Preliminary Experience with Pure Antiestrogens 1

Vol. 7, 4369s-4375s, December 2001 (Suppl.) Clinical Cancer Research 4369s

Anthony Howell z specific estrogenic (agonist) and antiestrogenic (antagonist) ac- CRC Department of Medical Oncology, University of Manchester, tivity, has been the antiestrogen of choice in the clinic for over Christie Hospital, Manchester M20 4BX, United Kingdom 25 years. The biological effects of tamoxifen are mediated primarily by inhibiting the actions of estrogen mediated through its binding to the ER. 3 The antiestrogenic activity of tamoxifen Abstract in the breast has established it as the standard for the treatment Endocrine therapy plays an important role in the man- of all stages of breast cancer. Tamoxifen given for different agement of all stages of breast cancer, and the development durations in an adjuvant setting has been associated with an up of effective endocrine therapies has focused on modifying to 47% reduction in the risk of contralateral breast cancer (2) the response of hormone-sensitive tumors to estrogen. The and a 45% reduction in invasive cancer in patients with ductal most widely used agents are the nonsteroidal antiestrogens carcinoma in situ (3). Furthermore, the prospective evaluation of or selective estrogen receptor (ER) modulators, the class to tamoxifen for the prevention of cancer in high-risk women in which tamoxifen, the standard in terms of antiestrogen ther- the National Surgical Adjuvant Breast and Bowel Project P1 apy, belongs. Tamoxifen is effective in both adjuvant and breast cancer prevention study (4) showed tamoxifen to reduce first-line settings and is now used as prophylactic therapy in the relative risk of invasive cancer by 49% in all age groups. high-risk individuals. However, the partial agonist activity Although these observations have not been confirmed in two of tamoxifen on the uterus, coupled with "tumor flare" and European studies, tamoxifen has been approved by the Food and the development of tamoxifen resistance, has limited its Drug Administration for breast cancer prevention in high-risk therapeutic utility. Attempts to eliminate the partial agonist individuals (5). activity of tamoxifen and increase its potency have led to the Long-term tamoxifen treatment is associated with at least development of fulvestrant (Faslodex), the first in a new two other clinical benefits normally associated with endogenous class of pure antiestrogens, the ER down-regulators. Fulves- systemic estrogen. These are the maintenance of bone density trant has a high affinity for the ER compared with tamox- (6, 7) and the lowering of circulating low-density lipoprotein ifen but has none of the agonist activities of tamoxifen. This cholesterol (8) with a beneficial effect on cardiovascular disease new agent is showing promising clinical activity in the treat- (5, 9), both issues of importance to perimenopausal and postm- ment of advanced breast cancer after tamoxifen therapy. enopausal women. However, tamoxifen is also associated with a Fulvestrant's lack of ER agonist activity may provide a slight increase in the risk of endometrial cancer (4, 9, 10) and as longer duration of response compared with tamoxifen, as it yet unsubstantiated concerns over second malignancies (11). did in a preclinical setting. Fulvestrant has demonstrated These observations are of particular concern when tamoxifen is that it is at least as effective as the third-generation aro- used in an adjuvant setting because patients may be receiving matase inhibitor anastrozole in patients whose disease has therapy for up to 5 years. Tamoxifen is also associated with a relapsed or recurred on prior endocrine therapy and is tumor-stimulatory effect, sometimes seen as a transient flare at currently being evaluated in Phase III trials versus tamox- the start of treatment (12), and perhaps most importantly with ifen for the first-line therapy of advanced breast cancer. the acquisition of "tamoxifen resistance," in which tamoxifen no Future clinical studies will evaluate fulvestrant in adjuvant longer inhibits tumor growth and, in some cases, actually pro- and neoadjuvant settings, together with its optimal sequenc- motes it (13). Antiestrogen therapy is also associated with an ing in relation to tamoxifen and other endocrine therapies. increased incidence of thromboembolic phenomena, including deep-vein thrombosis, pulmonary embolism, and possibly cere- Introduction brovascular events (14, 15). The most common serious adverse Antiestrogen therapy, and tamoxifen in particular, has im- event with tamoxifen is thromboembolism (4). However, de- proved the treatment of all stages of breast cancer over the last spite these negative aspects of tamoxifen therapy, the benefits 3 decades (1). The term "antiestrogen" encompasses all agents for the treatment and prevention of breast cancer are considered that antagonize the physiological effects of the female hormone to substantially outweigh the risks. estrogen or 1713-estradiol. Tamoxifen (Nolvadex), a nonsteroi- Furthermore, the success of tamoxifen in the treatment of dal, triphenylethylene-based antiestrogen (Fig. 1) with tissue- breast cancer has proved invaluable in the search for and development of new antiestrogens that selectively retain the favorable estrogenic and antiestrogenic properties of tamoxifen. In fact, it is the standard against which all new endocrine therapies, in- 1 Presented at the First International Conference on Recent Advances and Future Directions in Endocrine Therapy for Breast Cancer, June 21-23, 2001, Cambridge, MA. 2 To whom requests for reprints should be addressed, at CRC Depart- ment of Medical Oncology, University of Manchester, Christie Hospital, 3 The abbreviations used are: ER, estrogen receptor; SERM, selective Wilmslow Road, Withington, Manchester M20 4BX, United Kingdom. estrogen receptor modulator; ERD, ER down-regulator; PgR, progester- Phone: 44-(0)161-446-8037; Fax: 44-(0)161-446-3299; E-mail: mafia. one receptor; ERE, estrogen response element; ROW, Rest of the parker@ christie-tr.nwest.nhs.uk. World.

