Prevention strategies with aromatase inhibitors.

Goss PE, Strasser-Weippl K.   Clin Cancer Res. 2004 Jan 1;10(1 Pt 2):372S-9S.

Breast Cancer Prevention Program, Princess Margaret Hospital, Medical Oncology, Toronto, Ontario, Canada. pegoss@interlog.com

Aromatase (estrogen synthetase) inhibitors are superior to tamoxifen in terms of both efficacy and toxicity in the treatment of advanced breast cancer and also in the neoadjuvant setting. Recent results from the Arimidex, Tamoxifen, Alone or in Combination adjuvant trial showed a marked reduction in contralateral primary breast cancer with anastrozole, an apparent prevention effect. A similar effect was seen in the MA.17 adjuvant trial comparing letrozole with placebo after 5 years of adjuvant tamoxifen. This has accelerated interest in aromatase inhibitors as primary preventive therapy. Two studies being conducted by the National Cancer Institute of Canada's Clinical Trials Group select women by virtue of mammographic breast density. The International Breast Cancer Intervention Study 2 trial randomizes women at elevated risk to anastrozole or placebo. Because of its steroidal structure, exemestane may be more effective than the nonsteroidal aromatase inhibitors and may protect bone and lipid metabolism from the effects of estrogen ablation. Elevated prostaglandin E2 levels from cyclooxygenase-2 induction by preinvasive and invasive breast lesions increase a number of tumor-promoting pathways, including aromatase, as well as angiogenetic, antiapoptotic, and others. Additive or synergistic effects between celecoxib, a cyclooxygenase-2 inhibitor, and exemestane have been demonstrated and have led to the National Cancer Institute of Canada's Clinical Trials Group MAP.3 trial, which will randomize women at elevated risk to placebo or to exemestane with or without celecoxib. The efficacy and long-term toxicity data from the aromatase inhibitor prevention trials, and the identification of risk profiles from trial results, are awaited with interest.

A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer.

Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL.  N Engl J Med. 2003 Nov 6;349(19):1793-802. Epub 2003 Oct 09.

Division of Hematology-Oncology, Princess Margaret Hospital, Toronto, ON, Canada. pegoss@interlog.com

BACKGROUND: In hormone-dependent breast cancer, five years of postoperative tamoxifen therapy--but not tamoxifen therapy of longer duration--prolongs disease-free and overall survival. The aromatase inhibitor letrozole, by suppressing estrogen production, might improve the outcome after the discontinuation of tamoxifen therapy. METHODS: We conducted a double-blind, placebo-controlled trial to test the effectiveness of five years of letrozole therapy in postmenopausal women with breast cancer who have completed five years of tamoxifen therapy. The primary end point was disease-free survival. RESULTS: A total of 5187 women were enrolled (median follow-up, 2.4 years). At the first interim analysis, there were 207 local or metastatic recurrences of breast cancer or new primary cancers in the contralateral breast--75 in the letrozole group and 132 in the placebo group--with estimated four-year disease-free survival rates of 93 percent and 87 percent, respectively, in the two groups (P< or =0.001 for the comparison of disease-free survival). A total of 42 women in the placebo group and 31 women in the letrozole group died (P=0.25 for the comparison of overall survival). Low-grade hot flashes, arthritis, arthralgia, and myalgia were more frequent in the letrozole group, but vaginal bleeding was less frequent. There were new diagnoses of osteoporosis in 5.8 percent of the women in the letrozole group and 4.5 percent of the women in the placebo group (P=0.07); the rates of fracture were similar. After the first interim analysis, the independent data and safety monitoring committee recommended termination of the trial and prompt communication of the results to the participants. CONCLUSIONS: As compared with placebo, letrozole therapy after the completion of standard tamoxifen treatment significantly improves disease-free survival.

Challenges in the endocrine management of breast cancer.

Mouridsen HT, Rose C, Brodie AH, Smith IE.  Breast. 2003 Aug;12 Suppl 2:S2-19.

Department of Oncology, Rigshospitalet, Copenhagen, Denmark.

