GUJHS. 2003 Aug; Vol. 1, No. 1
Dorothy Alanna Fink*
According the National Cancer Institute (NCI), the incidence of breast cancer has increased over the past twenty years (NCI, 2002). Breast cancer is the second most common cause of cancer mortality in the United States (American Cancer Society, ACS, 2002). In 2003, ACS estimates that approximately 203,500 new cases of invasive breast cancer will be diagnosed among women in the United States, and approximately 40,000 people will die (ACS, 2002). These breast cancer rates are alarming, and in order to combat and treat the disease, researchers have conducted numerous clinical trials to determine the most effective drugs against breast cancer. From lumpectomies to mastectomies, doctors ultimately choose the most effective route of treatment based on the specific stage and how they predict the tumor will respond to treatment based on its molecular characteristics. After surgery or in conjunction with chemotherapy, many patients also take medications that affect their endocrine system. This paper will focus on the hormone therapy for treating breast cancer.
Estrogen and anti-estrogen therapy in breast cancer
The relationship between the endocrine system and breast cancer may not be immediately clear. However, many researchers have studied and reviewed the relationship between estrogen and breast cancer (Jordan, 1994; Thorpe, 1988; Vogel, 1996). In premenopausal woman, estrogen is mainly produced in the ovaries (Miller 1997). Two major roles this hormone has in a woman’s body is to stimulate the reproductive structures and develop secondary sexual characteristics. While estrogen is essential during a woman’s childbearing years, it continues to affect her body throughout her life. In fact, estrogen can significantly affect the health status of postmenopausal women. Instead of preparing a woman’s body to ultimately give birth and create a new life, as a woman ages, estrogen can ultimately promote tumor growth.
The proposed relationship between estrogen and breast cancer resulted in many studies and reviews that focused on the presence of estrogen receptors on breast tumors (Thorpe, 1988; Yamauchi, 1997). Because of this relationship, when treating patients with breast cancer, health care providers determine the hormonal status of the tumor. If estrogen receptors are found on the tumor, they indicate that the tumor is estrogen dependent, which means that the tumor requires estrogen for growth. These tumors are referred to as Estrogen Receptor Positive (ER+) tumors (Thorpe, 1988). If the tumor is deprived of estrogen, it will stop growing. There are two routes that can be taken to prevent the receptors from coming into contact with the estrogen present in a woman’s body (Lipton, 1995). One route is to block the estrogen receptors from estrogen molecules attaching, and the other is preventing estrogen biosynthesis so that ultimately there are not sufficient levels of circulating estrogen to bind to the receptors. Drugs that are referred to as antiestrogens prevent estrogen from locking into the receptors on the tumor, and drugs that decrease levels of estrogen in a woman’s body by blocking the aromatase enzyme are aromatase inhibitors.
First, antiestrogens are competitive inhibitors of estrogen because they compete with estrogen at the binding site. The drug that has been used for many years which uses this antiestrogenic approach is tamoxifen (Machia 2001). Because tamoxifen is similar in structure to estrogen, it competes with estrogen at the binding sites (Jordan 1994). If there are more tamoxifen molecules than estrogen molecules present at the breast tissue, the chances of a tamoxifen molecule attaching to the estrogen binding site is greater than the chances of the estrogen binding to the receptors. As with many drugs, a problem with tamoxifen is that it is very common for resistance to develop (Jordan, 1994; Newby, 1997; Yamauchi, 1997). Additional studies have linked the presence of another receptor, HER2/c-neu, to hormone therapy resistance (Newby, 1997; Yamauchi, 1997). If resistance develops to tamoxifen, women no longer benefit from the antiestrogenic effects of the drug, and ultimately, estrogen will again have the opportunity to bind to receptors on the tumor that are no longer occupied by tamoxifen. Thus, estrogen will promote cancer in the breast because tamoxifen will no longer exhibit its antiestrogenic effects. To combat the potential resistance that develops to tamoxifen, another way to prevent estrogen from binding to its receptors was developed.