Tamoxifen Toremifene Table 1 Preclinical and clinical assessment of new antiestrogens Preclinical in vitro and in vivo assessments ~NM~ ~NMe= 9ER binding 9ER-a and ER-13 transcriptional activation 9 Tumor antagonism 9 Estrogenic activityin breast and uterus 9Activity against tamoxifen-resistant cell lines 9 Estrogenic activityon bone and serum lipids 9 Mechanismof ER activation (coactivators, corepressors, and Cl ligand-independent activity) Clinical assessment Raloxifene Fulvestrant 9Activity as first-line therapy 9Activity in tamoxifen-resistant tumors 9Activity as neoadjuvant and adjuvant therapy 9Activity in prevention o 9 Sideeffect profile 9 Scheduling relative to aromatase inhibitors

Fig. 1 Chemical structures of three different nonsteroidal antiestrogens and fulvestrant. alogues of estradiol (28). ICI 164,384 has been studied extensively in a preclinical setting, but it is the more potent fulvestrant that is being actively studied in clinical trials in patients with breast cancer (25, 26). cluding third-generation aromatase inhibitors, are being and will Fulvestrant is distinguishable from tamoxifen and the other be measured in well-established preclinical and clinical settings SERMs, both pharmacologically and in terms of its molecular as summarized in Table 1. activity. Although both classes of agent mediate their effects through the ER, they differ significantly in their downstream New Antiestrogens effects (Table 2). Binding of estradiol and the nonsteroidal The last decade has seen an upsurge in the activity invested antiestrogens (SERMs) to the estrogen binding sites of the ER in the search for the successor to tamoxifen. The strategies used initiates a series of events, which include dissociation of heat have included the chemical modification of tamoxifen, either by shock proteins and ER dimerization. The dimerization process altering the side chains to produce new tamoxifen analogues facilitates the binding of the ER to specific DNA EREs in the such as toremifene (Ref. 16; Fig. 1), idoxifene (17), droloxifene vicinity of estrogen-regulated genes (30, 31). In addition, many (18), and TAT-59 (19, 20) or by altering the nonsteroidal proteins interact with the receptor to act as corepressors or triphenylethylene ring structure of tamoxifen to produce new coactivators; to further complicate matters, at least 50 transcrip- nonsteroidal ring structures such as the benzothiophene deriva- tional activating factors modulate the effects of estrogen on the tive raloxifene (Fig. 1) and (21, 22) or the benzopyran derivative target gene (32, 33). There are also known to be at least two EM-800 (23). These nonsteroidal antiestrogens have all been ERs, ER-oL and ER-[3 (34-36), which have different tissue classified as SERMs and exhibit mixed tissue-dependent ago- distributions. Both ERs contain two activating functions, AF-1 nist/antagonist activity. None of these nonsteroidal antiestro- and AF-2, both of which are active when estrogen binds to the gens have yet shown any significant advantage over tamoxifen receptors. Neither activating function is active when the benzo- in clinical trials in terms of either efficacy or tolerance (24). thiophene derivative raloxifene binds to the ER, and only AF-2 Also, the possibility of cross-resistance between most of these is inactive when tamoxifen binds to the ER. The latter scenario agents and tamoxifen may limit their potential usefulness in the leads to incomplete attenuation of transcription, with the AF-1 treatment of advanced disease after adjuvant tamoxifen therapy domain allowing selective gene expression to occur. Thus, the (24). Indeed, all of the triphenylethylene tamoxifen analogues, partial agonist activity of tamoxifen is attributed, in part, to its with the exception of toremifene (Fig. 1), have been withdrawn inability to inactivate AF-1. from development for the treatment of breast cancer. The activity of the steroidal antiestrogens such as fulves- Another avenue has been to produce steroidal analogues of trant is very different (Table 2). The steroidal antiestrogens bind estrogen with a bulky side chain at either the 7~ (25-28) or 11 [3 to the ER, but because of their long bulky side chains at the 7o~ position of estradiol (29), which are completely lacking in and 11 [3 positions, receptor dimerization appears to be sterically agonist activity. These agents have been termed "pure" anties- hindered (37). There is evidence that ER turnover is increased trogens and include ICI 164,384, fulvestrant (Faslodex; for- and that nuclear localization is disrupted with a concomitant merly ICI 182,780), and RU 58668. The most advanced of these reduction in the number of detectable ER molecules in the cell in terms of both preclinical and clinical evaluation is the steroi- both in vitro and in vivo (38). This is in marked contrast to the dal compound fulvestrant (Fig. 1; Ref. 28). stable or increased levels of ER expression associated with tamoxifen and its analogues. In vitro and in vivo studies suggest Fulvestrant: Mode of Action that as a consequence of ER down-regulation, ER-rnediated Fulvestrant is one of two steroidal antiestrogens with pure transcription is completely attenuated because fulvestrant inac- antiestrogenic activity developed from a series of 7~-alkyl an- tivates both AF-1 and AF-2, leading to complete suppression of

