Tamoxifen in premenopausal patients with metastatic breast cancer: a review.

REVIEW ARTICLE

Tamoxifen in Premenopausal Patients With Metastatic Breast Cancer: A Review By Margaret C. Sunderland and C. Kent Osborne The antiestrogen tamoxifen is the most widely used hormonal therapy for breast cancer. The drug exerts its antiproliferative effects primarily through estrogen receptor (ER)-mediated mechanisms, although other cellular actions may augment tumor inhibition. Clinically, tamoxifen has been less well studied in premenopausal than in postmenopausal patients. The drug has complex endocrine effects that are dependent on the treatment duration and dose, menopausal status, and target organ. In postmenopausal women receiving tamoxifen, serum estrogen levels remain low, and the normally elevated gonadotropin levels decrease. In contrast, serum estrogen levels are strikingly elevated in many premenopausal women, and gonadotropin concentrations are either unchanged or slightly increased. Large systematic trials in metastatic breast cancer have established tamoxifen as the recommended hormonal therapy for postmenopausal women with ER-positive tumors. Tamoxifen is also an active

agent for premenopausal metastatic disease, and response rates are comparable to those reported for oophorectomy. Clinical experience with tamoxifen in this younger age group, however, is more limited. Few premenopausal women (< 400) have been included in phase II and phase III trials. Two randomized trials (total of 160 patients) comparing oophorectomy with tamoxifen do not definitively establish therapeutic equivalence, and a survival advantage for either treatment cannot be excluded. Many questions remain concerning the appropriate role for tamoxifen in premenopausal patients. Still, tamoxifen has an attractive toxicity profile, and it offers a favorable therapeutic alternative for premenopausal women with ER-positive metastatic breast cancer who wish to avoid surgical or radiation castration. J Clin Oncol 9:1283-1297. D 1991 by American Society of ClinicalOncology.

INCE THE FIRST report of its efficacy in 1971,' the antiestrogen tamoxifen has become the most widely used hormonal therapy for breast cancer. In early trials, tamoxifen's use was limited to the treatment of metastatic disease in postmenopausal women. Tamoxifen is now the recommended therapy for metastatic disease in postmenopausal women with estrogen receptor (ER)-positive tumors. As clinical experience has accumulated, the indications for tamoxifen have expanded. We now know that, for postmenopausal women with axillary node-positive and ER-positive breast cancer, adjuvant tamoxifen prolongs disease-free survival and improves overall survival

alone, compared with a no-treatment control, to allow a firm conclusion. Whether tamoxifen as a sole adjuvant therapy will prove effective in prolonging survival for premenopausal women with early-stage disease thus requires further study. On the other hand, postoperative chemotherapy does decrease mortality in premenopausal patients, at

rates.

2

For premenopausal women, however, the appropriate role for tamoxifen is not so well defined. In

the treatment of primary breast cancer, adjuvant therapy with tamoxifen has delayed tumor recurrence for node-positive and node-negative pre-

menopausal patients in only a few trials,3" and delaying recurrence has apparently not improved total survival. Indeed, in the recent overview of

adjuvant tamoxifen trials, even a meta-analysis could not establish an effect of tamoxifen on

mortality in premenopausal women.6 Insufficient numbers of younger women (age < 50 years) had been entered on randomized trials of tamoxifen

least in those with node-positive disease, regard7 less of the tumor's hormone receptor status. In premenopausal metastatic disease, the value

of tamoxifen is likewise not clear. Although tamoxifen does have antitumor activity in younger patients, there are few randomized prospective trials

in this group. Premenopausal women were rarely included in the early clinical trials of tamoxifen.

Another endocrine treatment modality, oophorec-

tomy, was already an established, low-morbidity procedure. In addition, there was concern that

high endogenous estrogen levels would inhibit the

From the Division of Oncology, Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX. Submitted August 27, 1990; accepted December 26, 1990. Address reprint requests to C. Kent Osborne, MD, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr,San Antonio, TX 78284-7884. © 1991 by American Society of Clinical Oncology. 0732-183X/91/0907-0006$3.00/0

Journal of Clinical Oncology, Vol 9, No 7 (July), 1991: pp 1283-1297

Downloaded from ascopubs.org by DFG on December 15, 2016 from 130.133.008.114 Copyright © 2016 American Society of Clinical Oncology. All rights reserved.

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SUNDERLAND AND OSBORNE

drug's antiestrogenic action. However, continued use of tamoxifen showed favorable efficacy and such low toxicity that tamoxifen seemed an attractive alternative to oophorectomy. Today, for many physicians, tamoxifen has replaced ovarian ablation as the initial choice for endocrine therapy in premenopausal women with ER-positive metastatic breast cancer. Recently, the Food and Drug Administration approved the use of tamoxifen in this age group. Still, many questions remain concerning the efficacy of tamoxifen for metastatic disease in younger patients. MECHANISMS OF ANTITUMOR ACTION

The study of human breast cancer cells in long-term culture provides valuable insight into the mechanisms of action of estrogens and antiestrogens on breast cancer cell growth. In those cell lines derived from ER-positive breast cancers, the addition of estradiol to the culture medium stimulates cell proliferation; the addition of antiestrogens inhibits cell growth. Antiestrogen inhibition of cell growth is diminished when cells are grown for short periods in the total absence of estrogen, including removal from the culture media of the pH indicator, phenol red, which has weak estrogenlike activity.8 The growth-regulatory role of these hormones in vitro is manifested by a broad spectrum of events. Estrogen induces the activity of key enzymes required for DNA replication9'" and stimulates the synthesis of other cell proteins including progesterone receptor (PgR), plasminogen activator, and a variety of growth factors.H'12 Several polypeptides that stimulate cell proliferation, such as insulin-like growth factor-II (IGF-II),13' 14 trans-

inhibits, whereas the estrogen-ER complex promotes, gene transcription and protein synthesis.23 The degree of tumor-cell inhibition correlates with the affinity of tamoxifen and its active metabolites for ER.2 4 After binding to ER, tamoxifen antago-

nizes many of the cellular events affected by estrogen (Fig 1). Certain biologic actions of tamoxifen cannot be explained by its antiestrogenic properties.2 For example, high doses of tamoxifen in vitro block protein kinase C activation 26'27 and calmodulin activation. '"3 Tamoxifen also disrupts calcium currents across cell membranes, an effect that may influence cellular uptake of antitumor agents.31"32 Microsomal proteins also bind tamoxifen, 333' 4 although the importance and function of these antiestrogen binding sites are not known. Finally, tamoxifen modulates several immunoregulatory effects in vitro. In certain cell culture systems, tamoxifen increases antibody formation,35 inhibits suppressor T-cell lymphocyte activity,36 and enhances natural killer cell activity.37"

The precise subcellular actions for tumor inhibition by tamoxifen remain uncertain. Ultimately, in experimental model systems, tamoxifen slows estrogen-induced growth and leads to a cell-cycle blockade. Tumor cells are prevented from entering late phases of the cell cycle, and cells accumulate in early G,-phase.39 This transition delay through the cell cycle results in a cytostatic and reversible inhibition of cell proliferation rather than a lethal effect.4 Whether antiestrogens exert a cytocidal effect in addition to their cytostatic effect on cell proliferation is controversial. In vitro and in vivo data suggest that the predominant effect is a cytostatic one.3941 However, other studies suggest

5

forming growth factor-alpha (TGF-a)," and platelet-derived growth factor (PDGF)"6,1 7 are found in

a conditioned medium of hormone-responsive cells in culture. Estrogen also decreases the activity of TGF-[3, an inhibitory growth factor of epithelial cells.'8 " 9 The hypothesis that these secreted growth

factors mediate estrogen-induced growth is not proven and, in fact, is questioned by recent studies.20'21 Nevertheless, these growth factors may modulate tumor growth by autocrine or paracrine mechanisms. Antiestrogens, of which tamoxifen is the most well studied, exert their main antiproliferative effects by competing with estrogen for binding to ER proteins.22 Presumably, the drug-ER complex

Growth Inhibited

Fig 1.

Cellular effects of tamoxifen.