The second way to prevent estrogen from binding to its receptors in breast tumors is to actually prevent the formation of estrogen, instead of competing with estrogen at the binding site (Hamilton, 1999; Lipton, 1995; Massamura, 1994; Miller, 1997). These drugs are referred to as aromatase inhibitors because they prevent the formation of estrogen by targeting the aromatase enzyme. If no estrogen is produced, it cannot bind to the receptors and promote tumor growth. Therefore, the tumor is essentially deprived of estrogen.
Inhibiting estrogen synthesis
The ovaries are the primary source of estrogen in premenopausal women, which means they have high concentrations of aromatase in their ovaries (Miller, 1997). In postmenopausal women, fat, muscle, and the adrenal gland produce the androgens that are converted to estrogen via the aromatase enzyme (Novartis 2002, Figure 1). The androgen is called androstenedione (D4-A), and it is converted to estrone (E2 ) in peripheral tissues and subsequently reduced to estradiol (Lipton, 1995). Thus, the aromatase inhibitors prevent the production of estrogen by inhibiting the aromatic ring from forming in the steroid molecule (Miller, 1997). There are Type 1 and Type II Aromatase inhibitors. The Type I inhibitors are also referred to as steroidal inhibitors because they specifically attach to the substrate binding site on the enzyme because of their androgen-like structure (Miller, 1997). Thus, these inhibitors compete at the aromatase enzyme binding site with androstenedione. On the other hand, Type II inhibitors are non-steroidal because they bind competitively to the aromatase enzyme’s heme component of the cytochrome P450 subunit (Miller, 1997).
Early clinical trials of Aromatase Inhibitors
The initial studies of aromatase inhibitors focused on the new drugs as second line hormonal treatment (Hamilton, 1999). In other words, aromatase inhibitors were given to patients only after they developed resistance to the first line antiestrogenic drug tamoxifen.
There are many classes of aromatase inhibitors. Of the first, second, and third generation inhibitors, the third generation non-steroidal competitive aromatase inhibitor, letrozole, has emerged as the most effective aromatase inhibitor with the least side effects.
Table of 1st, 2nd, and 3rd generation inhibitors
The first study of letrozole, which has the trade name Femara, was reported in 1995 in CANCER. When studies of letrozole first began, the drug was compared to other second line aromatase inhibitors such as aminoglutethimide, fadrozole hydrocholoride, and lentaron (Lipton, 1995). These drugs all cause side effects such as a decrease in aldosterone levels, fluctuation of electrolyte balance, androgenic effects, central nervous system toxicity, and adrenal insufficiency (Lipton, 1995). In direct contrast, letrozole did not cause any of these side effects in patients (Lipton, 1995). The adrenal gland was not affected, and cortisol and aldosterone levels were not decreased as they were when the other drugs were administered. Thus, letrozole has the specificity to target the androstenedione (D4-A), which is produced by the adrenal gland, but it does not suppress the other functions of the adrenals (Figure 2). When letrozole is given to patients with breast cancer, they are able to maintain synthesis of the mineralocorticoids and glucocorticoids. Additionally, the first trials of letrozole in the phase I study showed that thyroid function was also not affected (Lipton, 1995).
The phase I studies of letrozole found that within twenty-four hours of taking the medication, the inhibitory effects on estrogen biosythesis were observable (Lipton, 1995). Additionally, serum estrone, estradiol, and estrone sulfate levels decreased, and “reached more than ninety-five percent suppression within two weeks of therapy” (Lipton , 1995).
Following the Phase I studies published in 1995, many more clinical trials have been focused on letrozole. In 1998, a double-blind randomized trial was published that compared letrozole to megestrol acetate, a progestin, as second line therapy for breast cancer (Dombernowsky, 1998). The study, which included five hundred fifty-one patients, found that 2.5 mg of letrozole taken once a day resulted in fewer side effects than those treated with megestrol acetate (Dombernowsky, 1998). In fact, megestrol acetate caused side effects such as edema, weight gain, hypertension, and thromboembolic disease that were not present in patients who took 2.5 mg of letrozole each day (Dombernowsky, 1998). The study also established that the 2.5 mg dose of letrozole resulted in a better response rate than only taking a 0.5 mg dose of letrozole daily.
