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Activity and Safety of the Antiestrogen EM-800, the Orally Active Precursor of Acolbifene, in Tamoxifen-Resistant Breast Cancer

From the Laval University Medical Research Center and Centre Hospitalier Universitaire de Québec; Hôpital du Saint-Sacrement; Hôpital Laval, Québec City; McGill University; Hôpital Sacré-Coeur; Centre Hospitalier Universitaire de Montréal (CHUM); Hôpital Charles-Lemoyne, Montreal; Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec, Canada

Address reprint requests to Fernand Labrie, MD, Oncology and Molecular Endocrinology Research Center, Laval University Medical Center, 2705 Laurier Blvd, T-3-67, Quebec City, Quebec, G1V 4G2, Canada; E-mail: fernand.labrie{at}crchul.ulaval.ca

	ABSTRACT

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PURPOSE: To determine the efficacy and safety of EM-800 (SCH-57050), the precursor of acolbifene, a new, highly potent, orally active, pure antiestrogen in the mammary gland and endometrium, for the treatment of tamoxifen-resistant breast cancer.

PATIENTS AND METHODS: Forty-three post menopausal/ovariectomized women with breast cancer who had received tamoxifen, either for metastatic disease or as adjuvant to surgery for 1 year, and had relapsed were treated in a prospective, multicenter, phase II study with EM-800 (20 mg/d [n = 21] or 40 mg/d [n = 22] orally).

RESULTS: Thirty-seven patients had estrogen receptor (ER)-positive tumors (>10 fmol/mg; mean, 146 fmol/mg cytosolic protein), three patients had ER-negative/progesterone receptor-positive tumors, and three patients had undetermined ER status. The objective response rate to EM-800 was 12%, with one complete response and four partial responses. Ten patients (23%) had stable disease for 3 months, and 7 patients (16%) had stable disease for 6 months. With a median follow-up of 29 months, median duration of response was 8 months (range, 7 to 71+ months). Treatment with EM-800 was well tolerated. No significant adverse events related to the study drug were observed clinically or biochemically.

CONCLUSION: EM-800 produced responses in a significant proportion of patients with tamoxifen-resistant breast cancer, thus showing that this highly potent, selective estrogen receptor modulator, which lacks estrogenic activity in the mammary gland and endometrium, has incomplete cross-resistance with tamoxifen, thus suggesting additional benefits in the treatment of breast cancer.

	INTRODUCTION

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Although 30% to 40% of patients with advanced breast cancer show an initial response to tamoxifen, the duration of response is usually limited to 12 to 18 months, with subsequent development of resistance to further administration of the antiestrogen [1]. Based on many clinical observations [2–6], and demonstrated in a series of studies performed with human breast cancer cell lines in vitro as well as in vivo with xenografts, it is believed that the loss of positive response to tamoxifen in breast cancer patients is as a result, at least in part, of the intrinsic estrogenic activity of the compound or its metabolites [7–12]. It has also been shown that the inhibitory effect of tamoxifen is limited to the hormone-dependent activation function (AF) of the estrogen receptor, known as AF-2, while this compound does not inhibit the hormone-independent pathway of activation known as AF-1 [13,14]. Therefore, to test the hypothesis that a more specific and potent antiestrogen completely devoid of estrogenic activity in human breast or endometrial carcinoma cells [14–30] would have improved clinical efficacy, we have administered the novel, orally active antiestrogen EM-800 (SCH-57050) to women who had experienced tamoxifen therapy failure.

EM-800 is the precursor of EM-652 [16]. This compound acts as a pure and highly potent antiestrogen in human breast and uterine cancer cells in vitro as well as in vivo in nude mice [15–30]. In fact, EM-800 is the most potent of the known antiestrogens and, to our knowledge, it is the only nonsteroidal antiestrogen shown to have no estrogenic activity either in human Ishikawa endometrial carcinoma cells, as assessed by changes in alkaline phosphatase activity, or in human breast carcinoma cells, as shown in cell proliferation studies [14–16,19,20,23–30]. Moreover, as mentioned above, EM-800 blocks both the AF-1 and AF-2 activities of the estrogen receptor [14], thus potentially decreasing the resistance to hormonal therapy.

