(CANCER RESEARCH (SUPPL.) 42. 3424s-3429s. August 1982]0008-5472/82/0042-OOOOS02.00

Antiestrogen Treatment of Breast Cancer: An Overview1

Olof H. Pearson, Andrea Manni, and Baha'uddin M. Arafah

Department of Medicine, Case Western Reserve University School of Medicine, University Hospitals, Cleveland, Ohio 44106

Abstract

The nonsteroidal antiestrogen tamoxifen has emerged as ahighly effective, nontoxic endocrine therapy for women withStage IV and II estrogen receptor-positive breast cancer. Ta

moxifen appears to act by blocking endogenous estrogenaction at the target tissue level rather than by suppression ofcirculating estrogen levels.

In a series of 113 consecutive, selected patients with StageIV breast cancer, tamoxifen induced objective remissions in50% lasting an average period of 21 + months and a medianperiod of 16 months. These results are comparable to previousresults with surgical hypophysectomy. Recent randomizedstudies comparing pharmacological doses of estrogen versustamoxifen in postmenopausal women with Stage IV breastcancer have shown comparable results with these two treatment modalities.

Antiestrogen therapy has been shown to be effective in somepatients after prior endocrine additive therapy and, in particular, after ablative procedures, such as ovariectomy, adrenal-

ectomy, and hypophysectomy. It has been shown that circulating estrogens are not completely eliminated following ablationof these endocrine glands, which may account for the effectiveness of antiestrogen in this setting.

Other endocrine therapies have been shown to be effectiveafter prior treatment with antiestrogen. Hypophysectomy caninduce remissions in 60% of patients who initially respondedto tamoxifen and in 25% of patients who failed to benefit fromtamoxifen. Recent studies have shown that aminoglutethimideplus hydrocortisone may also induce remissions in some patients after prior treatment with tamoxifen. This latter finding isof particular interest since aminoglutethimide is thought to workby blocking estrogen production, and the finding suggests thattamoxifen does not completely block all endogenous estrogenactivity. Fluoxymesterone has been shown to induce remissions after tamoxifen or after tamoxifen plus hypophysectomy,and there was no correlation between the response to antiestrogen and subsequent response to androgen.

Because of its effectiveness and minimal side effects, tamoxifen is considered to be an initial endocrine therapy of choicein women with breast cancer. However, it has its limitations, asdemonstrated by the results of secondary endocrine therapiessuch as hypophysectomy, medical adrenalectomy, and androgen therapy.

Nonsteroidal antiestrogen drugs were first reported to beeffective antitumor agents in women with advanced breastcancer a decade ago (1, 2). These drugs were novel in thattheir mechanism of action appeared to be competitive bindingto the estrogen receptor and blocking the entry of estrogens

1Presented at the Conference "Aromatase: New Perspectives for BreastCancer." December 6 to 9. 1981. Key Biscayne. Fla. Supported in part by

USPHS Grant CA-05197 and American Cancer Society, Inc.. Grant PDT-48W.

into the target tissue rather than suppression of circulatingestrogen levels. The antiestrogen tamoxifen has emerged asthe favored drug because of its minimal toxicity, and a largenumber of clinical trials have been carried out with tamoxifenin women with Stage IV and II breast cancer which indicate thatit is a highly effective therapeutic agent. The purpose of thisreport is to review some of the clinical studies with antiestro-gens which may help to evaluate their role in relationship toother modalities of endocrine therapy.

Early studies showed that tamoxifen could induce objectiveremissions in 30 to 40% of women with advanced breastcancer most of whom had previously been treated with otherendocrine and/or chemotherapeutic modalities (1, 27). Theresults of our initial study in 113 consecutive, selected patientswith Stage IV breast cancer (16), recently updated (15), areshown in Table 1. Fifty % of these patients obtained objectivetumor regression lasting for an average period of 21+ monthswith a median duration of 16 months. Survival after the onsetof tamoxifen treatment was significantly longer in those patientswho responded to treatment as compared to those who failedto benefit. Overall survival from the onset of metastasis wassignificantly prolonged in those patients who benefited fromantiestrogen therapy as compared to those who failed to respond (Chart 1). Tumor regression occurred in visceral, osseous, and soft tissue sites with about equal frequencies.Patients with estrogen receptor-positive tumors had a signifi

cantly higher remission rate (63%) than did those in whomestrogen receptor measurements were not done (44%).Women who were more than 10 years postmenopausal had asignificantly higher remission rate (58%) than did those whowere less than 10 years postmenopausal (41 %). These resultsof tamoxifen therapy in women with Stage IV breast cancerindicate a high order of effectiveness, which are quite comparable to our results in 200 women with surgical hypophysectomy where the incidence of objective remissions was 42%with an average duration of 18+ months and a median of 16months (14). Tamoxifen administration did not alter serumestrogen levels in postmenopausal women but did induce aslight decrease in serum gonadotrophin levels. Serum prolactinand growth hormone levels were unaffected by antiestrogentherapy (10).