Table 2 Modes of action of estradiol, tamoxifen, and fulvestrant no effect on overall density in another (43), and are being after binding to the ER investigated further. The absence of estrogenic activity has important consequences for the development of resistance, 1. The natural ligand E binds to the ER with high affinity and which is a major concern during tamoxifen therapy. In vitro dissociates HSP90 studies have demonstrated that tamoxifen-resistant cell lines 2. The E-ER complex homodimerizes and localizes preferentially in the cell nucleus remain sensitive to growth inhibition by fulvestrant (44-46), 3. E-ER homodimer binds to the ERE in the promoter region of whereas cells resistant to fulvestrant exhibit early cross-resis- estrogen-sensitive genes tance to tamoxifen (47). Also, tamoxifen-resistant tumors re- 4. Activation of transcription by ER involves two transcription main sensitive to fulvestrant in vivo (48). Preclinical studies in activation functions, AF-1 and AF-2, of the ER and transcriptional coactivators to stimulate the activity of RNA nude mice have shown fulvestrant to suppress the growth of polymerase II (RNA POL II) established MCF-7 xenografts for twice as long as tamoxifen T (SERMs) and to delay the onset of tumor growth for longer than tamox- 1. T binds to ER with low affinity compared with E and ifen (48). Taken collectively, these data suggest that fulvestrant dissociates HSP90. is a more effective estrogen antagonist than tamoxifen and is 2. T-ER complex homodimerizes and translocates to the cell nucleus. AF-1 but not AF-2 is active. able to produce a longer response in the animal model. More- 3. T-ER dimer binds DNA sequence to ERE in promoter region of over, other animal studies have confirmed the complete absence estrogen-sensitive genes of uterine-stimulating activity and shown fulvestrant to block 4. Transcription of E-responsive gene(s) is attenuated because AF- the uterotrophic action of tamoxifen (27). In ovariectomized, 2 is inactive and the T-ER complex attenuates coactivator binding; partial agonist activity results because AF-1 in T-ER estrogen-treated monkeys, the extent of involution of the endo- complex remains active. metrium was similar in animals treated with fulvestrant and in F (ERD) animals in which estrogen treatment was withdrawn (39). Over- 1. F binds to ER with high affinity and dissociates HSP90 all, these data indicate that the mode of action and the preclinical 2. Rapid degradation of ER triggered by binding effects of fulvestrant are distinct from those of tamoxifen and 3. Reduced rate of dimerization and nuclear localization of F-ER complex the newer SERMs and support the concept that fulvestrant 4. Reduced binding of F-ER to ERE represents a novel type of antiestrogen with clinical potential 5. No transcription of E-responsive genes; because AF-1 and AF-2 and possibly important implications for the endocrine manage- are inactive, no coactivators are recruited ment of breast cancer in terms of the sequencing of steroidal and '~ E, estradiol; HSP, heat shock protein; T, tamoxifen; F, fulves- nonsteroidal antiestrogen therapies. trant.