The high potency of EM-800 derives in part from the high affinity of its active metabolite (EM-652 [SCH-57068]) for the estrogen receptor (ER) [24,26]. In fact, EM-652 has the highest affinity for ER of any known compound to date, with a low dissociation constant of 0.05 nmol/L. In fact, EM-652 is 1.5- to 3.0-fold more potent than 17 beta-estradiol and diethylstibestrol in displacing [³H]estradiol from the ER in human breast cancer and normal uterine tissue. EM-652 is 200-fold more potent than tamoxifen, and is five-fold more potent than hydroxytamoxifen (the active metabolite of tamoxifen). In comparison to other antiestrogens. EM-800 has also demonstrated high potency in vivo. In a murine model, EM-800 was at least 30-fold more potent than tamoxifen in inhibiting estrogen-stimulated uterine growth. In addition, the maximal inhibitory effect on uterine weight achieved with EM-800 is 2.5-fold greater than the maximum effect achieved with tamoxifen [18].

The clinical potential of an antiestrogen more potent and more specific than tamoxifen is supported by the finding that tamoxifen-resistant human breast cancer cell lines remain sensitive to compounds showing pure antiestrogenic activity on cell proliferation in the mammary gland, under in vitro conditions [10,31–33] and when grown as xenografts in nude mice [12,15,34,35]. This compound has been shown to inhibit human breast cancer tumor growth in nude mice below the inhibition achieved with tamoxifen [15,27,28]. The current phase II study was conducted to assess the activity and safety of EM-800 in patients with tamoxifen-resistant breast carcinoma.

	PATIENTS AND METHODS

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Patients
Forty-two post menopausal or ovariectomized women and one premenopausal woman with tamoxifen-resistant breast cancer were enrolled between March 21, 1996, and June 13, 1997. The study was approved by the institutional review board of each hospital or university, and all patients gave informed consent. Eligible patients had progressive metastatic or locally advanced biopsy-proven or fine needle aspiration-proven inoperable breast cancer that had responded to tamoxifen (complete response [CR] or partial response [PR]) or had remained stable for at least 6 months before progression. Thus, 21 patients had acquired tamoxifen resistance while being treated with tamoxifen for advanced disease. Patients originally treated with adjuvant tamoxifen for at least 1 year after surgery who subsequently progressed either while on tamoxifen (18 patients) or after its discontinuation (four patients) were also eligible. For these 22 patients, differentiation between acquired and de novo tamoxifen resistance could not be made since a possible response before progression cannot be detected. In fact, this tamoxifen resistance could be acquired or existing (de novo) before the start of treatment. Tamoxifen therapy must have been discontinued at least 1 month before initiating treatment with EM-800, unless the investigator judged that the disease was rapidly progressing. Eligible patients could not have received previous treatment for metastatic disease (including systemic cytostatic or hormonal treatment) other than tamoxifen. Adjuvant chemotherapy was allowed but must have been completed 1 year before study entry. Eligible patients had Eastern Cooperative Oncology Group performance status of 2, a life expectancy 6 months, and measurable lesion(s) according to WHO criteria [36]. Tumors had to be ER-positive, progesterone receptor-positive (>10 fmol/mg cytosolic protein or positive by immunocytochemistry), or of unknown status. All patients underwent a baseline staging evaluation. Baseline hematology, clinical chemistry, and urinalysis had to be normal according to the accepted values of each hospital.

Exclusion criteria included cancer other than breast carcinoma (except successfully treated in situ carcinoma of the cervix or skin carcinoma other than melanoma), CNS involvement by cancer, lymphangitic pulmonary metastases, severe infection, and severe liver or kidney disease. Patients with neutropenia or thrombocytopenia unrelated to chemotherapy were also excluded.

Treatment
Patients were treated with a daily oral dose (20 or 40 mg) of EM-800. The drug was administered with 240 mL of tap water in the evening (at bedtime, at least 2 hours after the last meal) for 6 months or until progression or unacceptable toxicity. The first eight patients were treated with 20 mg/d EM-800. Following confirmation by an independent review board of the tolerance and safety of the 20-mg dose in at least four patients treated for at least 1 month, a second group of eight patients were treated with 40 mg/d EM-800. Thereafter, patients were randomly allocated to receive either 20 mg or 40 mg EM-800. Patients and investigators were blinded to the dose level. Patients were to be removed from the study for any of the following: development of serious drug-related adverse event, poor compliance (ie, treatment interruption for 7 consecutive days), or disease progression confirmed on two observations at least 1 month apart.

