][Medline]

7 Gustafsson JA. Therapeutic potential of selective estrogen receptor modulators. Curr Opin Chem Biol 1998;2:508–11.[CrossRef][ISI][Medline]

8 Osborne CK, Jarman M, McCague R, Coronado EB, Hilsenbeck SG, Wakeling AE. The importance of tamoxifen metabolism in tamoxifen-stimulated breast tumor growth. Cancer Chemother Pharmacol 1994;34:89–95.[CrossRef][ISI][Medline]

9 Liu H, Lee E-S, Gajdos C, Pearce S, Chen B, Osipo C, et al. Apoptotic action of 17B-estradiol in raloxifene-resistant MCF-7 cells in vitro and in vivo. J Natl Cancer Inst 2003;95:1586–97.[Abstract/Free Full Text]

10 MacGregor JI, Jordan VC. Basic guide to the mechanisms of antiestrogen action. Pharmacol Rev 1998;50:151–96.[Abstract/Free Full Text]

11 Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, et al. 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.[Abstract/Free Full Text]

12 Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127–37.[CrossRef][ISI][Medline]

13 Yamauchi H, Stearns V, Hayes DF. When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer. J Clin Oncol 2001;19:2334–56.[Abstract/Free Full Text]

14 Carlomagno C, Perrone F, Gallo C, De Laurentiis M, Lauria R, Morabito A, et al. c-erbB2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases. J Clin Oncol 1996;14:2702–8.[Abstract]

15 De Placido S, De Laurentiis M, Carlomagno C, Gallo C, Perrone F, Pepe S, et al. Twenty-year results of the Naples GUN randomized trial: predictive factors of adjuvant tamoxifen efficacy in early breast cancer. Clin Cancer Res 2003;9:1039–46.[Abstract/Free Full Text]

16 Pietras R, Arboleda J, Reese D, Wongvipat N, Pegram M, Ramos L, et al. HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene 1995;10:2435–46.[ISI][Medline]

17 Witters LM, Kumar R, Chinchilli VM, Lipton A. Enhanced anti-proliferative activity of the combination of tamoxifen plus HER-2-neu antibody. Breast Cancer Res Treat 1997;42:1–5.[CrossRef][ISI][Medline]

18 Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001;19:2596–606.[Abstract/Free Full Text]

19 Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 2000;18:3758–67.[Abstract/Free Full Text]

20 Bonneterre J, Thurlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 2000;18:3748–57.[Abstract/Free Full Text]

21 ATAC Trialists’ Group T. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359:2131–9.[CrossRef][ISI][Medline]

22 Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793–802.[Abstract/Free Full Text]

23 Ingle JN, Suman VJ. Aromatase inhibitors versus tamoxifen for management of postmenopausal breast cancer in the advanced disease and neoadjuvant settings. J Steroid Biochem Mol Biol 2003;86:313–9.[CrossRef][ISI][Medline]

24 Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081–92.[Abstract/Free Full Text]

25 Winer EP, Hudis C, Burstein HJ, Bryant J, Chlebowski RT, Ingle JN, et al. American Society of Clinical Oncology technology assessment working group update: use of aromatase inhibitors in the adjuvant setting. J Clin Oncol 2003;21:2597–9.[Free Full Text]

26 Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Janicke F, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 2001;19:3808–16.[Abstract/Free Full Text]

27 Smith I, Dowsett M, Impact Trialists T. Comparison of anastrozole vs. tamoxifen alone and in combination as neoadjuvant treatment of estrogen receptor-positive operable breast cancer in postmenopausal women: the IMPACT trial [abstract 1]. Breast Cancer Res Treat 2003;82:S6

28 Albain K, Elledge RM, Gradishar WJ, Hayes DF, Rowinsky EK, Hudis C, et al. Open-label, phase II, multicenter trial of ZD1839 (‘Iressa’) in patients with advanced breast cancer. Breast Cancer Res Treat 2002;76:S33.

29 Robertson JFR, Gutteridge E, Cheung K, Owers R, Koehler M, Hamilton L, et al. Gefitinib is active in acquired tamoxifen resistant oestrogen receptor positive and ER negative breast cancer: results from a phase II study. [abstract 23] Proc ASCO 2003;22:7.

30 Baselga J, Albanell J, Ruiz A, Lluch A, Gascon P, Gonzalez S, et al. Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. [abstract 24] Proc ASCO 2003;22:7.

31 Lynch T, Bell D, Sordella R, Gurubhagavatula S, Okimoto R, Brannigan B, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. (April 29, 2004). New Engl J Med 2004;50. (DOI: 10.1056/NEJMoa040938).

32 Paez JG, Janne P, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. (April 29, 2004). Science 2004. (DOI: 10.1126/science. 1099314).


This article has been cited by other articles in HighWire Press-hosted journals:


             
Copyright © 2004 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement