EDITORIAL

Is There a Role for Epidermal Growth Factor Receptor Inhibitors in Breast Cancer Prevention?

Gottfried E. Konecny, Cindy A. Wilson, Dennis J. Slamon

Affiliation of authors: David Geffen School of Medicine, University of California at Los Angeles.

Correspondence to: Dennis J. Slamon, MD, PhD, Peter Ueberroth Bldg. 3360B, 10945 Le Conte Ave., University of California, Los Angeles, CA 90095-7077 (e-mail: dslamon{at}mednet.ucla.edu)

Growth and differentiation of both normal and malignant human breast cancer cells are known to be regulated by steroid hormone and peptide growth factor receptors. Among the peptide growth factor receptors frequently implicated in breast cancer are members of the type I receptor tyrosine kinase family, which includes HER1 (epidermal growth factor receptor [EGFR]), HER2 (c-erbB-2), HER3, and HER4. Hetero- and homo-oligomerization of these growth factor receptors results in tyrosine kinase activation, receptor phosphorylation, and subsequent activation of substrates involved in cellular signal transduction. In experimental models (13) and clinical correlative studies (47), it has been shown that the peptide growth factor receptor and steroid hormone receptor pathways are closely linked to one another. Growth factor receptor activation can result in direct phosphorylation and activation of the estrogen receptor (ER) in an estrogen-independent manner and lead to a ligand-independent reduced expression of ER (3). Transfection studies in hormone-sensitive breast cancer cell lines have demonstrated that increased expression of EGFR or HER2 promotes hormone-independent growth (13). Moreover, increased EGFR and HER2 expression has also been associated with acquired tamoxifen resistance in breast cancer cells that were initially hormone-sensitive (8). Importantly, treatment of EGFR- or HER2-transfected breast cancer cells with an EGFR or HER2 inhibitor resulted in the reversal of endocrine resistance and restored the sensitivity toward tamoxifen (911). Thus, breast cancer cells appear to have the capacity to switch between proliferation that is dependent on steroid hormones and proliferation that is dependent on growth factors, depending on whether the later pathway is activated or inhibited. A better understanding of the interaction between the steroid hormone receptor and growth factor receptor pathways will allow us to improve established therapies and develop new concepts for the treatment and prevention of breast cancer.

In the current issue of the Journal, Lu et al. (12) investigate the effect of gefitinib (ZD1839 or Iressa), an orally administered, selective, and reversible inhibitor of the EGFR tyrosine kinase, on the development of ER-negative breast cancer. Their study was intended to provide a preclinical rationale for the development of the EGFR inhibitor gefitinib as a potential preventive of ER-negative human breast cancer.

The concept of breast cancer prevention originally stemmed from the results of large adjuvant tamoxifen trials, many of them carried out by the National Surgical Adjuvant Breast and Bowel Project (NSABP), which showed a statistically significant reduction in contralateral breast cancer (13). With the support of these data, the NSABP began their breast cancer prevention trial (NSABP P-1) to evaluate the role of tamoxifen in reducing the risk of primary invasive breast cancer in women at increased risk of the disease (14). In this study, 13 388 women at increased risk of breast cancer were randomly assigned to 5 years of tamoxifen or placebo. A 49% reduction in invasive breast cancer occurred (175 tumors with placebo versus 89 tumors with tamoxifen); this reduction was mainly among ER-positive tumors (130 such tumors in the placebo group and 41 in the tamoxifen group). The results of more recent trials, such as the Multiple Outcomes of Raloxifene Evaluation (MORE) and the International Breast Cancer Intervention (IBIS) trials confirmed the effectiveness of antiestrogens such as tamoxifen and raloxifene in reducing the risk of breast cancer (15,16). In all of these studies, however, the reduction was confined to ER-positive tumors. It is in this precise situation that gefitinib appears to be specifically suitable for the chemoprevention of ER-negative breast cancer, because increased expression of EGFR or HER2 has been linked to the development of estrogen independence in preclinical experiments (13,8) and in clinical correlative studies (1719).

The current work of Lu et al. (12) demonstrates that gefitinib statistically significantly delayed the formation of ER-negative tumors in an MMTV-c-erbB-2 transgenic mouse model (median time to tumor development was 230 days in untreated mice versus 310 days in treated mice; P<.001). The inhibition of HER2-driven tumor formation by an EGFR inhibitor is, however, somewhat surprising at first glance. Gefitinib is a small molecule inhibitor with specificity for the EGFR tyrosine kinase. Gefitinib inhibits the isolated EGFR and HER2 tyrosine kinase with 50% inhibitory concentrations of 0.033 µM and 3.7 µM, respectively (20). In intact cells, however, HER2 is known to be the preferred co-receptor for EGFR, HER3, and HER4 (21,22). The results of recent studies suggest that gefitinib interferes with HER2 function in intact cells by the formation of inactive unphosphorylated EGFR-HER2 heterodimers (23), which potentially explains the activity of an EGFR inhibitor in a HER2-driven tumor model. HER2 also increases the overall level of activated EGFR by both enhancing its recycling and reducing its internalization. Thus, EGFR inhibitors should be more effective in cells that overexpress HER2 than in cells that do not overexpress HER2, where EGFR recycling is reduced and internalization is enhanced (24).

Lu et al. (12) further demonstrate a strong growth-inhibitory effect of gefitinib in normal human epithelial cells (HMEC and 184) and nontransformed immortal cells (MCF10A and 184B5). The capability of gefitinib to block the proliferation of normal epithelial cells was also confirmed in tissue biopsies of the MMTV-c-erbB-2 transgenic mouse model. Gefitinib treatment resulted in increased expression of the cell cycle inhibitor p27 in normal mammary glands and tumor tissue by 49% and 50%, respectively, resulting in reductions of cell proliferation of 20% and 42% in normal mammary glands and tumor tissue, respectively. The effect of gefitinib on proliferation of normal or precancerous breast cells supports its role as a chemopreventive agent, because it decreases the rate of proliferation in normal epithelial breast cells that are at risk for transformation. However, the mechanisms of a chemopreventive effect of gefitinib could be more complex because the mammary epithelium is organized into two layers, a luminal epithelium and a basal myoepithelial layer. EGFR expression is found predominantly in cells of the basal myoepithelial layer and is much higher in these cells than in the luminal cells (25). The normal mammary epithelial cell lines used in the experiments of Lu et al. display characteristics of basal myoepithelial cells, which express high levels of EGFR and low levels of ER and require EGF for growth in vitro (26). Gefitinib completely inhibited the growth of these normal mammary epithelial cell lines, which suggests that gefitinib may block an early step in the initiation of a subset of hormone-independent breast cancers with a basal myoepithelial phenotype. In addition, gefitinib might also interfere with the initiation of tumors of luminal origin, because EGF signaling appears to play an important role in the regulation of breast epithelial progenitor cells that give rise to both basal myoepithelial and luminal mammary epithelial cells (27,28).

Although the presented preclinical results support the development of gefitinib as a chemopreventive agent, its future development may be challenged by the following two issues. First, the development of tamoxifen as a preventive agent was based on comprehensive efficacy data derived from numerous large adjuvant clinical trials, and development was further supported by extensive information on its short-term and long-term side effects. Comparable efficacy and toxicity data, however, are not yet available for gefitinib. Gefitinib has mostly been studied in non-small-cell lung cancer, where partial responses occurred with oral doses of 250 mg/day in 12.0% of the patients after they had received at least two chemotherapy regimens (29) or in 18.4% of the patients after they had received one or two chemotherapy regimens (30). In breast cancer patients, efficacy data are currently limited to two phase II studies—one that reported one patient with a minor response and three patients with stable disease of more than 6 months among 34 patients with metastatic breast cancer (31) and another that reported two patients with partial responses and three patients with stable disease of more than 6 months among 19 patients with tamoxifen-resistant metastatic breast cancer (32). Thus far, gefitinib has been evaluated in patient populations unselected for the relevance of the EGFR-signaling pathway. However, two other targeted therapies—trastuzumab (Herceptin) and imatinib mesylate (Gleevec)—were assessed in patients with tumors known to overexpress or to express the target that contributed to the malignant phenotype (33,34). It is quite likely that EGFR inhibitors demonstrate antitumor activity for only a subpopulation of patients in whom EGFR is pathogenetically involved in tumor formation or growth. Before we develop gefitinib as a chemopreventive agent, further research is needed to find and validate predictive factors that can be used to identify patients and healthy women likely to respond to gefitinib as a therapeutic and chemopreventive agent.