Another study published in 1998 compared letrozole to aminoglutethimide, which is also an aromatase inhibitor (Gershanovich). The study included five hundred fifty-five patients, and the results of the study concluded that letrozole was more efficient than aminoglutethimide in time to progression, time to treatment failure, and overall survival (Gershanovich, 1998). As with previous studies that were completed on letrozole, this study focused on the aromatase inhibitors as second line drugs.
In the past year, more studies have been published on letrozole. A phase II trial was completed on letrozole versus megestrol acetate (Buzdar, 2001). In contrast to the study in 1998, which found that letrozole was superior to megestrol acetate in terms of overall objective tumor response, this study did not find any significant differences between the two drugs (Buzdar, 2001). However, the study did find that there was a decreased risk of treatment failure and time until disease progression (Buzdar, 2001). Additionally, the adverse side effects of megestrol acetate were also reported (Buzdar, 2001).
Aromatase inhibitors as first line therapy
Most recently, there have been two rapid publications about letrozole versus tamoxifen in the Journal of Clinical Endocrinology published in 2001 (Ellis, 2001; Mouridsen, 2001). Both trials demonstrated that letrozole is superior to tamoxifen as a first line hormone therapy drug. Until this point, every clinical trial conducted supported letrozole as a second line drug. However, there is now evidence that supports the aromatase inhibitor as a first line drug. It is important to note that both of these clinical trials were conducted by separate groups.
Thus, after letrozole was compared to other second line drugs for hormonal therapy of breast cancer, it was also compared to tamoxifen, a first line drug. Although tamoxifen has been the anti hormonal drug of choice for many years, many times women become insensitive to it and therefore must resort to a second line treatment. Thus, if antiestrogenic therapy does not continue to work, and the disease progresses, experimental trials have shown the letrozole is the drug of choice because it has the least side effects and best results.
Once it is established that a tumor is estrogen dependent, the appropriate hormone therapy is given to the patient. However, there are also other receptors that can determine the way a tumor will respond to treatment. When epidermal growth factor receptors are present on the tumor, many studies have demonstrated that the tumor is resistant to tamoxifen (Newby, 1997). Recent studies have also compared letrozole to tamoxifen in patients who have both estrogen receptors and epidermal growth factor receptors. A Phase III randomized trial found that sixty percent of patients responded to letrozole, while thirty-six percent responded to tamoxifen (Ellis, 2001). When the tumors had both the estrogen and epidermal growth factor receptors, the difference in response rates between letrozole and tamoxifen were even greater. In fact, the response percentage was eighty-eight for letrozole and only twenty-one for tamoxifen. Thus, letrozole is not only a more efficient alternative for estrogen receptor tumors, but it is also an alternative to tamoxifen for tumors that express erbB-1 or erB-2.
Letrozole has been discussed as being effective both as a second and first line hormone therapy drug. Recent articles published in the Journal of Clinical Oncology also provide compelling evidence as to why one should choose letrozole over tamoxifen for first line therapy because of the longer time letrozole provides before the disease progresses. However, as discussed earlier, tamoxifen and letrozole work at different levels to prevent estrogen from binding to the receptors on the tumor and promoting growth.
While tamoxifen competitively binds to the receptors, letrozole actually prevents the synthesis of estrogens. Since the two drugs target different pathways and have different mechanisms of action, one may believe that both drugs should be given in combination so that if the letrozole does not stop all estrogen biosynthesis, the tamoxifen will be present to compete with the estrogen at the receptors. Research has been completed that should ultimately discourage one from taking both hormonal therapies during the same time. According to a study published in Clinical Cancer Research, when letrozole and tamoxifen were given to patients in combination, the plasma levels of letrozole decreased (Dowsett, 1999). Thus, it is believed that tamoxifen may promote letrozole metabolizing enzymes that decrease the level of letrozole. Thus, the decreased levels of letrozole could ultimately prevent it from inhibiting tumor progression.