The goal of endocrine therapy in breast cancer is to block the action of estrogen on the tumor cells either by inhibiting estrogen from binding to the specific estrogen receptor or by inhibiting its synthesis. Tamoxifen, a selective estrogen receptor modulator, is the standard endocrine treatment for hormone receptor-positive breast cancer, both in the adjuvant and metastatic settings. Tamoxifen inhibits the binding of estrogen to the receptor, resulting in inhibition of hormone action. However, as tamoxifen is also weakly estrogenic, it may not be optimally effective and increases the risk of endometrial cancer and stroke. Furthermore, patients may be refractory or may become resistant to tamoxifen treatment. Since aromatase inhibitors (AI) block the synthesis of estrogen and have no intrinsic estrogenic activity, they have the potential to be more effective than tamoxifen. Their different mechanism of action and chemical structures may also circumvent tamoxifen resistance. Consequently, AIs are currently being evaluated as an alternative to tamoxifen treatment. A preclinical model has recently been developed to compare the efficacy of AIs and antiestrogens in different treatment schemes and to assist in the design of clinical trials. Current studies with the MCF-7Ca xenograft model are exploring the effects of combination and sequential therapy on tumor growth. The efficacy of AIs in the treatment of hormone receptor-positive breast cancer was first demonstrated in five multicenter second-line trials enrolling several hundreds of postmenopausal patients with metastatic breast cancer who had failed tamoxifen treatment. More recently, anastrozole demonstrated efficacy at least equivalent to that of tamoxifen in first-line randomized, phase III clinical trials in postmenopausal women with hormone receptor-positive or unknown metastatic breast cancer, whereas letrozole demonstrated superiority. The steroidal AI exemestane is currently under evaluation. Letrozole is the only AI to have been studied in a randomized, phase III trial in the neoadjuvant setting. In this trial, more patients underwent breast-conserving surgery with letrozole than with tamoxifen. Smaller phase II studies also suggest that both anastrozole and exemestane are active in the neoadjuvant setting. Because neoadjuvant trials permit temporal sampling of breast tissue, substudies in the phase III trial with letrozole have examined the impact of such biomarkers as estrogen receptor, progesterone receptor and epidermal growth factor receptor family members, HER-1 and HER-2, on patient response. AIs are currently under evaluation in the adjuvant setting, and preliminary results of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial have been reported. AIs have proven as safe as tamoxifen in trials in patients with metastatic breast cancer. Ongoing clinical trials in the adjuvant setting include companion studies of end-organ effects, particularly bone metabolism and lipid metabolism evaluations. Quality-of-life assessments are also parts of major clinical trials. A head-to-head quality-of-life assessment of anastrozole compared with letrozole demonstrated patient preference for letrozole. These assessments also clearly indicated the eagerness of patients to participate actively in treatment decisions


Eur J Cancer 2000 Sep 1;36 Suppl 4:81-82

Clinico-pharmacological aspects of different hormone treatments.

Lonning PE

Department of Oncology, Haukeland University Hospital, N-5021, Bergen, Norway

During the last decade, several new drugs and classes of drugs have become available for breast cancer treatment. Thus, in addition to tamoxifen we have got several new selective oestrogen receptor modulators (SERMs) with a partially different pharmacological profile. The first generation aromatase inhibitor, aminoglutethimide, has been replaced by more potent and less toxic inhibitors belonging to the triazole class (anastrozole and letrozole) and, more recently, the steroidal aromatase inactivator exemestane. These drugs have all revealed a better toxicity profile and, in general, an improved antitumour activity, compared with conventional therapy. Faslodex, the first representative of the so-called 'pure' oestrogen antagonists, has shown beneficial effects in patients resistant to tamoxifen [4].

Endocr Relat Cancer 1999 Jun;6(2):231-4

Use of aromatase inhibitors in the adjuvant treatment of breast cancer.

Baum M

Institute of Surgical Studies, University College London, UK.

The value of endocrine treatment of early breast cancer has been illustrated by the antioestrogen, tamoxifen, which has now been available for nearly 30 years. However, if the recognised side effects and pharmacological properties of tamoxifen are taken into consideration, it is possible that other endocrine treatments that are now available can provide equal or superior efficacy, along with improved tolerability. One such group of agents is the aromatase inhibitors specifically the new-generation triazole aromatase inhibitors, such as anastrozole and letrozole, which have both shown tolerability and efficacy advantages over standard treatments in postmenopausal women with advanced breast cancer. There are convincing reasons why the new generation of aromatase inhibitors have advantages over tamoxifen. For instance, from their agonist properties, the effects on the endometrium and tumour stimulation seen with tamoxifen would not be expected, nor would the visual disturbances that have been associated with the triphenylethylene compounds, including tamoxifen.

Endocr Relat Cancer 1999 Mar;6(1):75-92

Use of aromatase inhibitors in breast carcinoma.

Santen RJ, Harvey HA

Department of Medicine, University of Virginia Health Sciences Center, Charlottesville 22908, USA.

Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens to estrogens, is the major mechanism of estrogen synthesis in the post-menopausal woman.  Inhibition of aromatase, the terminal step in estrogen biosynthesis, provides a way of treating hormone-dependent breast cancer in older patients. Aminoglutethimide was the first widely used aromatase inhibitor but had several clinical drawbacks. Newer agents are considerably more selective, more potent, less toxic and easier to use in the clinical setting. This article reviews the clinical data supporting the use of the potent, oral competitive aromatase inhibitors anastrozole, letrozole and vorozole and the irreversible inhibitors 4-OH androstenedione and exemestane. The more potent compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the evidence supporting the notion that aromatase inhibitors lack cross-resistance with antiestrogens and suggest that the newer, more potent compounds may have a particular application in breast cancer treatment in a setting of adaptive hypersensitivity to estrogens. Currently available aromatase inhibitors are safe and effective in the management of hormone-dependent breast cancer in post-menopausal women failing antiestrogen therapy and should now be used before progestational agents. There is abundant evidence to support testing these compounds as first-line hormonal therapy for metastatic breast cancer as well as part of adjuvant regimens in older patients and quite possibly in chemoprevention trials of breast cancer.