TAMOXIFEN IN PREMENOPAUSAL BREAST CANCER

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that antiestrogens may also have lethal effects for

IGF-I levels. A reduction in circulating IGF-I conceivably could contribute to tumor growth inhibition. Similarly, agonist properties of tamoxifen are seen in patients. In tumors from tamoxifentreated patients, PgR levels were higher in a second biopsy taken 2 weeks after starting the drug than pretreatment PgR levels.56 In the clinic, the estrogenic actions of tamoxifen may account for the "tumor flare" experienced by some patients at the start of therapy. Modulation of natural-killer-cell activity also has been reported in patients on tamoxifen.57

some cells.42 ,43

Several aspects of the complex biochemistry and pharmacology of tamoxifen are relevant to a consideration of its efficacy in premenopausal patients. First, the inhibition of estrogen-dependent breast cancer cell growth by tamoxifen is dosedependent. At low concentrations, the inhibitory effects of tamoxifen, mediated through ER, can be completely reversed by estradiol." To preserve the antiestrogenic effect, tamoxifen must be present in a concentration 100 to 1,000 times greater than estradiol, a ratio that emphasizes estradiol's greater affinity for ER.4 5,46At very high concentrations of tamoxifen, the inhibitory effects are not reversible and are probably not mediated through ER.4" Second, although tamoxifen behaves primarily as an estrogen antagonist, it may act as a partial agonist. The dominant effect depends on the concentration of circulating estrogens and tamoxifen, the experimental model system, the species, and the target organ site being studied.48' 49 In cell

cultures, at very low concentrations, tamoxifen may act as an estrogen agonist; PgR synthesis increases, and tumor cells proliferate.",s' Under some conditions, using a specific ER-positive cell line, tamoxifen stimulates tumor growth at concentrations that usually inhibit growth. 52' 53 This paradoxical effect also might be explained by the weak estrogenic properties of tamoxifen. Modulation of the host immune function also may play a role. 53 The complexity of tamoxifen's action is illustrated further in animal models. In the immunedeficient (athymic) mouse, transplanted ERpositive breast cancer cells can be propagated as subcutaneous tumors. In these animals, tamoxifen has an antitumor effect on estradiol-stimulated tumor growth. 54 Uterine weight in tamoxifentreated mice increases simultaneously, a trophic effect that parallels estradiol action.48 Whether results obtained from laboratory models are applicable to humans is speculative. Nonetheless, several interesting biologic effects of tamoxifen are observed in patients. In a recent study, breast cancer patients on tamoxifen had lower levels of insulin-like growth factor-I (IGF-I), a breast cancer mitogen, compared with a control group of patients (P < .01). 55 Low IGF-I values were not associated with age, weight, or menopausal status, and regression analysis indicated that tamoxifen had the strongest association with

CLINICAL PHARMACOLOGY OF TAMOXIFEN

Several compounds have been identified as metabolites of tamoxifen. The major metabolite is N-desmethyltamoxifen; its binding affinity for ER is comparable to that of tamoxifen. 58 Another metabolite, 4-hydroxytamoxifen, is a considerably more potent antiestrogen, binding to ER with even higher affinity than estradiol. Tamoxifen has a long biologic half-life of about 7 days.59 On continuous therapy, steady-state lev-

els of tamoxifen are achieved within 4 weeks, and the drug remains detectable in serum for many weeks after treatment is stopped. When given 40 mg of tamoxifen daily, patients exhibit mean serum levels of 300 ng/mL, but a broad range of drug levels can be seen.' Unfortunately, serum levels of tamoxifen have limited clinical value. In addition to the broad range of normal drug concentrations, serum levels do not correlate with antitumor response."' 6" In a nonrandomized trial, the mean peak concentration of tamoxifen was higher in patients receiving 40 mg/d compared with those receiving 20 mg/d, but serum concentration did not correlate with objective response.6" These results are difficult to interpret because growth inhibition may depend on the local concentrations of tamoxifen and estradiol in the breast cancer cell, as well as serum concentrations. Although one study has examined the concentrations of tamoxifen in tumor tissue,62 actual intracellular concentrations cannot be measured. Even if cellular drug levels were attainable, the optimal tamoxifen/estradiol ratio for tumor growth inhibition has not been established. Our understanding of tamoxifen's pharmacokinetic actions is incomplete. Little is known about the relative contributions of metabolites to tumor inhibition. Furthermore, metabolism of tamoxifen


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specifically in premenopausal women has not been examined in detail. A few young women were included in the pharmacology studies but direct comparisons between menopausal groups were not done. Finally, although isomeric interconversion between trans-tamoxifen (an antiestrogen) and cis-tamoxifen (a weak estrogen) occurs in vitro, little is known about this potentially important pathway in vivo.63 ENDOCRINE EFFECTS

Tamoxifen has complex endocrine effects. Results from many studies suggest that these effects are dependent on age, duration and dose of tamoxifen, menopausal status, and target organ (Table 1). In postmenopausal women, most studies report that the normally elevated gonadotropins, folliclestimulating hormone (FSH), and luteinizing hormone (LH) decrease with tamoxifen therapy, 64al-68 though levels remain in the normal range. Decreased gonadotropin levels persist when measured at 6 months and 12 months of therapy. 69 70

Neither the rate nor the magnitude of change of FSH is associated with disease response to tamoxifen. One study found that FSH returned to pretreatment levels after 1 or 2 months in patients who improved with therapy,7 1 but other studies did not confirm this early observation.

Postmenopausal women on estrogen replacement also show a decline in gonadotropin levels. 72 Thus, tamoxifen may be acting as an estrogen agonist on the hypothalamic-pituitary axis in older women. Studies of gonadotropin secretion in response to gonadotropin-releasing hormone have not helped to define the precise site of action. On continuous tamoxifen therapy, stimulated FSH and LH output is reported to increase,6 6 decrease,6973 or remain unchanged.70 There is general agreement that serum estradiol and progesterone levels are unaffected by tamoxifen in postmenopausal women.65,68,69,71,74,75 One report described a small increase in estradiol in patients whose tumors had failed to respond to tamoxifen. 70 However, this association was not found in other trials. 69'76 In contrast to the endocrine changes induced by tamoxifen in postmenopausal women, quite different effects occur in premenopausal women. Estradiol and progesterone levels show a striking elevation, often to more than two or three times normal.64 69 ' 77 8-0 Powles et a18' reported a mean estradiol increase at 3 months of 700 pmol/L over baseline values. Levels as high as 1,200 pmol/L have been reported in a few patients receiving very high doses of tamoxifen.82 The elevated hormone levels follow a pattern consistent with the normal menstrual cycle. In premenopausal women receiv-

Table 1. Endocrine Effects of Tamoxifen Characteristic Estradiol or estrone Progesterone FSH LH Prolactin Thyroid-stimulating hormone Growth hormone Histology Uterine Vaginal Antithrombin III Thyroxine-binding globulin Steroid hormone-binding globulin Total cholesterol Low-density lipoprotein High-density lipoprotein

Premenopausal Increased No change No change or increased GnRH-stimulated response decreased No change Decreased or no change TRH-induced rise attenuated No change

Prolonged luteal phase and antiprogestin effect Antiestrogen effects Decreased Increased Increased Decreased or no change Decreased Increased or no change

Postmenopausal No change No change Decreased Decreased Decreased or no change No change Decreased

Increased cell maturity Decreased Increased Increased Decreased or no change Decreased Increased or no change

NOTE. See text for explanations and references. Abbreviations: GnRH, gonadotropin-releasing hormone; TRH, thyrotropin-releasing hormone.


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ing concomitant cytotoxic therapy and tamoxifen, elevated levels of serum estradiol also are observed, persisting until onset of ovarian suppression.8 3,84 Despite the supraphysiologic levels of estradiol, FSH and LH are unchanged or only slightly increased from pretherapy levels. 70' 78 's0 85-87 When

chronically elevated, estrogen normally suppresses gonadotropin production. Thus, at high estrogen concentrations, tamoxifen should cause an increase in gonadotropins by decreasing negative feedback. Elevated estrogen levels, independent of gonadotropin secretion, imply that tamoxifen acts directly on the ovary to increase estrogen production. Alternatively, hyperestrogenemia without a corresponding decline in FSH and LH suggests that tamoxifen may block estrogen action at some point(s) in the hypothalamic-pituitary axis. Rather than postulating a direct ovarian effect by tamoxifen, a second possibility is that the increase of estradiol may actually be stimulated by an undetected increase in gonadotropins. Although many investigators have measured gonadotropin levels, the data are inconclusive. The cyclic and pulsatile secretion of FSH and LH is particularly difficult to examine without repeated sampling or pooled sera; monthly measures of gonadotropins are inadequate to detect subtle changes. The antiestrogenic properties of tamoxifen usually are not sufficient to suppress ovarian function. Many patients on long-term tamoxifen therapy continue to have regular ovulation and menstrual cycles. For example, in the adjuvant trial reported by Ribeiro and Swindell,8 premenopausal women were randomized to tamoxifen (20 mg daily) or no further therapy after surgery. In the tamoxifentreated group (n = 199), menstrual cycles remained normal in half the patients. Temporary oligomenorrhea or amenorrhea developed in 28%. After tamoxifen was discontinued, menses returned to normal in all but one patient. The effects of tamoxifen on the pituitary gland also can be examined by measuring prolactin levels at baseline and after stimulation with thyrotropin-releasing hormone (TRH). In normal individuals, prolactin secretion is potentiated by estra8 In premenopausal breast cancer patients diol." on tamoxifen, prolactin levels decrease signifi80 's6or remain unchanged,""' the normal cantly69' prolactin secretory response to TRH or estrogen,