Letrozole is one example of an aromatase inhibitor which offers an alternative route for women with estrogen receptor positive breast cancer instead of the common anti-estrogen approach. Although tamoxifen has been used for years as the first line hormone therapy drug, if more studies are completed that continue to support the superior efficacy of letrozole and other aromatase inhibitors, they may indeed emerge as the first line drugs for primary treatment of ER positive breast cancer in post-menopausal women.
*Georgetown University School of Nursing and Health Studies, 3700 Reservoir Rd. NW, Washington, DC. 20057. firstname.lastname@example.org
American Cancer Society, “What are the key statistics for breast cancer?” http://www.cancer.org/eprise/main/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statistics_for_breast_cancer_5?sitearea=CRI; Internet; Accessed 1 March 2002.
Brodie, Angela M.H., and Vincent C.O. Njar. “Aromatase Inhibitors and Breast Cancer.” Seminars in Oncology 23 (August 1996): 10-20.
Buzdar, A., J. Douma, N. Davidson, R. Elledge, M. Morgan, R. Smith, L. Porter, J. Nabholtz, X. Xiang, and C. Brady. “Phase III, Multicenter, Double-Blind, Randomized Study of Letrozole, an Aromatase Inhibitor, for Advanced Breast Cancer Versus Megestrol Acetate.” Journal of Clinical Oncology 19 (July 2001):3357-3366.
Dombernowsky, P., I. Smith, G. Falkson, R. Leonard, L. Panasci, J. Bellmunt, W. Bezwoda, G. Gardin, A. Gudgeon, M. Morgan, A. Fornasiero, W. Hoffman, J. Michel, T. Hatschek, T. Tjabbes, H.A. Chaudri, U. Hornberger, and P.F. Trunet. “Letrozole, a New Oral Aromatase Inhibitor for Advanced Breast Cancer: Double-Blind Randomized Trial Showing a Dose Effect and Improved Efficacy and Tolerability Compared with Megestrol Acetate.” Journal of Clinical Oncology 16 (February 1998): 453-461.
Dowsett, M, C. Pfister, S.R.D. Johnston, D.W. Miles, S.J. Houston, J.A. Verbeek, H. Gundacker, A.Sioufi, and I.E. Smith. “Impact of Tamoxifen on the Pharmacokinetics and Endocrine Effects of the Aromatase Inhibitor Letrozole in Postmenopausal Women with Breast Cancer.” Clinical Cancer Research 5 (September 1999): 2338-2343.
Ellis, Matthew J., Andrew Coop, Baljit Singh, Louis Mauriac, Antonio Llombert-Cussac, Fritz Janicke, William R. Miller, Dean B. Evans, Margaret Dugan, Carolyn Brady, Erhard Quebe-Fehling, and Mike Borgs. “Letrozole is More Effective Neoadjuvant Endocrine Therapy than Tamoxifen for Erb-1- and/or Erb-2-Positive, Estrogen Receptor-Positive Primary Breast Cancer: Evidence From a Phase III Randomized Trial.” Journal of Clinical Oncology 19 (September 2001): 3808-3816.
Gershanovich, M., H.A. Chaudri, D. Campos, H. Lurie, A. Bonaventura, M. Jeffrey, F. Buzzi, I. Bodrogi, H. Ludwig, P. Reichardt, N. O’Higgins, G. Romieu, P. Friederich, and M. Lassus. “Letrozole, a new oral aromatase inhibitor: Randomised trial comparing 2.5mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer.” Annals of Oncology 9 (June 1998): 639-645.