Anticancer Drugs 2000 Aug;11(7):591-601

Cost-utility analysis of second-line hormonal therapy in advanced breast cancer: a comparison of two aromatase inhibitors to megestrol acetate.

Dranitsaris G, Leung P, Mather J, Oza A

Department of Pharmacy, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Canada. gdranit@istar.ca

Randomized trials comparing the aromatase inhibitors, anastrozole and letrozole, to megestrol acetate (MA) in postmenopausal women with advanced breast cancer demonstrated that both agents are better tolerated than MA with comparable efficacy. In addition, one trial revealed that tumor response and time to treatment failure were significantly better with letrozole. The model suggested a similar duration of quality-adjusted progression-free survival between drugs (letrozole 150 days, anastrozole 153 days and MA 146 days).

Crit Rev Oncol Hematol 2000 Feb;33(2):137-42

Steroidal aromatase inhibitors in elderly patients.

Bajetta E, Zilembo N, Bichisao E, Pozzi P, Toffolatti L

Division of Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

The choice of treatment for elderly breast cancer patients needs particular care because the presence of physiological functional impairments can modify the drug bioavailability in an unpredictable manner. Hormonal treatment remains one of the choices and, although tamoxifen has proved to be effective in any setting, the use of selective aromatase inhibitors is arousing. Depending on their chemical structure, aromatase inhibitors are either steroidal (such as exemestane and formestane) or non-steroidal (such as letrozole, vorozole and anastrozole). Formestane has been studied in elderly patients with breast cancer and has been found to induce an overall response rate of 51% (95% CI, 35-67%). Formestane has also been demonstrated to be as effective as tamoxifen. Exemestane and non-steroidal aromatase inhibitors appear to be very promising drugs.

Hum Reprod Update 2000 May-Jun;6(3):212-24

A pharmacological review of selective oestrogen receptor modulators.

Goldstein SR, Siddhanti S, Ciaccia AV, Plouffe L Jr

Department of Obstetrics and Gynecology, NYU Medical Center, NY 10016, USA.

Selective oestrogen receptor modulators (SERMs) are structurally diverse non-steroidal compounds that bind to oestrogen receptors and produce oestrogen agonist effects in some tissues and oestrogen antagonist effects in others. SERMs are being evaluated for a number of oestrogen-related diseases, including post-menopausal osteoporosis, hormone-dependent cancers, and cardiovascular disease. Several compounds that exhibit a SERM profile are currently available for clinical use, including clomiphene, tamoxifen, and toremifene (which are triphenylethylenes) and raloxifene (a benzothiophene). Tamoxifen and toremifene are both used to treat breast cancer. Tamoxifen may have beneficial effects on bone mineral density and serum lipids. The effects of toremifene on serum lipids are similar to that of tamoxifen. Both compounds have stimulatory effects on the endometrium. Raloxifene, indicated for the treatment and prevention of post-menopausal osteoporosis, has beneficial effects on bone mineral density and serum lipids, but does not increase the risk of endometrial hyperplasia or endometrial cancer. Recently, raloxifene was shown to reduce the incidence of vertebral fractures in otherwise healthy women with osteoporosis; in the same study, a reduced incidence of breast cancer was also observed. Similar to oestrogens, SERMs increase the incidence of venous thromboembolism.

J Soc Gynecol Investig 2000 Jan-Feb;7(1 Suppl):S38-46

Selective estrogen receptor modulators (SERMs) in clinical practice.

Plouffe L Jr

Eli Lilly and Co., US Medical Endocrine Division, Indianapolis, Indiana, USA.

The objective of this literature review is to familiarize the reader with the clinical data on selective estrogen receptor modulators (SERMs) and antiestrogens currently in use in the US, excluding data on breast effects. Four compounds in the SERM and antiestrogen families are presently in clinical use in the US: clomiphene (CC), tamoxifen (TAM), toremifene (TOR), and raloxifene (RLX). The clinical database on these compounds is among the largest available. Each compound demonstrates a specific profile for its target tissue effects, and this may differ between premenopausal and postmenopausal women. CC is the most widely used agent for ovulation induction. TAM is indicated in the management of breast cancer and for prevention in women at high risk. TAM may have additional effects on the cardiovascular and skeletal systems. TOR also is used for its effects on breast tissue and may have positive cardiovascular effects. RLX is approved in the management of osteoporosis with data supporting favorable effects on the cardiovascular system and breast tissue. TAM and TOR appear to have stimulatory effects on the uterus and endometrium, whereas RLX is neutral. Few adverse events have been attributed to these agents, with hot flashes being the most common one. There appears to be an increased risk of thromboembolic events with continuous use of TAM, TOR, and RLX. SERMs and antiestrogens continue to be studied extensively. Their evolving profiles support key roles for these agents in modern day medicine, particularly in the management of postmenopausal women's health.