Clinical Studies The data regarding the clinical potential of fulvestrant in the expression of estrogen-dependent genes. Thus, not only is patients with breast cancer are also encouraging. Administration fulvestrant described as a pure antiestrogen, it is also now of a short-acting, propylene glycol-based formulation of fulves- described as an ERD. trant at doses of 6 or 18 mg daily by i.m. injection for 1 week to postmenopausal breast cancer patients before surgery resulted Preclinical Studies in a reduction in proliferation, as measured by Ki67 labeling The preclinical characteristics of fulvestrant, which define index, and a reduction or absence of expression of ER and PgRs this compound as a "pure" antiestrogen devoid of estrogen-like in ER-positive tumors (26). Treatment with fulvestrant also activity, have been reviewed extensively (28, 39, 40) and pro- resulted in a clinically significant reduction in the expression of vided the first evidence that fulvestrant may offer a potential the estrogen-regulated gene pS2, but this was unrelated to tumor therapeutic advantage over tamoxifen. These characteristics in- ER status. Similar experiments with tamoxifen had produced no clude an affinity for the ER approximately 100 times that of change in ER expression, slightly increased PgR expression, and tamoxifen, the specific absence of estrogen-like activity on the a reduction in the Ki67 labeling index after a median 21 days of uterus both in vitro and in vivo, and the capacity to completely treatment. block the stimulatory activities of both estrogens and antiestro- Although fulvestrant reduced ER expression to almost un- gens with partial agonist activity, such as tamoxifen. For exam- detectable levels, no other changes suggestive of an endocrine- ple, in the rat uterus, in contrast to estradiol and tamoxifen, insensitive phenotype were observed (24). This, coupled with fulvestrant did not induce genes such as calbindin D, insulin-like the absence of changes in Ki67 in ER-negative tumors treated growth factor I, vascular endothelial growth factor, and c-los with fulvestrant, suggests that the effect is the result of antag- and, when administered before estradiol or tamoxifen, it com- onism of estrogen at the ER level. This antiestrogenic effect has pletely blocked the induction of these genes by these agents been confirmed in a study of premenopausal patients scheduled (24). Moreover, fulvestrant has been shown not to block the for hysterectomy for benign gynecological disease who were uptake of [3H]estradiol in the brain, suggesting that fulvestrant randomized to receive either 7 consecutive daily doses of the does not cross the blood-brain barrier (41) and therefore in short-acting formulation of fulvestrant or observation before humans may not cause the hot flushes associated with the surgery. No increase in endometrial thickness was observed in nonsteroidal antiestrogens. The preclinical animal data on the the fulvestrant-treated patients (49), and there was also signifi- effects of fulvestrant on bone density are conflicting, with cantly lower ER expression in the myometrium of the treated reports of reduced cancellous bone volume in one study (42) and group (50).

Median Duration of Response

Fulvestrant 26 months 100 Acetate 9o

7O Fig. 2 Duration of response for fulvestrant versus the progestin megestrol acetate in patients : 9 ...... ~ :~: :::: ::::: :: with tamoxifen-resistant breast cancer [reprinted 5O with the permission of Churchill Livingstone (Harcourt Heath Sciences); Ref. 53].