Hamilton, A., and M. Piccart. “The third-generation non-steroidal aromatase inhibitors: A review of their clinical benefits in the second-line hormonal treatment of advanced breast cancer.” Annals of Oncology 10 (1999): 377-384.
Ingle, J.N. “Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic interaction in postmenopausal women with metastatic breast cancer.” Clinical Cancer Research 5 (1999): 1642-1649.
Jordan, V. Craig. “Molecular Mechanisms of Antiestrogen Action in Breast Cancer.” Breast Cancer Research and Treatment 31 (1994): 41-52.
Lamb, Harriet M. and Julie C. Adkins. “Letrozole: A review of its use in postmenopausal women with advanced breast cancer.” Drugs 56 (December 1998): 1125-1140.
Lipton, Allan, Laurence M. Demers, Harold A. Harvey, Kathleen B. Kambic, Howard Grossberg, Carolyn Brady, H. Adlercruetz, Patrick F. Trunet, and Richard J. Santen. “Letrozole: A Phase I Study of a New Potent Oral Aromatase Inhibitor of Breast Cancer.” CANCER 75 (April 1995): 2132-2138.
Machia, Joelle. “Breast Cancer: Risk, Prevention, and Tamoxifen.” American Journal of Nursing 101 (April 2001): 26-35.
Masamura, Shigeru, Herman Adlercreutz, Harold Harvey, Allan Lipton, Laurence M. Demers, Richard J. Santen, and Steven J. Santer. “Aromatase inhibitor development for treatment of breast cancer.” Breast Cancer Research and Treatment 33 (1994): 19-26.
Miller, W.R. “Aromatase Inhibitors and Breast Cancer.” Cancer Treatment Review 23 (1997): 171-187.
Mouridsen, Henning, Mikhail Gershanovich, Yan Sun, Ramon Perez-Carrion, Corrado Boni, Alain Monnier, Justus Appffelstaedt, Robert Smith, Harm P. Sleeboom, Fritz Janicke, Anna Pluzanska, Magdolna Dank, Dominique Becquart, Poonamalle P. Bapsy, Eeva Salminen, Ray Snyder, Mecedes Lassus, J. Arnold Verbeek, Beatrix Staffler, Hilary A. Chaudri-Ross, and Margaret Dugan. “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.” Journal of Clinical Oncology 19 (May 2001): 2596-2606.
National Cancer Institute, “Breaset-U.S. Racial/Ethnic Cancer Patterns.” http://www.nci.nih.gov/cancer_information/doc.aspx?viewid=A738FB64-96F6-483E-AD40-6D61D06ED2E9; Internet; Accessed 1 March 2002.
Newby, Jacqueline C., Stephen R.D. Johnston, Ian E. Smith, and Mitch Dowsett. “Expression of Epidermal Growth Factor Receptor and c-erbB2 during the development of Tamoxifen Resistance in Human Breast Cancer.” Clinical Cancer Research 3 (September 1997): 1643-1651.
Novartis Oncology, “FEMARA: Letrozole Tablets.” http://www.femara.com/; Internet; Accessed 1 March 2002.
Stockler, M., N.R.C. Wilcken, D. Ghersi, and R. John Simes. “Systemic reviews of chemotherapy and endocrine therapy in metastatic breast cancer.” Cancer Treatment Reviews 26 (2000): 151-168.
Thorpe, S.M. “Estrogen and progesterone receptor determinations in breast cancer.” Acta Oncologica 27 (1988): 1-19.
Vogel, Charles. L. “Hormonal approaches to breast cancer treatment and prevention: An overview.” Seminars in Oncology 23 (August 1996): 2-9.
Yamauchi, Hideko, Annie O’Neill, Rebecca Gelman, Walter Carney, Donald Y. Tenney, Silvia Hosch, and Daniel F. Hayes. “Prediction of Response to Antiestrogen Therapy in Advanced Breast Cancer Patients by Pretreatment Circulating Levels of Extracellular Domain of the HER-2/c-neu Protein.” Journal of Cini