69 is attenuated."'" These observations are consistent with an antiestrogenic effect of tamoxifen on the pituitary. In postmenopausal patients, similar 6 69 7 results are reported. ' ,' Tamoxifen has variable effects on reproductive organs. Premenopausal women show antiestrogenic effects on maturational indices of vaginal epithelium 87'9 and uterine tissue. 9' Endometrial biopsies during the luteal phase also suggest an antiprogestin effect. 80'"'92 In postmenopausal women on tamoxifen, however, estrogenic effects have been noted on vaginal epithelium and endometrial tissue. 9294 Recently, a small but significant increase in endometrial carcinoma was reported among postmenopausal breast cancer patients on longterm tamoxifen. 95' 96 Preliminary results of a recently completed Southwest Oncology Group trial (manuscript in preparation) found that four of 641 patients treated with 1 year of tamoxifen developed endometrial cancer compared with zero of 325 patients treated with chemotherapy. Other tamoxifen adjuvant studies have not yet reported an increased incidence of endometrial cancer, although patient follow-up in these trials is shorter.3 Serum protein changes induced by tamoxifen are similar for premenopausal and postmenopausal patients and reflect the drug's weak estrogenic effects. Levels of antithrombin III, total cholesterol, and low-density lipoprotein decrease with long-term therapy. 81'97, 98 Levels of steroid hormone-binding globulin (SHBG) and thyroxine99 -102 Since SHBG binding globulin often increase.81 ,'" is the major transport protein for estrogenic steroids, increased SHBG levels may lower the plasma concentration of free estradiol. As a result, less estrogen may be available to the breast cancer cell. The contrasting endocrine studies in premenopausal and postmenopausal women suggest that tamoxifen expresses an agonist or antagonist effect on the hypothalamic-pituitary axis depending on the endogenous estrogen levels. Tamoxifen causes a decrease in FSH without changes in estrogen concentrations in postmenopausal women. In premenopausal women, tamoxifen causes an elevation of estrogen levels without gonadotropin suppression. Thus, tamoxifen may act as an agonist when endogenous estrogens are low and may act as an antagonist when circulating estrogens are high. This partial agonist/antagonist hypothesis would explain most of the observed endocrine


1288


effects. The patterns of prolactin secretion and hepatic protein synthesis are the exceptions. In the liver, estrogenic metabolites active on hepatocytes may be quickly conjugated and excreted and thus may not be measurable in serum. These endocrine studies raise important questions about the use of antiestrogens in the treatment of premenopausal women. Clearly, the variable physiologic effects of tamoxifen in patients suggest that the hormonal milieu into which the drug is introduced is important. Theoretically, significant elevations of estradiol in premenopausal women could reverse the inhibitory effect of tamoxifen on breast cancer cells and, thus, decrease antitumor action. Laboratory models, as described earlier, have described this phenomenon (estrogen rescue of tamoxifen inhibition) in vitro and in vivo.8,941 PHASE II CLINICAL TRIALS IN PREMENOPAUSAL PATIENTS

Experience with tamoxifen therapy in premenopausal women is more limited than that acquired in the large, systematic studies of postmenopausal patients. In the recent overview of adjuvant therapy in early breast cancer, premenopausal women represented only 10% of the patients receiving tamoxifen without chemotherapy (1,062 of 10,123 women). 6 Although one trial with brief follow-up has reported that adjuvant tamoxifen is equally effective in pre- and postmenopausal patients, 3 the cumulative data suggest that tamoxifen is somewhat less effective in younger patients.6 Clinical experience with the use of tamoxifen in premenopausal women with metastatic disease also is somewhat limited. Phase II and phase III trials evaluating tamoxifen for metastatic disease include only 366 patients. A few premenopausal patients participated in early clinical trials of tamoxifen, but no single trial had more than seven patients.11°-6 Formal evaluation of tamoxifen's efficacy in premenopausal women began after reports from five groups of investigators in 1976 suggested a 17 potential benefit in these younger patients." "" Since then, seven additional phase II trials have been published 2 '"5 "' 8 (Table 2). The median age of the patients on the phase II trials was 45 years with a range of 29 to 56 years of age. The percentage of women who had received prior adjuvant chemotherapy varied from 0% to

38%, and only three patients had received prior hormonal therapy. The proportion of patients obtaining a complete response or partial response with tamoxifen ranges from 20% to 45%, with a mean response rate of 31% (89 of 285). The response rate increases to 44% (126 of 285) by adding patients with stable disease as the best response to tamoxifen. Metastatic disease in soft tissue or lymph nodes responded more frequently to tamoxifen therapy than did metastatic disease in bone or visceral sites. In three trials, 43% to 60% of patients with predominantly soft tissue disease improved with tamoxifen."16 "1 Few responses were seen among patients with visceral-dominant metastatic disease. These differences may partially reflect (1) the inherent difficulties in assessing response in certain sites and (2) the propensity for ERnegative tumors to metastasize to visceral sites. Most phase II trials also excluded patients with liver metastases. For those patients with known steroid receptor status, a greater likelihood of response was associated with an ER-positive assay. The response rate for patients with both ER-positive and PgRpositive tumors was 45% (14 of 31).86,12,13 In contrast, no patients with ER-negative tumors had disease regression with tamoxifen, although one patient had stable disease."' For premenopausal women, response to tamoxifen is comparable to that of castration. In the older medical literature, response rates of 30% after surgical oophorectomy have been reported."',12 Recent studies using ER and PgR assays to guide patient selection report response rates to castration of 37% to 75%.121,122 In all trials, tamoxifen was prescribed on a twice daily schedule, but the dosages varied from 20 mg/d to 120 mg/d. Most patients received 40 mg daily. At these dosages, menstrual irregularities were common. In 179 patients in whom the effects of tamoxifen on menses could be evaluated, 44 patients (25%) developed amenorrhea. Oligomenorrhea or irregular cycles occurred in a similar proportion. Older women nearing menopause were more likely than younger women to develop ovarian dysfunction." 8 Extended duration of therapy also was associated with abnormal menses.85 In most trials, tamoxifen-induced amenorrhea was not associated with any improvement in response rates. Sawka et al,85 in contrast, reported


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TAMOXIFEN IN PREMENOPAUSAL BREAST CANCER Table 2. Phase II Trials Evaluating Tamoxifen in Premenopausal Women No. of Patients

Study

Tamoxifen Dose (mg/d)

Stable Disease Disease

No.

%

No.

2 5

20 45

0 0

12

%

Median Duration of Response (months)

Steroid Hormone Status

5 and 9+ 15

NA 5 ER+ 4 ER2 ER? 19 ER+PgR+ 13 ER+PgRERPgR? ERIPgR37 ER+PgR? 5 ER-PgR4 ER+ 6 ER11 ER? NA 12 ER+ 44 ER-

Heuson"' 2 Manni and Pearsons

10 11

Sawka et al, Pritchard et al"s'"

74

40

20

27

21

20-40

8

38

26 56

20-40 20

7 22

27 40

5

9

NAt 11

44

20-30

12

27

10

23

12.7

43

40

13

30

10

25

3

Wado et al1"

4

Yoshida et al" Hoogstraten et al1.156

7

Margreiter et al1"

8

Planting et al"

40 40-120

CR and PR Response Response Rate Rate

16

NA

13

2.5-18+*

NA

21.5 (4-36)

10 ER+PgR+ 1 ER-PgR+ 6 ER+PgR18 ER-PgR9 ERPgR? 2 ER+PgR+ 2 ER+PgR2 ER-PgR+ ER-PgR?

Sites of Disease No.