Evaluation of Response
Tumor response was evaluated according to the WHO criteria [36]. Chest radiography, computed tomography scan of lung for lesions less than 2 cm in diameter, abdominal ultrasound and computed tomography scan of liver (in cases having a positive ultrasound), bone radiography, and isotopic bone scan were performed at start of treatment. In patients with locally advanced disease with no evidence of metastases, these tests were repeated after 6 months of treatment unless the patient developed particular signs or symptoms of progression during the study. If exams were positive for metastases at the start of treatment, the exams were repeated at 1, 3, and 6 months for evaluation of response. Superficial or palpable lesions (cutaneous metastases, lymph nodes) were measured in two dimensions at monthly intervals. Hematology and blood chemistry analysis, as well as urinalysis, were performed at start of treatment, at 1, 2, and 4 weeks, and at monthly intervals thereafter. Vital signs were measured and a tolerability questionnaire was filled out at the same time intervals.

	RESULTS

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Patient and Treatment Characteristics
Forty-three patients were enrolled; 21 patients received 20 mg/d EM-800, and 22 patients received 40 mg/d EM-800. The demographic and baseline clinical characteristics of the patients are shown in Table 1. The median age was 66 years (range, 43 to 86 years). Thirty-seven patients had ER-positive tumors (> 10 fmol/mg cytosolic protein), three patients had ER-negative/progesterone receptor-positive tumors, and three patients were of unknown ER status. The mean ER level was 146 fmol/mg (range, 7 to 686 fmol/mg) in 34 patients for whom a quantitative determination was available. Twenty-two patients had been treated with tamoxifen in the adjuvant setting only, 16 patients had been treated with tamoxifen for advanced metastatic disease only, and five patients had received the antiestrogen both as adjuvant therapy and then for advanced metastatic disease. The median time to relapse from the start of tamoxifen therapy was 34 weeks (range, 5 to 159 weeks).

With respect to any association between response to EM-800 and the disease stage before tamoxifen therapy, four of five (80%) objective tumor responses to EM-800 were observed in patients who had received adjuvant tamoxifen therapy (Table 4). However, when SD is included in the comparison, the proportion of responding patients (improvement or stabilization of disease following EM-800 treatment) was similar between subgroups: six of 22 (27%) patients who had received tamoxifen as adjuvant therapy, and seven of 16 (44%) patients who had received tamoxifen for advanced disease. Both of these subgroups were well balanced with respect to sites of metastases, with 43% of patients in each group having liver or lung metastases.

View this table: [in this window] [in a new window]   Table 5. Summary of Adverse Events Occurring in 10% of Patients at Either Dose Level by WHO Grade

	DISCUSSION

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These results appear superior to those obtained with other antiestrogens or SERMs that have been investigated as salvage therapy in tamoxifen-resistant patients. For example, two large phase II studies of high-dose toremifene in patients with tamoxifen-refractory advanced breast cancer demonstrated objective response rates of only 4% and 5%, thus leading the authors to conclude that there is significant cross-resistance between toremifene and tamoxifen [40,41]. Salvage therapy with raloxifene in 14 patients produced no CR or PR, although five patients (36%) had SD [42].

As mentioned above, these studies performed with fulvestrant have shown an efficacy comparable to the aromatase inhibitor anastrazole in women who had failed endocrine therapy [38,39]. While both acolbifene (EM-652, EM-800) and fulvestrant exert pure antiestrogenic activity in the mammary gland and uterus, the possible advantages of EM-652 are its oral bioavailability and its protective effect on bone loss [16,43]. In addition to its protective effect on bone, the other potential advantages of EM-652 compared to aromatase inhibitors are the observations that aromatase inhibitors do not completely block the stimulatory effect of estrogen precursors on human breast cancer cells (MCF-71S6) [44] and do not prevent the stimulatory effect of the estrogenic steroid androstene-3 beta, 17 beta-diol [45], two effects achieved with EM-652.

The responses to EM-800 observed in the present study, and those observed with fulvestrant, are consistent with the suggestion that progression in patients treated with tamoxifen may be as a result, at least in part, of the partial estrogenic effects of tamoxifen, which can lead to stimulation of the proliferation of breast cancer cells [4–16,23,25–29]. A potentially important mechanism of tamoxifen resistance is related to the finding that tamoxifen does not inhibit the ligand-independent AF-1 activity of ER, whereas EM-800 does [14]. This observation further suggests a possible mechanism by which EM-800 and fulvestrant can induce responses in patients with tamoxifen-refractory tumors.