3O 9 ~ p o.04 I# ~2O 9-,- MA (n =3S) 10 ..... Fulvestmnt (n = 13)

0 6 12 18 24 30 36 Months

In a much larger preoperative study, the antitumor effects tract, suggesting that fulvestrant might have fewer side effects in of single-dose, long-acting fulvestrant have been compared with terms of menopausal symptoms than tamoxifen. Thus, fulves- those of tamoxifen in postmenopausal primary breast cancer trant at the drug concentrations used in this study was effective patients before surgery (51). In this study, 201 patients were as a second-line antiestrogen therapy, supporting a mechanism randomized to receive either fulvestrant over a range of doses of action distinct from tamoxifen. In addition, this Phase II study (50, 125, or 250 mg) administered i.m., tamoxifen administered clearly indicated that fulvestrant was well tolerated. Also, com- p.o. at a dose of 20 mg/day, or a matching tamoxifen placebo for parison with a well-matched historical control group of patients 14-21 days before surgery. A dose-dependent reduction in the treated with the progestin megestrol acetate suggested a longer levels of ER expression was observed across all three doses of duration of response for patients receiving fulvestrant (26 fulvestrant compared with placebo. Also, when the fulvestrant months versus 14 months; Fig. 2; Ref. 53). dose normally used clinically (250 mg) was compared with tamoxifen, there was a significantly greater reduction in the ER Pharmacokinetics index for fulvestrant. A dose-dependent reduction in PgR ex- The pharmacokinetics of multiple-dose fulvestrant admin- pression was also observed after fulvestrant treatment, which istration have been assessed in the Phase II trial described above was greater for all three doses of fulvestrant than for tamoxifen, (25) and more recently in a subset of patients enrolled in a Phase which actually resulted in stimulation of PgR (51) expression. III trial (54). In the Phase II trial, peak levels of fulvestrant At all three doses, fulvestrant reduced proliferation. These data occurred a median of 8-9 days after dosing and then declined, once again provide evidence that fulvestrant acts as an ERD but they were still above the projected therapeutic threshold at with clear antiestrogenic and antiproliferative activity (51). Fur- day 28 (25). Mean Cma x (which occurred on day 7) increased thermore, the effect on PgR provides evidence of a more com- from 10.5 ng/ml during the first month to 12.6 ng/ml at month plete blockade of this ER-dependent pathway compared with 6. The area under the curve had also increased by 47% at 6 tamoxifen, which increases PgR levels as a result of its partial months, suggesting some drug accumulation. In addition, the agonist activity (51). pharmacokinetic properties of single-dose fulvestrant have been The clinical efficacy of fulvestrant has also been demon- investigated in two multicenter randomized trials in postmeno- strated in a small Phase II trial in 19 patients with tamoxifen- pausal patients with either primary (55) or advanced breast refractory disease who received a long-acting monthly i.m. cancer (56), and have been reviewed elsewhere (57). Signifi- injection starting with 100 mg in the first month and increasing cantly, the administration regimen (1 • 5 or 2 • 2.5 ml i.m. to 250 mg for the second and subsequent months in the absence injections) did not appear to alter the pharmacokinetic profile of of local and systemic toxicity. Thirteen patients achieved a fulvestrant (56). clinical benefit, with a median duration of 25 months, with seven patients demonstrating a partial response, and six patients demonstrating stable disease (25, 52). These data clearly con- Phase III Data firmed the lack of cross-resistance with tamoxifen observed in The Phase II second-line and preoperative trials reported preclinical studies. Furthermore, luteinizing hormone and folli- above provided the initiative for two Phase III studies, one in cle-stimulating hormone levels rose after the patients were re- North America and one in Europe, Australia, and South Africa moved from tamoxifen but then reached a plateau, suggesting (ROW), which compared the efficacy and tolerability of fulves- that there is no effect of fulvestrant on the pituitary-hypotha- trant (250 mg) administered once monthly with those of the lamic axis. Hot flushes and sweats were not induced, and no third-generation aromatase inhibitor anastrozole (Arimidex; 1 negative effects were observed on the liver, brain, or genital mg) administered p.o. once daily in postmenopausal women