Site NA

1 6 4

ST B V NA

15 2 4

ST B V NA

27 23 7 15 22 7

ST B V ST B V

23 7 13

ST B V

Abbreviations: NA, data not available; ST, soft tissue; B, bone; V, visceral; CR, complete response; PR, partial response; +, positive; -, negative; ?, unknown. *Median not given. tAll responders had a response duration of "more than 6 months."

more responses in women who developed menstrual irregularities (20 of 29 patients; 69%) compared with those who retained normal menses (six of 17; 35%). The authors discounted the significance of this apparent benefit, noting that women with progressive disease were not continued on tamoxifen for the prolonged periods associated with increased menstrual abnormalities. In evaluating the data from studies that include premenopausal patients, it is critical to know how menstrual status was determined. In several trials, patients were selected by self-reports of recent menstruation within the past year, and menopausal status was not confirmed by serum FSH 7 Reliance on the subjective report of levels.85' 11,'8 normal menses may underestimate the number of women with low (postmenopausal) levels of estrogen. In one study, 41 patients who reported menses had FSH levels determined before and after initiation of tamoxifen. Thirteen of these women had elevated baseline FSH levels consis-

tent with postmenopausal endocrine status (FSH > 50 IU/L).8 5 There were no major differences in response rates between those patients with low (premenopausal) baseline FSH (56%) and high (postmenopausal) FSH (47%). Nevertheless, this study suggests that many patients entering premenopausal studies of tamoxifen may, in fact, be postmenopausal endocrinologically. Ultimately, data that support our clinical decisions about tamoxifen therapy for premenopausal women must be derived from studies that verify menopausal status by appropriate hormone levels. Dose Considerations The optimal dose of tamoxifen has been addressed in several studies. For postmenopausal women, there are occasional anecdotal reports of patients who have objective disease responses 24 after the dose of tamoxifen is increased.1231 However, prospective trials have not confirmed any significant or consistent benefit from escalat-


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ing doses. Stewart et a1" 25 increased tamoxifen from 20 mg to 40 mg daily at the time of disease progression in 36 consecutive postmenopausal patients. In 30 assessable patients, the authors observed no objective response to the higher dose, although seven patients had stabilization of disease lasting 2 to 15 months. In the largest randomized trial, postmenopausal women received either 90 mg/d or 30 mg/d of tamoxifen.126 The rates of response were 36% and 37%, respectively, and time to response, duration of response, or time to treatment failure did not differ between the two dosages. Because tamoxifen increases serum estradiol in premenopausal women, higher doses of tamoxifen, theoretically, might be advantageous. Unfortunately, there are no prospective randomized trials in premenopausal women to evaluate this strategy. In a nonrandomized trial, Tormey et a1127 studied many dose levels between 4 and 200 mg/m2 in 52 women. Although most patients were postmenopausal, three premenopausal women were included. One patient receiving 32 mg/im2 twice daily had stable metastatic disease, and two patients receiving 50 and 60 mg/m 2 twice daily did not respond to tamoxifen. The authors did not find a dose-response effect for tamoxifen in the postmenopausal group. Investigators in one phase II trial escalated the dose of tamoxifen until onset of amenorrhea, in an attempt to optimize the antiestrogenic effects.83 In two patients, increasing the dosage to 80 mg/d and 120 mg/d was successful in inducing amenorrhea. Normal menses continued in three other patients given 50 mg, 60 mg, and 80 mg, although the duration of tamoxifen therapy in this group was short due to disease progression. No clear therapeutic advantage was achieved with the high dosages of tamoxifen. The other phase II trials used a uniform dose of tamoxifen, and response rates did not differ significantly for women receiving 20 mg/d compared with those receiving 40 mg/d. Whether a better outcome can be attained in premenopausal breast cancer patients with higher dosages of tamoxifen than standard dosages (20 to 40 mg/d) cannot be answered from the available data. PredictingResponse to Oophorectomy Patients with breast cancer who respond to initial endocrine therapy frequently respond to a

second-line endocrine therapy when they develop progressive disease. A few studies have examined the response to oophorectomy after an initial trial of tamoxifen with conflicting results. As part of the phase II trial reported by Sawka et al,85 85 premenopausal patients receiving tamoxifen as firstline hormone therapy were offered ovarian ablation at the outset if tamoxifen was ineffective, or at the time of disease progression if an initial response was obtained. Of the assessable 74 patients, 39 women received ovarian ablation, 21 patients had surgical oophorectomy, and 18 patients had ovarian irradiation. Most of those responsive to tamoxifen, nine of 15 patients (60%), had a second disease response with castration. Fourteen patients who had progressive disease on tamoxifen received ovarian ablation. Two patients, both with ER-positive and PgR-positive tumors, had stable disease, but no other responses were observed in this group. Thus, the response to tamoxifen predicted the subsequent response to castration (P = .021) in this series of patients. In contrast, findings from a Southwest Oncology Group (SWOG) study did not support the predictive value of initial tamoxifen response."' None of the 14 premenopausal women who initially responded to tamoxifen had a subsequent response to oophorectomy. Yet, five of 22 patients who did not respond to tamoxifen achieved complete or partial responses with surgical oophorectomy. An important difference between the SWOG study"' and that by Sawka et alss is that tamoxifen was discontinued at the time of disease progression in the latter trial. In the SWOG study, patients remained on tamoxifen without interruption after oophorectomy. For the patient group that initially responded to tamoxifen and later progressed, it is interesting to speculate that, at the time of progression, tamoxifen was actually stimulating tumor growth via its partial agonist activity.4 Oophorectomy, then, would not be expected to induce regression if an estrogen agonist (tamoxifen) was being given to the patient. As described earlier, acquired tamoxifen resistance due to the development of tamoxifen-stimulated growth has been reported in an experimental , model.5354 Another possible, though unlikely, explanation for the disparate results in these two studies may be a "withdrawal response" after cessation of


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tamoxifen. The mechanism for an endocrine withdrawal response is not clear, but it also could be due to the acquired ability of tamoxifen to stimulate tumor growth after an initial inhibitory effect. Disease regression after stopping tamoxifen 28has been reported sporadically in the literature.1 -131 The largest experience was reported by Taylor et al'32 in an abstract. They found an objective response to tamoxifen withdrawal in three of 82 patients (4%). A British trial reported an 8% response rate (five of 61 patients).1 ' In both studies, patients who improved after withdrawal of tamoxifen had responded previously to the drug. These reports include only postmenopausal women. Presumably, a withdrawal response to tamoxifen is possible for premenopausal women, but it has not been reported. Another possible reason for the conflicting results may be the timing and methods used for response assessment. Although radionuclide bone scans are highly sensitive, they have low specificity, and false-positive readings for bony abnormalities are possible when evaluating serial scans. Patients responding to tamoxifen may show an ostensibly worsening scan during the first 2 months of treatment. This may lead to premature alterations of therapy, and might explain why some patients responded to oophorectomy after an initial "failure" with tamoxifen in the SWOG study." 5 Finally, because levels of tamoxifen can be de5 some tected many weeks after discontinuation," responses to oophorectomy may have been partly induced by the continued influence of tamoxifen. Besides the large trials described above, other investigators have addressed the value of tamoxifen response in predicting response to subsequent oophorectomy. Planting et al" 8 described the response to oophorectomy after tamoxifen therapy in 24 patients. Half the patients who had initial disease regression on tamoxifen had a second objective response to ovarian ablation. Of the 12 patients who had failed initial tamoxifen therapy, two patients had an objective response, and two patients had stable disease to subsequent ablative therapy. In contrast, Pearson et al'34 did not see any responses to oophorectomy in 16 patients who had initially progressed on tamoxifen. Nine patients had initially improved on tamoxifen therapy, and seven had a second response to castration. The results from seven groups of investigators (including the four discussed above) are combined

in Table 3. Of 54 patients who obtained a complete or partial response to tamoxifen, 27 (50%) had an objective response or disease stabilization to subsequent oophorectomy. For those patients who initially failed tamoxifen, an objective response was infrequently observed (nine of 71 patients; 13%). The high proportion of premenopausal patients who remained responsive to a second hormonal therapy is consistent with the experience attained in postmenopausal patients. In addition, this favorable result supports the concept that hormone-sensitive tumors tend to respond to a variety of hormonal manipulations in succession. Still, the cumulative data also suggest that a failure to respond to tamoxifen does not preclude a response to subsequent ovarian ablation. For specific patients who remain candidates for hormonal therapy, ovarian ablation after failure to respond to initial tamoxifen therapy is an acceptable, albeit, low-yield treatment option. PHASE III CLINICAL TRIALS IN PREMENOPAUSAL PATIENTS

Two randomized, prospective studies have compared the therapeutic benefits of tamoxifen versus oophorectomy in premenopausal women (Table 4). A British study by Buchanan et a1136 randomized 122 patients to either tamoxifen or surgical oophorectomy as initial therapy for metastatic disease. ER assays were not required for eligibility, and for most patients, tumor ER status was not known, a major deficiency of the study. All patients had serum FSH levels within the premenopausal range, or they reported normal menses before entry into the study. Patients receiving tamoxifen had an objective response rate of 24% (13 of 55) with a response duration of 20 months. The response rate to oophorectomy was 21% (11 of 52) with a duration Table 3. Response to Oophorectomy After Tamoxifen Response to Ovarian Ablation CR, PR Response to Tamoxifen

CR, PR SD PD

No. of Patients

54 27 71

SD

PD

NA

No.

%

No.

%

No.

%

No.

%

19 5 9

35 19 13

8 7 6

15 26 8

26 11 55

48 41 77

1 4 1

2 15 1

Abbreviations: SD, stable disease; NC, no change; NA, nonassessable. Data compiled from references 85, 115, 117, 118, 122, 134, 135.