Consistent with other studies, most responses occurred in patients with bone, lymph node, skin, and breast metastases, whereas no objective tumor response was observed in patients with liver metastases. Others have also documented the unfavorable prognosis of patients with liver metastases [5]. There was, however, no apparent association between EM-800 response and the duration of previous tamoxifen therapy. Although the numbers are small, patients treated with tamoxifen in the adjuvant setting appeared more likely to achieve an objective response to EM-800; the proportion of patients who achieved an objective response or SD was 27% in the patients who had tamoxifen in the advanced disease state compared to 44% in the adjuvant setting. It might be proposed that patients who experienced adjuvant tamoxifen failure may have had less advanced disease than patients who failed to respond to tamoxifen for the treatment of advanced metastatic disease. However, a comparison of these subgroups reveals no major differences in sites of disease. In the two groups, 45% and 38% of patients had liver and/or lung metastases. Moreover, no clear association was observed between best response and the number of sites of progression at the start of EM-800 treatment. Finally, no clear dose-response relationship was observed in this study; two objective responses occurred in the 20-mg, while three were observed in the 40-mg dose group.

The majority of the AEs observed in the present study were mild to moderate in severity and were not considered by the investigators to be related to the study drug. Although nausea and vomiting were considered possibly related to treatment with EM-800, phase I studies performed in normal healthy women showed a similar incidence of nausea and vomiting in the EM-800 and placebo groups (unpublished data). Serious AEs, including grade 3/4 bone and/or muscle pain, nausea, abdominal pain, vomiting, and constipation occurred in a total of nine patients in the 40-mg dose group but were not considered by the investigators to be related to the study drug. These results are consistent with the absence of significant findings in preclinical toxicology studies performed in female rats and monkeys with EM-800 (25 mg/kg body weight), a dose approximately 35-fold higher than the highest dose used in the present study. No toxic effects were observed in animals tested daily for 12 months other than the endocrine changes expected from a pure antiestrogen. EM-800 was also well tolerated in a phase I study in 145 normal postmenopausal women who received daily doses of EM-800 up to 40 mg for up to 14 days. As indicated above, long-term follow-up of patients in the present study who remained on EM-800 therapy for more than 5 years also demonstrates the safety of EM-800 during long-term use. The AEs observed in the present study are not different from those observed in two large studies comparing fulvestrant and anastrozole in a similar category of patients [38,39]. Fulvestrant and anastrozole were also well tolerated, with the most common AEs being nausea, vasodilatation, asthenia, vomiting, and bone pain.

The present data are supported by numerous preclinical studies. In fact, while hormonal therapy of breast cancer was believed to be limited to a tumorostatic action as originally described with tamoxifen [7,8], it has recently been observed that alcobifene (EM-652) achieves the cure of 60% of human breast tumors in nude mice [30]. Probably as a result of a more complete inhibition of the estrogen receptor [14,16,19,20,26], the tumorocidal action of alcobifene is a new paradigm of estrogen blockade. Moreover, alcobifene and fulvestrant not only completely inhibit the stimulatory effect of estradiol on the proliferation of MCF-7/S6 cells but further inhibit cell growth by 80% below basal values [44].

Taken together, these data suggest that EM-800 may improve the rate, quality, and duration of responses in patients with tamoxifen-resistant advanced breast cancer. In addition, given the highly potent antiestrogenic activity, lack of any estrogenic stimulatory effect in the mammary gland and endometrium, as well as the good tolerability demonstrated in preclinical and clinical studies, EM-800 or its active metabolite EM-652 should also be investigated in the neoadjuvant and adjuvant settings and as front-line therapy for metastatic disease. It is reasonable to expect that EM-800 may be more effective than tamoxifen for the front-line treatment of breast and endometrial cancer, and its use should also decrease or eliminate the risk of carcinogenicity associated with the long-term use of tamoxifen [46]. EM-800 has been shown to prevent bone loss in the ovariectomized rat [16,43] and to decrease serum cholesterol and triglycerides in the rat [47].

In conclusion, this orally bioavailable, nonsteroidal SERM having pure and highly potent antiestrogenic activity in the mammary gland has a number of important advantages over all other antiestrogens and should be actively investigated for the treatment of ER-positive breast cancer and other estrogen-sensitive malignancies. Moreover, the characteristics of EM-800 make it an ideal compound for prevention of breast and endometrial cancer because of the potential added benefits in terms of prevention of osteoporosis and cardiovascular disease in postmenopausal women.

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Fernand Labrie, Schering-Plough. Performed contract work within the last 2 years: Fernand Labrie, Schering-Plough.

	Acknowledgment

 
We thank Dr Alain Bélanger for his supervision of the analytic procedures and Dr Luc Deschênes for his clinical implication and advice.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted May 19, 2003; accepted December 9, 2003.

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