whose disease had progressed on or after prior endocrine ther- Table 3 Summary of clinical efficacy and side effect profiles of apy (58, 59). The vast majority (>96%) of patients across both fulvestrant and tamoxifen trials had received prior tamoxifen therapy. The North American Clinical activity Tamoxifen Fulvestrant trial was a double-blind trial and recruited patients from 83 Prevention + NDa centers in the United States and Canada, whereas the second Neoadjuvant + + trial was an open-label study conducted principally in Europe Adjuvant + Ongoing Advanced + + and recruited patients from 82 centers. Altogether, 400 and 451 Tamoxifen resistance 0 + patients were analyzed for efficacy in the North American and Agonist activity on uterus + - ROW trials, respectively. The primary end point in both trials Bone density + ? was time to disease progression, with secondary end points Lipids ~ = across both trials that included objective response, duration of Blood-brain barrier + NT response, time to death, tolerability, quality of life, and phar- a ND, not determined; ~, a favorable change; =, no change; NT, macokinetics. not tested. The median time to disease progression was numerically longer with fulvestrant compared with anastrozole for both the North American (5.4 versus 3.4 months) and ROW (5.5 versus 5.1 months) trials but was not statistically significant in either tamoxifen, and preliminary data from two Phase III studies trial. The objective response rates were not significantly differ- show it to be as effective as the third-generation aromatase ent in either trial (17.5% for both arms in the North American inhibitor anastrozole as a second-line endocrine therapy in post- trial and 20.7% versus 15.7% for fulvestrant and anastrozole, menopausal patients who have failed on prior tamoxifen therapy respectively, in the ROW trial). In those patients who re- (58, 59). sponded, median duration of response to fulvestrant and anas- It is well recognized that patients whose disease progresses trozole was 19.3 and 10.5 months, respectively, in the North after responding to tamoxifen can achieve further responses American trial and 14.3 and 14.0 months, respectively, in the with third-generation steroidal (exemestane) and nonsteroidal ROW trial. The clinical benefit rates (defined as complete and (anastrozole and letrozole) aromatase inhibitors, and these are partial responses and disease stabilization lasting -> 24 weeks) currently being investigated as a first-line therapy in metastatic for fulvestrant versus anastrozole were 42.2% versus 36.1% for adjuvant and neoadjuvant settings. Fulvestrant is also being the North American trial and 44.6% versus 45.0% for the ROW investigated in these clinical settings. Thus, fulvestrant not only trial. In both trials, the most frequently reported adverse events provides an alternative to tamoxifen, it also offers the opportu- were gastrointestinal disturbances (e.g., nausea, vomiting, con- nity of a further response, at least equivalent to that of anastro- stipation, and diarrhea): 53.4% and 39.7% of patients suffered zole, in patients who have failed on tamoxifen and has potential from at least one gastrointestinal disturbance in the North Amer- as a subsequent therapy after tamoxifen in an adjuvant setting. ican and ROW trials, respectively. Overall, the incidence of The results of the ongoing Phase III clinical trials are eagerly adverse events was similar for the recipients of anastrozole and awaited, particularly those comparing fulvestrant with tamox- fulvestrant in both trials. The withdrawal rates in the fulvestrant ifen as a first-line therapy in advanced disease and the adjuvant and anastrozole groups were low in both trials, with 2.5% versus studies. 2.6% of patients withdrawing due to an adverse event in the North American trial and 3.2% versus 2.2% of patients withdrawing due to an adverse event in the ROW trial (58, 59). Thus, Open Discussion in both studies, fulvestrant was at least as effective as the Dr. Per Lonning: You mentioned that the 125-rag dose aromatase inhibitor anastrozole, with a longer duration of re- was abandoned early in the trial because of very low response. sponse in the North American trial, confirming fulvestrant as an Now, we have something like 100 patients with evaluable re- effective treatment in postmenopausal patients with advanced sponses to that dose. Now, if you look at general pharmacoki- breast cancer recurring or progressing even after tamoxifen netics about when you give a drug to a population, 95% confi- therapy. Fulvestrant was also well tolerated and is the first dence intervals for the area under the curve is a ratio of 1:4 for antiestrogen reported to be at least as effective as a new gener- a drug with predictable pharmacokinetics. That tells you that if ation aromatase inhibitor. This is of particular significance in you double the dose for a drug, a large number of the patients light of the fact that two trials comparing anastrozole with will get similar drug levels with the two doses. So it's really a tamoxifen in the first-line treatment of breast cancer have shown concern to me that the response rate to the 125-mg dose was that anastrozole to be superior to tamoxifen both in terms of time to low, and I think we really need to see the data, because between progression and in terms of a lower incidence of thromboem- fulvestrant and Arimidex, there could be a benefit in favor of bolic events and vaginal bleeding (60, 61). fulvestrant. It may be by chance. Dr. Kent Osborne: In the American study there are some responses to the lower dose. There are pharrnacokinetic studies Conclusion with those doses of fulvestrant. I don't think the confidence Fulvestrant is clearly the first in a new class of antiestro- intervals are as broad as you might have predicted. You're not gen. This novel steroidal ERD is currently being investigated in having to worry about bioavailability, which is so different in Phase III trials. Its mode of action (Table 2) and clinical efficacy lots of patients, with an i.m. injection. I've asked the pharma- and side effect profile (Table 3) are distinct from those of cokinetics researcher what would happen if you double the dose