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SUNDERLAND AND OSBORNE Table 4. Phase III Trials in Premenopausal Women Comparing Tamoxifen and Oophorectomy

Study Ingle et al'•.

Buchanan et al'•

No. Assessable

Response Rate CR+PR (%)

Median Response Duration (months)

Median Survival (months)

Tamoxifen 20 mg/d

26

27

15.1

30.0

Oophorectomy

27

37

15.9

18.3

Tamoxifen 40 mg/d

55

24

20

15

Oophorectomy

52

21

7

25

Treatment Arm

of response of 7 months. The difference in response duration was not statistically significant. The median survival time (25 months) for patients having surgery was longer than for patients receiving tamoxifen (15 months), but again, this difference did not reach statistical significance. The trial by Ingle et al122 at the Mayo clinic entered only 54 patients between 1981 and 1984 before closure due to the low accrual rate. Patients with ER-negative receptor assays were not eligible to participate. The proportion of patients with ER-positive tumors was 81% and 77% in the tamoxifen arm and oophorectomy arm, respectively. The ER status of the remaining patients was unknown. Menopausal status was not assessed by either serum estradiol or FSH levels, but 24 of 26 patients randomized to tamoxifen were actively menstruating at the start of therapy. The remaining patients were within 1 year of their last menstrual period. In the 27 patients randomized to receive oophorectomy, 10 treatment responses (37%) were observed. Complete or partial responses were seen in seven of the 26 patients (27%) receiving tamoxifen. No significant differences between the treatment arms were found for either duration of response or for total survival. In the Mayo clinic trial, tamoxifen appeared to be ineffective in patients with visceral-dominant disease.12 2 Among the 30 patients with visceral involvement, there were no responses in 14 patients receiving tamoxifen, but eight of the 16 patients randomized to receive oophorectomy obtained a response. These patients also had significantly longer time to progression. When soft tissue

ERStatus 20 ER+ 0 ER7 ER? 22 ER+ 0 ER5 ER? 13 ER+ 12 ER30 ER? 16 ER+ 13 ER23 ER?

was the dominant disease site, three of five patients (60%) responded to tamoxifen and only one of six patients (16%) responded to oophorectomy. These observations were not noted in the other phase III trial. Although it is true that no statistically significant differences were found between the treatment arms for both trials, it may not be reliably concluded that tamoxifen and oophorectomy are equivalent therapies. Small patient numbers are a distinct problem when evaluating trials that attempt to assess whether a new therapy is as effective as the standard therapy. The design of "equivalence" studies often requires very large numbers of patients to be entered onto a trial for conclusions to be stated with confidence. "'7 Total survival duration and time to disease progression should be major end points for a study of this type. Tumor response is difficult to assess accurately in breast cancer patients, and survival duration is a more important indicator of true patient benefit. Total survival is especially important in an analysis that compares a permanent treatment (ovarian ablation) with one in which the treatment usually is stopped when the disease progresses (tamoxifen). Continued suppression of estrogen-dependent clones in the ablated group still might impact on survival, though the tumor is predominantly estrogen-independent. The 53 eligible patients in the Mayo Clinic trial took 4 years to accure, and the published analysis was done 1 year after the study was closed."'2 2 Thus, this study had a power of only 0.22 (two-sided test) to rule out a 50% improvement in survival by one treatment (ie, median survival of 3 years compared



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with 2 years)."13 In fact, this trial had adequate power (0.79) to detect only a huge, threefold difference in survival (ie, 6 years compared with 2 years). The estimated tamoxifen/oophorectomy disease progression hazards ratio reported for this trial was 1.1 (95% confidence interval, 0.61 to 1.98), slightly favoring oophorectomy, and that for survival was 0.74 (95% confidence interval, 0.35 to 1.58), slightly favoring tamoxifen. However, moderate to large advantages for either treatment in time to progression or in survival cannot be excluded by this small trial. Although the trial reported by Buchanan et al' 36 had twice as many patients, it still had a power of only 0.33 to detect even a 50% improvement by one treatment. It had adequate power to detect only a 2.5-fold improvement. This trial would have required a total of 358 patients to have adequate power (0.8) to detect a 50% advantage in survival by one of the treatments. The actual hazards ratios and confidence intervals for progression and survival were not reported for this trial, although in contrast to the Mayo Clinic trial, curves for freedom from relapse slightly favored tamoxifen while those for survival favored oophorectomy. Thus, the cumulative data must be considered inconclusive since even if there is a true difference in survival as large as 50% between these two treatments, neither of these studies would have been able to detect it.

antiproliferative effect predominantly via ERmediated mechanisms, although other cellular effects of tamoxifen could influence tumor growth or the response of the host. Tamoxifen is effective in postmenopausal patients with advanced breast cancer, and comparative trials have shown therapeutic equivalence to other standard endocrine agents. The favorable toxicity profile has made this agent the hormonal treatment of choice for this age group. Tamoxifen is also active in premenopausal patients with advanced disease. However, the available data are somewhat limited because (1) young women with ER-positive tumors are not as common as older patients, and (2) randomized trials comparing a medical with a surgical treatment modality are difficult to conduct. Therapeutic equivalence to the previous standard approach (oophorectomy) has not been proven, and a large survival advantage cannot be excluded for either modality. Still, tamoxifen does offer a favorable alternative for patients who wish to avoid surgical or radiation castration. Several questions remain to be answered: (1) What is the optimal dose of tamoxifen in premenopausal patients? (2) Is the increasing estrogen level observed in patients on tamoxifen of any clinical significance? (3) Is tamoxifen less effective than the other approaches in patients with visceral dominant disease? (4) What is the relative efficacy and toxicity of tamoxifen compared with medical castration with GnRH agonists? These questions need answering to define more precisely the role of tamoxifen in premenopausal primary and advanced breast cancer.

CONCLUSION

The antiestrogen tamoxifen is a valuable addition to the therapeutic armamentarium for the management of breast cancer. The drug exerts its

REFERENCES 1. Cole MP, Jones CTA, Todd IDH: A new antioestrogenic agent in late breast cancer. An early clinical appraisal with ICI 46474. Br J Cancer 25:270-275, 1971 2. Henderson IC: Adjuvant systemic therapy: State of the art, 1989. Breast Cancer Res Treat 14:3-22, 1989 3. Fisher B, Costantino J, Redmond C, et al: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogenreceptor-positive tumors. N Engl J Med 320:479-484, 1989 4. Nolvadex Adjuvant Trial Organisation: Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. Analysis at eight years by "Nolvadex" Adjuvant Trial Organisation. Br J Cancer 57:608-611, 1988 5. Adjuvant tamoxifen in the management of operable breast cancer: The Scottish trial: Report from the Breast Cancer Trials Committee. Lancet 2:171-175, 1987

6. Early Breast Cancer Trialist's Collaborative Group: Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. N Engl J Med 319:16811692, 1988 7. Consensus Conference: Adjuvant therapy for breast cancer. J Am Med Assoc 254:3461-3463, 1985 8. Katzenellenbogen BS, Kendra KL, Norman MJ, et al: Proliferation, hormonal responsiveness, and estrogen receptor content of MCF-7 human breast cancer cells grown in the short-term and long-term absence of estrogens. Cancer Res 47:4355-4360, 1987 9. Aitken SC, Lippman ME: Effect of estrogens and antiestrogens on growth-regulatory enzymes in human breast cancer cells in tissue culture. Cancer Res 45:1611-1620, 1985 10. Edwards DP, Murthy SR, McGuire WL: Effects of