As a chemopreventive agent, gefitinib would be given to healthy women at risk for the disease most likely over a period of several years. The success of a preventive drug, however, will ultimately be defined by its risk-to-benefit ratio. Gefitinib has been generally well tolerated in the various clinical trials in which it has been tested. Mild (Common Toxicity Criteria-National Cancer Institute grade I/II) adverse events, however, were reported frequently. The most common side effects of gefitinib were rash, pruritus, dry skin, or acneiform rash, which occurred in 62% and 75% of the patients treated with 250 and 500 mg/day, respectively (29). Mild diarrhea occurred in 56% and 70% of the patients at 250 and 500 mg/day, respectively (29). Although these toxicities were generally mild, manageable, noncumulative, and completely reversible with cessation of the drug, these side effects might cause healthy women to stop taking gefitinib as a chemopreventive agent. In addition, a rare but potentially life threatening adverse event—interstitial lung disease—has been reported with the drug. This potential side effect associated with the use of gefitinib is reported to occur in 1%–2% of patients (35). Importantly, the incidence of interstitial lung disease among 23 000 patients in the U.S. expanded access program was reported to be lower [0.3% (36)] and no case of interstitial lung disease was reported in the U.S. phase II study of 216 patients (29). Although interstitial lung disease is a very rare adverse event, its extremely infrequent occurrence may represent an important challenge for the broad use of gefitinib as a chemopreventive agent in healthy women.

We agree with Lu et al. (12) that tyrosine kinase inhibitors are very promising agents to be studied as chemopreventive agents for breast cancer; however, a better understanding of the molecular pathways associated with clinical response would allow a more accurate and targeted selection of women who may maximally benefit from such prevention strategies. This clearly is an important area that merits further study. The preclinical data in the current report underscore the potential importance of this area of translational research.

REFERENCES

1 van Agthoven T, van Agthoven TL, Portengen H, Foekens JA, Dorssers LC. Ectopic expression of epidermal growth factor receptors induces hormone independence in ZR-75-1 human breast cancer cells. Cancer Res 1992; 52: 5082–8.[Abstract]

2 Benz CC, Scott GK, Sarup JC, Johnson RM, Tripathy D, Coronado E, et al. Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 1993; 24: 85–95.[ISI][Medline]

3 Pietras RJ, Arboleda J, Reese DM, Wongvipat N, Pegram MD, 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]

4 Zeillinger R, Kury F, Czerwenka K, Kubista E, Sliutz G, Knogler W, et al. HER-2 amplification, steroid receptors and epidermal growth factor receptor in primary breast cancer. Oncogene 1989; 4: 109–14.[ISI][Medline]

5 Marsigliante S, Muscella A, Ciardo V, Barker S, Leo G, Baker V, et al. Enzyme-linked immunosorbent assay of HER-2/neu gene product (p185) in breast cancer: its correlation with sex steroid receptors, cathepsin D and histologic grades. Cancer Lett 1993; 75: 195–206.[ISI][Medline]

6 Quenel N, Wafflart J, Bonichon F, de Mascarel I, Trojani M, Durand M, et al. The prognostic value of c-erbB2 in primary breast carcinomas: a study on 942 cases. Breast Cancer Res Treat 1995; 35: 283–91.[ISI][Medline]

7 Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 2003; 95: 142–53.[Abstract/Free Full Text]

8 Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JM, Harper ME, et al. Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology 2003; 144: 1032–44.[Abstract/Free Full Text]

9 Kurokawa H, Lenferink AE, Simpson JF, Pisacane PI, Sliwkowski MX, Forbes JT, et al. Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res 2000; 60: 5887–94.[Abstract/Free Full Text]

10 Witters L, Engle L, Lipton A. Restoration of estrogen responsiveness by blocking the HER-2/neu pathway. Oncol Rep 2002; 9: 1163–6.[ISI][Medline]

11 Massarweh S, Shou J, Mohsin SK, Ge M, Wakeling AE, Osborne CK, et al. Inhibition of epidermal growth factor/HER2 receptor signaling using ZD1839 ("Iressa") restores tamoxifen sensitivity and delays resistance to estrogen deprivation in HER2-overexpressing breast tumors [abstract 130]. Proc ASCO 2002; 21: 33a.