even further to 500 mg, which is the dose I favor. He said the Breast and Bowel Project P-1 Study. J. Natl. Cancer Inst. (Bethesda), serum levels would double in the majority of patients. 90: 1371-1388, 1998. Dr. Lonning: The 1:4 ratio with the confidence intervals in 5. Chlebowski, R. T., Collyar, D. E., Somerfield, M. R., et al. American general relates to drugs that are completely absorbed. If you Society of Clinical Oncology technology assessment on breast cancer risk reduction strategies: tamoxifen and raloxifene. J. Clin. Oncol., 17: have drugs with more unpredictable absorption like megestrol 1939-1955, 1999. acetate, you get a 1:10 ratio. I've never seen a drug with a 6. Love, R. R., Mazess, R. B., Barden, H. S., et al. Effects of tamoxifen smaller confidence interval than 1:4. on bone mineral density in postmenopausal women with breast cancer. Dr. Anthony Howell: We published the pharmacokinetics, N. Engl. J. Med., 326: 852-856, 1992. and they're in that British Journal of Cancer paper (Br. J. 7. Bilmoria, M. M., Jordan, V. C., and Morrow, M. Additional benefits Cancer, 74: 300-308, 1996). It did show relatively small con- of tamoxifen for postmenopausal patients. In: V. C. Jordan (ed.), Ta- moxifen: A Guide for Clinicians and Patients, pp. 75-89. Huntington, fidence intervals, and there was also accumulation with time. NY: PRR Inc., 1996. With the first injection you achieved what were thought to be 8. Love, R. R., Newcomb, P. A., Wiebe, D. A., et al. Effects of therapeutic biologically effective levels at that time, or else tamoxifen therapy on lipid and lipoprotein levels in postmenopausal these studies would never have gone on at all. patients with node-negative breast cancer. J. Natl. Cancer Inst. (Bethes- Dr. Osborne: Having granted that, though, I think this da), 82: 1327-1332, 1990. dose issue is a real issue, primarily because of that 125-mg dose. 9. Love, R. R., Wiebe, D. A., Newcomb, P. A., et al. Effects of The fact that there were very few responses tells me that we're tamoxifen on cardiovascular risk factors in postmenopausal women. Ann. Intern. Med., 115: 860-864, 1991. pretty close to the ineffective dose, and we may not be at the 10. Fisher, B., Costantino, J. P., Redmond, C. K., et al. Endometrial optimal dose, particularly in premenopausal women in whom cancer in tamoxifen-treated breast cancer patients: findings from the there is competing estrogen to bind the receptor. So I think it's National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. a very important issue and deserves more study. J. Natl. Cancer Inst. (Bethesda), 86: 527-37, 1994. Dr. Kathleen Pritehard: We can give them a couple of 11. Jordan, V. C., and Morrow, M. Should clinicians be concerned injections at 2-week intervals for the first month. about the carcinogenic potential of tamoxifen? Eur. J. Cancer, 11: Dr. Osborne: I'm just hoping that the insurance companies 1714-1721, 1994. don't read the fine print, because that's what I'm going to do in 12. Plotkin, D., Lechner, J. J., Jung, W. E., et al. Tamoxifen flare in advanced breast cancer. J. Am. Med. Assoc., 240: 2644-2646, 1978. my ad hoc study-give them a double dose at first to get the level 13. Howell, A., Dodwell, D. J., Anderson, H., et al. Response after up there. withdrawal of tamoxifen. Ann. Oncol., 3: 611-617, 1992. Dr. Howell: That was the argument with tamoxifen, obvi- 14. Hendrick, A., and Subramanian, V. P. Tamoxifen and thromboem- ously, to give a loading dose of 40 mg qds. bolism. J. Am. Med. Assoc., 243: 514-515, 1980. Dr. Alan Wakeling: Tell us about that tamoxifen study 15. Lipton, A., Harvey, H. A., and Hamilton, R. W. Venous thrombosis with the loading dose. as a side effect of tamoxifen treatment. Cancer Treat. 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Anthony Howell

Clin Cancer Res 2001;7:4369s-4375s.

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