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estrogen and antiestrogen on DNA polymerase in human breast cancer. Cancer Res 40:1722-1726, 1980 11. Salomon DS, Zwiebel JA, Bano M, et al: Presence of transforming growth factors in human breast cancer cells. Cancer Res 44:4067-4077, 1984 12. Lippman ME, Dickson RB, Gelmann EP, et al: Growth regulation of human breast cancer occurs through regulated growth factor secretion. J Cell Biochem 35:1-16, 1987 13. Yee D, Cullen K, Pail S, et al: Insulin-like growth factor II mRNA expression in human breast cancer. Cancer Res 48:6691-6696, 1988 14. Osborne CK, Coronado EB, Kitten LJ, et al: Insulinlike growth factor-II (IGF-II): A potential autocrine/ paracrine growth factor for human breast cancer acting via the IGF-I receptor. Mol Endocrinol 3:1701-1709, 1989 15. Bates SE, Davidson NE, Valverius EM, et al: Expression of transforming growth factor alpha and its ribonucleic acid in human breast cancer: Its regulation by estrogens and its function. Mol Endocrinol 2:543-555, 1988 16. Rosengurt E, Sinett-Smith J, Taylor-Papadimitriou J: Production of PDGF-like growth factor by human breast cancer cell lines. Int J Cancer 36:247-252, 1985 17. Bronzert DA, Pantazis P, Antoniades HN, et al: Synthesis and secretion of platelet-derived growth factor by human breast cancer cell lines. Proc Natl Acad Sci USA 84:5763-5767, 1989 18. Knabbe C, Lippman ME, Wakefield LM, et al: Evidence that transforming growth factor-13 is a hormonally regulated negative growth factor in human breast cancer cells. Cell 48:417-428, 1987 19. Sporn MB, Roberts AB: Transforming growth factorbeta. Multiple actions and potential clinical applications. J Am Med Assoc 262:938-941, 1989 20. Arteaga CL, Coronado E, Osborne CK: Blockade of the epidermal growth factor receptor inhibits transforming growth factor a-induced but not estrogen-induced growth of hormone-dependent human breast cancer. Mol Endocrinol 2:1064-1069, 1988 21. Arteaga CL, Osborne CK: Growth inhibition of human breast cancer cells in vitro with an antibody against the type I somatomedin receptor. Cancer Res 49:6237-6241, 1989 22. .King WJ, Green GL: Monoclonal antibodies localise oestrogen receptor in the nuclei of target cells. Nature 307:745-749, 1984 23. Jordan VC, Tormey DC: Antiestrogen therapy for breast cancer: Current strategies and future prospects, in Osborne CK (ed): Endocrine Therapies in Breast and Prostate Cancer. Boston, MA, Kluwer Academic, 1988, pp 97-110 24. Coezy E, Borgna J-L, Rochefort H: Tamoxifen and metabolites in MCF-7 cells: Correlation between binding to estrogen receptor and inhibition of cell growth. Cancer Res 42:317-323, 1982 25. Vignon F, Bouton M-M, Rochefort H: Antiestrogens inhibit the mitogenic effect of growth factors on breast cancer cells in the total absence of estrogens. Biochem Biophys Res Commun 146:1502-1508, 1987 26. O'Brian CA, Liskamp RM, Solomon DH, et al:

Inhibition of protein kinase C by tamoxifen. Cancer Res 45:2462-2465, 1985 27. Horgan K, Cooke E, Hallett MB, et al: Inhibition of protein kinase C mediated signal transduction by tamoxifen: Importance for antitumor activity. Biochem Pharmacol 35:4463-4465, 1986 28. Lam H-YP: Tamoxifen is a calmodulin antagonist in the activation of cAMP phosphodiesterase. Biochem Biophys Res Commun 118:27-32, 1984 29. Musgrove EA, Wakeling AE, Sutherland RL: Points of action of estrogen antagonists and a calmodulin antagonist within the MCF-7 human breast cancer cell cycle. Cancer Res 49:2398-2404, 1989 30. Greenberg DA, Carpenter CL, Messing RO: Calcium channel antagonist properties of the antineoplastic antiestrogen tamoxifen in the PC-12 neurosecretory cell line. Cancer Res 47:70-74, 1987 31. Hug V, Hortobagyi GN, Drewinka B, et al: Tamoxifencitrate counteracts the anti-tumor effects of cytoxic drugs in vitro. J Clin Oncol 3:1672-1677, 1985 32. Osborne CK, Kitten K, Arteaga CL: Antagonism of chemotherapy-induced cytotoxicity for human breast cancer cells by antiestrogens. J Clin Oncol 7:710-717, 1989 33. Kon OL: An antiestrogen-binding protein in human tissues. J Biol Chem 258:3173-3177, 1983 34. Watts CKW, Sutherland RL: Studies on the ligand specificity and potential identity of microsomal antiestrogenbinding sites. Mol Pharmacol 31:541-551, 1987 35. Nagy E, Berczi I: Immunomodulation by tamoxifen and pergolide. Immunopharmacol 12:145-153, 1986 36. Paavonen T, Andersson LC: The oestrogen antagonists, tamoxifen and FC-1157a, display oestrogen-like effects on human lymphocyte functions in vitro. Clin Exp Immunol 61:467-474, 1985 37. Gulino A, Santoni A, Screpanti I, et al: Antitumoral antiestrogen stimulates natural killer (NK) activity in C3H mouse. J Leukocyte Biol 38:159, 1985 (abstr) 38. Mandeville R, Ghali SS, Chausseau J-P: In vitro stimulation of human NK activity by an estrogen antagonist (tamoxifen). Eur J Cancer Clin Oncol 20:983-985, 1984 39. Sutherland RL, Green MD, Hall RE, et al: Tamoxifen induces accumulation of MCF-7 human mammary carcinoma cells in the GdGI phase of the cell cycle. Eur J Cancer Clin Oncol 19:615-621, 1983 40. Osborne CK, Boldt DH, Clark GM, et al: Effects of tamoxifen on human breast cancer cell cycle kinetics: Accumulation of cells in early G, phase. Cancer Res 43:3583-3585, 1983 41. Osborne CK, Coronado EB, Robinson JP: Human breast cancer in the athymic nude mouse: Cytostatic effects of long-term antiestrogen therapy. Eur J Cancer Clin Oncol 23:1189-1196, 1987 42. Bardon S, Vignon F, Montcourrier P, et al: Steroid receptor-mediated cytotoxicity of an antiestrogen and an antiprogestin in breast cancer cells. Cancer Res 47:14411448, 1987 43. Briinner N, Bronzert D, Vindelov LL, et al: Effect on growth and cell cycle kinetics of estradiol and tamoxifen on MCF-7 human breast cancer cells grown in vitro and in nude mice. Cancer Res 49:1515-1520, 1989 44. Lippman M, Bolan G, Huff K: The effects of estro-


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TAMOXIFEN IN PREMENOPAUSAL BREAST CANCER gens and antiestrogens on hormone-responsive human breast cancer in long term tissue culture. Cancer Res 36:45954601, 1976 45. Darbre PD, Curtis S, King RJB: Effects of estradiol and tamoxifen on human breast cancer cells in serum-free culture. Cancer Res 44:2790-2793, 1984 46. Furr BJA, Jordan VC: The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 25:127-205, 1984 47. Sutherland RL, Hall RE, Taylor IW: Cell proliferation kinetics of MCF-7 human mammary carcinoma cells in culture and effects of tamoxifen on exponentially growing and plateau-phase cells. Cancer Res 43:3993-4006, 1983 48. Gottardis MM, Robinson SP, Satyaswaroop PG, et al: Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res 48:812-815, 1988 49. Jordan VC, Robinson SP: Species-specific pharmacology of antiestrogens: Role of metabolism. Fed Proc 46:18701874, 1987 50. Horwitz KB, Koseki Y, McGuire WL: Estrogen control of progesterone receptor in human breast cancer: Role of estradiol and anti-estrogen. Endocrinology 103:17421751, 1978 51. King RBJ: An overview of molecular aspects of steroid hormone activation, in Cooke BA, King RBJ, Van der Molen HJ (eds): Hormones and Their Actions, Part I. Amsterdam, The Netherlands, Elsevier, 1988, p 29 52. Simon WE, Albrecht M, Trams G, et al: In vitro growth promotion of human mammary carcinoma cells by steroid hormones, tamoxifen, and prolactin. J Natl Cancer Inst 73:313-321, 1984 53. Gottardis MM, Wagner RJ, Borden EC, et al: Differential ability of antiestrogens to stimulate breast cancer cell (MCF-7) growth in vivo and in vitro. Cancer Res 49:47654769, 1989 54. Osborne CK, Hobbs K, Clark GM: Effect of estrogens and antiestrogens on growth of human breast cancer cells in athymic nude mice. Cancer Res 45:584-590, 1985 55. Colletti RB, Roberts JD, Devlin JT, et al: Effect of tamoxifen on plasma insulin-like growth factor I in patients with breast cancer. Cancer Res 49:1882-1884, 1989 56. Howell A, Harland RNL, Barnes DM, et al: Endocrine therapy for advanced carcinoma of the breast: Relationship between the effect of tamoxifen upon concentration of progesterone receptor and subsequent response to treatment. Cancer Res 47:300-304, 1987 57. Berry J, Green BJ, Matheson DS: Modulation of natural killer cell activity by tamoxifen in stage I postmenopausal breast cancer. Eur J Cancer Clin Oncol 23:517520, 1987 58. Kemp JV, Adam HK, Wakeling AE, et al: Identification and biological activity of tamoxifen metabolites in human serum. Biochem Pharmacol 32:2045-2052, 1983 59. Fabian C, Sternson L, Barnett M: Clinical pharmacology of tamoxifen in patients with breast cancer: Comparison of traditional and loading dose schedules. Cancer Treat Rep 64:765-773, 1980 60. Bratherton DG, Brown CH, Buchanan R, et al: A comparison of two doses of tamoxifen (Nolvadex) in postmenopausal women with advanced breast cancer: 10 mg bd versus 20 mg bd. Br J Cancer 50:199-205, 1984