12 Lu C, Speers C, Zhang Y, Xu X, Hill J, Steinbis E, et al. Effect of epidermal growth factor receptor inhibitor on development of estrogen receptor-negative mammary tumors. J Natl Cancer Inst 2003; 95: 1825–33.[Abstract/Free Full Text]

13 Fisher B, Redmond C. New perspective on cancer of the contralateral breast: a marker for assessing tamoxifen as a preventive agent. J Natl Cancer Inst 1991; 83: 1278–80.[ISI][Medline]

14 Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90: 1371–88.[Abstract/Free Full Text]

15 Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation [Erratum published in JAMA 1999;282:2124]. JAMA 1999; 281: 2189–97.[Abstract/Free Full Text]

16 Cuzick J, Forbes J, Edwards R, Baum M, Cawthorn S, Coates A, et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet 2002; 360: 817–24.[CrossRef][ISI][Medline]

17 Wright C, Nicholson S, Angus B, Sainsbury JR, Farndon J, Cairns J, et al. Relationship between c-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer. Br J Cancer 1992; 65: 118–21.[ISI][Medline]

18 Nicholson RI, McClelland RA, Gee JM, Manning DL, Cannon P, Robertson JF, et al. Epidermal growth factor receptor expression in breast cancer: association with response to endocrine therapy. Breast Cancer Res Treat 1994; 29: 117–25.[ISI][Medline]

19 Houston SJ, Plunkett TA, Barnes DM, Smith P, Rubens RD, Miles DW. Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer. Br J Cancer 1999; 79: 1220–6.[CrossRef][ISI][Medline]

20 Moulder SL, Yakes FM, Muthuswamy SK, Bianco R, Simpson JF, Arteaga CL. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 2001; 61: 8887–95.[Abstract/Free Full Text]

21 Sliwkowski MX, Schaefer G, Akita RW, Lofgren JA, Fitzpatrick VD, Nuijens A, et al. Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 1994; 269: 14661–5.[Abstract/Free Full Text]

22 Klapper LN, Glathe S, Vaisman N, Hynes NE, Andrews GC, Sela M, et al. The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc Natl Acad Sci U S A 1999; 96: 4995–5000.[Abstract/Free Full Text]

23 Anido J, Matar P, Albanell J, Guzman M, Rojo F, Arribas J, et al. ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells. Clin Cancer Res 2003; 9: 1274–83.[Abstract/Free Full Text]

24 Hendriks BS, Opresko LK, Wiley HS, Lauffenburger D. Quantitative analysis of HER2-mediated effects on HER2 and epidermal growth factor receptor endocytosis: distribution of homo- and heterodimers depends on relative HER2 levels. J Biol Chem 2003; 278: 23343–51.[Abstract/Free Full Text]

25 Santini D, Ceccarelli C, Tardio ML, Taffurelli M, Marrano D. Immunocytochemical expression of epidermal growth factor receptor in myoepithelial cells of the breast. Appl Immunohistochem Mol Morphol 2002; 10: 29–33.[ISI][Medline]

26 Ethier SP. Human breast cancer cell lines as models of growth regulation and disease progression. J Mammary Gland Biol Neoplasia 1996; 1: 111–21.[Medline]

27 Coleman S, Silberstein GB, Daniel CW. Ductal morphogenesis in the mouse mammary gland: evidence supporting a role for epidermal growth factor. Dev Biol 1988; 127: 304–15.[ISI][Medline]

28 Deugnier MA, Faraldo MM, Janji B, Rousselle P, Thiery JP, Glukhova MA. EGF controls the in vivo developmental potential of a mammary epithelial cell line possessing progenitor properties. J Cell Biol 2002; 159: 453–63.[Abstract/Free Full Text]

29 Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003; 290: 2149–58.[Abstract/Free Full Text]

30 Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003; 21: 2237–46.[Abstract/Free Full Text]

31 Baselga J, Albanell J, Ruiz A, Lluch A, Gascon P, Gonzales S, et al. Phase II and tumor pharmacodynamic study of gefitinib (ZD1839) in patients with advanced breast cancer [abstract 24]. Proc ASCO 2003; 22: 7.

32 Robertson JF, Gutteridge E, Cheung KL, Owers R, Koehler M, Hamilton L, et al. Gefitinib (ZD1839) is active in acquired tamoxifen (TAM)-resistant oestrogen receptor (ER)-positive and ER-negative breast cancer: results from a phase II study [abstract 23]. Proc ASCO 2003; 22: 7.

33 Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783–92.[Abstract/Free Full Text]

34 Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–7.[Abstract/Free Full Text]

35 Inoue A, Saijo Y, Maemondo M, Gomi K, Tokue Y, Kimura Y, et al. Severe acute interstitial pneumonia and gefitinib. Lancet 2003; 361: 137–9.[CrossRef][ISI][Medline]

36 AstraZeneca United States. AstraZeneca data on file. Available at: http://www.astrazeneca-us.com/modules/PRMS/display.asp?id=1842629. [Last accessed: November 18, 2003.]



             
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