61. Fabian C, Sternson L, El-Serafi M, et al: Clinical pharmacology of tamoxifen in patients with breast cancer: Correlation with clinical data. Cancer 48:876-882, 1981 62. Daniel P, Gaskell SJ, Bishop H, et al: Determination of tamoxifen and biologically active metabolites in human breast tumors and plasma. Eur J Cancer Clin Oncol 17:1183-1189, 1981 63. Katzenellenbogen BS, Norman MJ, Eckert RL, et al: Bioactivities, estrogen receptor interactions, and plasminogen activator-inducing activities of tamoxifen and hydroxytamoxifen isomers in MCF-7 human breast cancer cells. Cancer Res 44:112-119, 1984 64. Jordan VC, Fritz NF, Tormey DC: Endocrine effects of adjuvant chemotherapy and long-term tamoxifen administration on node-positive patients with breast cancer. Cancer Res 47:624-630, 1987 65. McFadyen IJ, Raab G, Forrest APM, et al: The effect of tamoxifen and stilboestrol on plasma hormone levels in postmenopausal women with advanced breast cancer. Clin Oncol 5:251-256, 1979 66. Debruyne G, Dhont M, Vandekerckhove D: Effect of long-term tamoxifen treatment on prolactin and gonadotropin secretion in women with breast cancer. IRCS Med Sci Reprod Obstet Gynecol 8:560, 1980 67. Helgason S, Wilking N, Carlstr6m K, et al: A comparative study of the estrogenic effects of tamoxifen and 1713-estradiol in postmenopausal women. J Clin Endocrinol Metab 54:404-408, 1982 68. Boccardo F, Guarneri D, Rubagotti A, et al: Endocrine effects of tamoxifen in post-menopausal breast cancer patients. Tumori 70:61-68, 1984 69. Delrio G, De Placido S, Pagliarulo C, et al: Hypothalamic-pituitary-ovarian axis in women with operable breast cancer treated with adjuvant CMF and tamoxifen. Tumori 72:53-61, 1986 70. Willis KJ, London DR, Ward HWC, et al: Recurrent breast cancer treated with the antioestrogen tamoxifen: Correlation between hormonal changes and clinical course. Br Med J 1:425-428, 1977 71. Golder MP, Phillips MEA, Fahmy DR, et al: Plasma hormones in patients with advanced breast cancer treated with tamoxifen. Eur J Cancer Clin Oncol 12:719-723, 1976 72. Fex G, Adielsson G, Mattson W: Oestrogen-like effects of tamoxifen on the concentration of proteins in plasma. Acta Endocrinol 97:109-113, 1981 73. Tanaka M, Abe K, Ohnami S, et al: Tamoxifen in advanced breast cancer: Response rate, effect on pituitary hormone reserve and binding affinity to estrogen receptor. Jpn J Clin Oncol 8:141-148, 1978 74. Wilking N, Carlstrom K, Skoldefors H, et al: Effects of tamoxifen on the serum levels of estrogen and adrenocortical steroids in postmenopausal breast cancer patients. Acta Chir Scand 148:345-349, 1982 75. Kiang DT, Kennedy BJ: Tamoxifen (antiestrogen) therapy in advanced breast cancer. Ann Intern Med 87:687690, 1977 76. Daxenbichler G, Margreiter R, Dapunt O: Changes in serum hormone levels after tamoxifen treatment. Cancer Treat Rep 63:1213, 1979 (abstr) 77. Senior BE, Cawood ML, Oakey RE, et al: A comparison of the effects of clomiphene and tamoxifen treatment


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on the concentrations of oestradiol and progesterone in the peripheral plasma of infertile women. Clin Endocrinol 8:381-389, 1978 78. Ravdin PM, Fritz NF, Tormey DC, et al: Endocrine status of premenopausal node-positive breast cancer patients following adjuvant chemotherapy and long-term tamoxifen. Cancer Res 48:1026-1029, 1988 79. Sherman BM, Chapler FK, Crickard K, et al: Endocrine consequences of continuous antiestrogen therapy with tamoxifen in premenopausal women. J Clin Invest 64:398404, 1979 80. Groom GV, Griffiths K: Effect of the anti-oestrogen tamoxifen on plasma levels of luteinizing hormone, folliclestimulating hormone, prolactin, oestradiol and progesterone in normal pre-menopausal women. J Endocrinol 70:421428, 1976 81. Powles TJ, Hardy JR, Ashley SE, et al: Chemoprevention of breast cancer. Breast Cancer Res Treat 14:23-31, 1989 82. Manni A, Pearson OH: Antiestrogen-induced remissions in premenopausal women with stage IV breast cancer: Effects on ovarian function. Cancer Treat Rep 64:779-785, 1980 83. Dnistrian AM, Greenberg EJ, Dillon HJ, et al: Chemohormonal therapy and endocrine function in breast cancer patients. Cancer 56:63-70, 1985 84. Rose DP, Davis TE: Effects of adjuvant chemohormonal therapy on the ovarian and adrenal function of breast cancer patients. Cancer Res 40:4043-4047, 1980 85. Sawka CA, Pritchard KI, Paterson AHG, et al: Role and mechanism of action of tamoxifen in premenopausal women with metastatic breast carcinoma. Cancer Res 46: 3152-3156, 1986 86. Ricciardi I, lanniruberto A: Tamoxifen-induced regression of benign breast lesions. Obstet Gynecol 54:80-84, 1979 87. Manni A, Trujillo JE, Marshall JS, et al: Antihormone treatment of stage IV breast cancer. Cancer 43:444450, 1979 88. Ribeiro G, Swindell R: The Christie Hospital adjuvant tamoxifen trial-Status at 10 years. Br J Cancer 57:601-603, 1988 89. Franks S: Regulation of prolactin secretion by oestrogens: Physiological and pathological significance. Clin Science 65:457-462, 1983 90. Tajima C: Luteotropic effects of tamoxifen in infertile women. Fertil Steril 42:223-227, 1984 91. NeumannovA M, Kauppila A, Kivinen S, et al: Shortterm effects of tamoxifen, medroxyprogesterone acetate, and their combination on receptor kinetics and 1713hydroxysteroid dehydrogenase in human endometrium. Obstet Gynecol 66:695-700, 1985 92. Ferrazzi E, Cartel G, Mattarazzo R, et al: Oestrogenlike effect of tamoxifen on vaginal epithelium. Br Med J 1:1351-1352, 1977 (letter) 93. Boccardo F, Bruzzi P, Rubagotti A, et al: Estrogenlike action of tamoxifen on vaginal epithelium in breast cancer patients. Oncology 38:281-285, 1981 94. Bonte J, Ide P, Billiet G, et al: Tamoxifen as a possible chemotherapeutic agent in endometrial adenocarcinoma. Gynecol Oncol 11:140-161, 1981

95. Fornander T, Rutqvist LE, Cedermark B, et al: Adjuvant tamoxifen in early breast cancer: Occurrence of new primary cancers. Lancet 1:117-120, 1989 96. Hardell L: Tamoxifen as risk factor for carcinoma of corpus uteri. Lancet 2:563, 1988 (letter) 97. Enck RE, Rios CN: Tamoxifen treatment of metastatic breast cancer and antithrombin III levels. Cancer 53:2607-2609, 1984 98. Jordan VC, Fritz NF, Tormey DC: Long-term adjuvant therapy with tamoxifen: Effects on sex hormonebinding globulin and antithrombin III. Cancer Res 47:45174519, 1987 99. Sakai F, Cheix F, Clavel M, et al: Increases in steroid binding globulins induced by tamoxifen in patients with carcinoma of the breast. J Endocrinol 76:219-226, 1978 100. Jensen IW: Oestrogen-like effect of tamoxifen on concentration of thyroxin-binding globulin. Lancet 2:10201021, 1985 (letter) 101. Bruning PF, Bonfrer JMG, Hart AAM, et al: Tamoxifen, serum lipoproteins and cardiovascular risk. Br J Cancer 58:497-499, 1988 102. Bertelli G, Pronzato P, Amoroso D, et al: Adjuvant tamoxifen in primary breast cancer: Influence on plasma lipids and antithrombin III levels. Breast Cancer Res Treat 12:307-310, 1988 103. Mouridsen H, Palshof T, Patterson J, et al: Tamoxifen in advanced breast cancer. Cancer Treat Rev 5:131-141, 1978 104. Smith IE, Harris AL, Morgan M, et al: Tamoxifen versus aminoglutethimide in advanced breast carcinoma: A randomized cross-over trial. Br Med J 283:1432-1434, 1981 105. Ward HWC, Arthur K, Banks AJ, et al: Antioestrogen therapy for breast cancer-A report on 300 patients treated with tamoxifen. Clin Oncol 4:11-17, 1978 106. Corkery J, Leonard RCF, Henderson IC, et al: Tamoxifen and aminoglutethimide in advanced breast cancer. Cancer Res 42:3409s-3415s, 1982 (suppl) 107. Lerner HJ, Band PR, Israel L, et al: Phase II study of tamoxifen: Report of 74 patients with stage IV breast cancer. Cancer Treat Rep 60:1431-1435, 1976 108. Morgan LR, Jr, Schein PS, Woolley PV, et al: Therapeutic use of tamoxifen in advanced breast cancer: Correlation with biochemical parameters. Cancer Treat Rep 60:1437-1443, 1976 109. Manni A, Trujillo J, Marshall JS, et al: Antiestrogeninduced remissions in stage IV breast cancer. Cancer Treat Rep 60:1445-1450, 1976 110. Tormey DC, Simon RM, Lippman ME, et al: Evaluation of tamoxifen dose in advanced breast cancer: A progress report. Cancer Treat Rep 60:1451-1459, 1976 111. Heuson JC: Current overview of EORTC clinical trials with tamoxifen. Cancer Treat Rep 60:1463-1466, 1976 112. Pritchard KI, Thomson DB, Myers RE, et al: Tamoxifen therapy in premenopausal patients with metastatic breast cancer. Cancer Treat Rep 64:787-796, 1980 113. Wada T, Koyama H, Terasawa T: Effect of tamoxifen in premenopausal Japanese women with advanced breast cancer. Cancer Treat Rep 65:728-729, 1981 114. Yoshida M, Murai H, Miura S: Tamoxifen therapy for premenopausal and postmenopausal Japanese females


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TAMOXIFEN IN PREMENOPAUSAL BREAST CANCER with advanced breast cancer. Jpn J Clin Oncol 12:57-64, 1982 115. Hoogstraten B, Fletcher WS, Gad-el-Mawla N, et al: Tamoxifen and oophorectomy in the treatment of recurrent breast cancer. A Southwest Oncology Group study. Cancer Res 42:4788-4791, 1982 116. Hoogstraten B, Gad-el-Mawla N, Maloney TR, et al: Combined modality therapy for first recurrence of breast cancer. A Southwest Oncology Group study. Cancer 54:22482256, 1984 117. Margreiter R, Wiegele J: Tamoxifen (Nolvadex) for premenopausal patients with advanced breast cancer. Breast Cancer Res Treat 4:45-48, 1984 118. Planting AST, Alexieva-Figusch J, Blonk-v.d. Wijst J, et al: Tamoxifen therapy in premenopausal women with metastatic breast cancer. Cancer Treat Rep 69:363-368, 1985 119. Taylor SG: Endocrine ablation in disseminated mammary carcinoma. Surg Gynecol Obstet 115:443-448, 1962 120. Veronesi V, Pizzocaro G, Rossi A: Oophorectomy for advanced carcinoma of the breast. Surg Gynecol Obstet 141:569-570, 1975 121. McGuire WL, Vollmer EP, Carbone PP (eds): Estrogen Receptors in Human Breast Cancer. New York, NY, Raven, 1975 122. Ingle JN, Krook JE, Green SJ, et al: Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer. J Clin Oncol 4:178-185, 1986 123. Westerberg H, Nordenskjold B, de Schryver A, et al: Anti-oestrogen therapy of advanced mammary carcinoma. Acta Radiol Ther Phys Biol 15:513-518, 1976 124. Manni A, Arafah BM: Tamoxifen-induced remission in breast cancer by escalating the dose to 40 mg daily after progression on 20 mg daily: A case report and review of the literature. Cancer 48:873-875, 1981 125. Stewart JF, Minton MJ, Rubens RD: Trial of tamoxifen at a dose of 40 mg daily after disease progression during tamoxifen therapy at a dose of 20 mg daily. Cancer Treat Rep 66:1445-1446, 1982 126. Rose C, Theilade K, Boesen E, et al: Treatment of advanced breast cancer with tamoxifen. Evaluation of the

dose-response relationship at two dose levels. Breast Cancer Res Treat 2:395-400, 1982 127. Tormey DC, Lippman ME, Edwards BK, et al: Evaluation of tamoxifen doses with and without fluoxymesterone in advanced breast cancer. Ann Intern Med 98:139144, 1983 128. Legault-Poisson S, Jolivet J, Poisson R, et al: Tamoxifen-induced tumor stimulation and withdrawal response. Cancer Treat Rep 63:1839-1841, 1979 129. Stein W, Hortobagyi GN, Bluemenschein GR: Response of metastatic breast cancer to tamoxifen withdrawal: Report of a case. J Surg Oncol 22:45-46, 1983 130. Rudolph R: Response of metastatic breast cancer to tamoxifen (tam) withdrawal. Proc Am Soc Clin Oncol 4:62, 1985 (abstr) 131. Belani CP, Pearl P, Whitley NO, et al: Tamoxifen withdrawal response. Report of a case. Arch Intern Med 149:449-450, 1989 132. Taylor SG, Gelman R, Cumming F, et al: A randomized comparison of tamoxifen vs. CMF using creatinine clearance for dose modification in elderly breast cancer patients. An ECOG study. Proc Am Assoc Cancer Res 25:179, 1984 (abstr) 133. Canney AA, Griffiths T, Latief TN, et al: Clinical significance of tamoxifen withdrawal response. Lancet 1:36, 1987 (letter) 134. Pearson OH, Manni A, Arafah BM: Antiestrogen treatment of breast cancer: An overview. Cancer Res 42:3424s-3429s, 1982 (suppl) 135. Kalman AM, Thompson T, Vogel CL: Response to oophorectomy after tamoxifen failure in a premenopausal patient. Cancer Treat Rep 66:1867-1868, 1982 136. Buchanan RB, Blamey RW, Durrant KR, et al: A randomized comparison of tamoxifen with surgical oophorectomy in premenopausal patients with advanced breast cancer. J Clin Oncol 4:1326-1330, 1986 137. Makuch RW, Johnson MF: Some issues in the design and interpretation of "negative" clinical studies. Arch Intern Med 146:986-989, 1986 138. Bernstein D, Lagakos SW: Sample size and power determination for stratified clinical trials. J Stat Comput Simul 8:65-73, 1978


Endometrial polyp surveillance in premenopausal breast cancer patients using tamoxifen.

Extended therapy with letrozole and ovarian suppression in premenopausal patients with breast cancer after tamoxifen.

Luteal versus follicular phase surgical oophorectomy plus tamoxifen in premenopausal women with metastatic hormone receptor-positive breast cancer.

Adjuvant tamoxifen-induced mammographic breast density reduction as a predictor for recurrence in estrogen receptor-positive premenopausal breast cancer patients.

Uptake of tamoxifen in consecutive premenopausal women under surveillance in a high-risk breast cancer clinic.

Chemotherapy in Premenopausal Breast Cancer Patients.

Meakin adjuvant regimen in premenopausal patients with breast cancer.

Systemic Treatment in Premenopausal Patients with Breast Cancer.

Metastatic breast cancer in patients with schizophrenia.

Tamoxifen-induced ovarian hyperstimulation during premenopausal hormonal therapy for breast cancer in Japanese women.

Combined goserelin and tamoxifen in premenopausal advanced breast cancer: duration of response and survival.

Breast cancer prevention with tamoxifen. The role of tamoxifen in the prevention of breast cancer.

Ovarian cancer and long-term tamoxifen in premenopausal women.

Breast cryoablation in patients with bone metastatic breast cancer.

Tailored Tamoxifen Treatment for Breast Cancer Patients: A Perspective.

Tamoxifen with ovarian function suppression versus tamoxifen alone as an adjuvant treatment for premenopausal breast cancer: a meta-analysis of published randomized controlled trials.

HER2- metastatic breast cancer patients with multiple metastatic sites: a chart review study in the US.

Adjuvant Tamoxifen Plus Ovarian Function Suppression Versus Tamoxifen Alone in Premenopausal Women With Early Breast Cancer: Patient-Reported Outcomes in the Suppression of Ovarian Function Trial.

Five years of stable disease with maintenance therapy using bevacizumab and tamoxifen in a patient with metastatic breast cancer.

Adjuvant therapy with a doxorubicin regimen and long-term tamoxifen in premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial.

Tamoxifen-associated skin reactions in breast cancer patients: from case report to literature review.

Circulating hormones and breast cancer risk in premenopausal women: a randomized trial of low-dose tamoxifen and fenretinide.

Ocular findings in breast cancer patients using tamoxifen.

Tamoxifen-associated endometrial carcinoma in postmenopausal breast cancer patients.