Tamoxifen induces remissions in premenopausal women withStage IV breast cancer with an incidence and duration ofremissions which appear to be comparable to those of surgicalovariectomy (13, 21). It is of interest that tumor regressionoccurs despite continued cyclic menstrual bleeding in most ofthe patients. This suggests that it is not necessary to eliminateall estrogen action to obtain mammary tumor regression. Tamoxifen has been shown to induce a marked increase inovarian estrogen secretion, perhaps mediated by increasedpituitary gonadotropin secretion, which may counteract tosome extent the effects of the antiestrogen (10). Thus far, all

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Antiestrogens in Breast Carcinoma

Table 1

Overall results of tamoxifen therapy in 113 patients

Reproduced from Breast Cancer Research and Treatment (15) by permission of Martinus Nijhoff Publishers.

PatientsRemissionsNo

changeFailuresNo.56849%50743Duration

(mos.)Mean

Median21+(4-54+)a1623(9-45) 19remission5

40+039 +'15

+Survival

(mos.)Mean'(11-71+)'(13-65+)(2-75+)Median443311alive2023

a Numbers in parentheses, range6 p < 0.0005 versus "failures" group.

1.0

ÃŒO.0.8>>acD(/*Z0.6

g

iO 0.4o.UJ>

<0.2

REMISSIONS +, NO CHANGE

FAILURES

1 23456789YEARS

Chart 1. Life table plots of survival from onset of metastasis for patients whobenefited from tamoxifen (remissions plus no change) and for those who failed torespond, p < 0.001 (generalized Wilcoxon test). Bars, 2 S.E. Reproduced fromBreast Cancer Research and Treatment (15) by permission of Martinus NijhoffPublishers.

patients who failed to benefit from tamoxifen have subsequentlyfailed to respond to ovariectomy. Although further studies areneeded, these preliminary results suggest that antiestrogen isan effective initial endocrine treatment for premenopausalwomen with Stage IV breast cancer.

Randomized Studies

Kiang ef al. (8) compared the results of tamoxifen versushypophysectomy in 26 women who had previously respondedto ovariectomy or to additive hormone therapy (estrogen orandrogen). In this small series of patients, the incidence andduration of remission were similar for these 2 modalities oftreatment.

Two studies comparing the effects of tamoxifen versus pharmacological doses of estrogen in postmenopausal women withadvanced breast cancer have been reported (6, 25). In bothstudies, no prior endocrine therapy was used, and cross-over

studies were attempted. No significant difference in incidenceor duration of remission was found between estrogen versustamoxifen therapy in these 2 studies. The incidence of sideeffects was much greater with estrogen therapy, and bothgroups of investigators felt that antiestrogen was the preferredinitial therapy for postmenopausal patients.

Randomized trials of aminoglutethimide versus antiestrogenare reported in this supplement (9).

Antiestrogen Therapy after Prior Endocrine Therapy

Early studies with tamoxifen indicated that a response toprevious endocrine therapy (usually additive hormonal treat

ment) improved the chance of a second remission on antiestrogen to 31 of 46 (67%) (20). In 34 women who failed to respondto previous endocrine therapy, 5 (15%) achieved a remissionon antiestrogen treatment. Similar findings were noted in ourinitial study (16). When tamoxifen was used as a secondarytreatment after stilbestrol, Stewart ef al. (25) noted the sameincidence and duration of remissions as when antiestrogen wasused as a primary treatment. Two patients who failed onstilbestrol therapy responded to tamoxifen. Ingle ef al. (6)reported that, of 25 patients who had had objective tumorprogression without a regression on stilbestrol, only 3 (12%)had a partial regression with tamoxifen as secondary therapy.Of 6 patients in whom disease progression occurred during thewithdrawal phase after stilbestrol therapy, 4 patients responded to tamoxifen treatment. Kiang ef al. (8) obtainedremissions with tamoxifen as secondary treatment in 4 of 6patients who had initially responded to stilbestrol therapy. Inaddition, 2 of 3 patients responded to tamoxifen after previousremission on androgen therapy.

It has now been well documented that antiestrogens caninduce tumor regression in some patients after initial endocrine-

ablative procedures, such as ovariectomy, adrenalectomy, andhypophysectomy. In our study, 8 of 9 premenopausal womenwho obtained objective remissions following ovariectomy responded to tamoxifen as a secondary therapy. Two of 4 patients who had undergone combined ovariectomy-adrenalec-

tomy subsequently responded to antiestrogen treatment. Theresults of tamoxifen therapy in 29 patients who had initiallyresponded to surgical hypophysectomy followed by relapseare shown in Table 2. One-fourth of these patients obtainedobjective tumor regression, and one-fourth had no progression

of disease on tamoxifen treatment with a median duration of16.5 months. The completeness of hypophysectomy was documented by finding undetectable levels of serum prolactin,thyroid-stimulating hormone, and growth hormone after provocative stimuli. Nevertheless, serum estrone and estradiolwere detectable at low levels (5 to 40 pg/ml) in these patients.These results suggest that estrogens, even in small amounts,can directly stimulate tumor growth in the absence of thepituitary gland and that antiestrogens can counteract this effect.

From these studies, it is apparent that antiestrogens are veryeffective when used as a secondary form of endocrine therapy.A response to initial, additive, hormonal therapy appears tohave predictive value for a response to antiestrogen as asecondary therapy. It is now well documented that endocrine-

ablative procedures such as ovariectomy, adrenalectomy, andhypophysectomy do not eliminate circulating estrogens andthat low levels of circulating estrogens after endocrine glandablations may be effective in stimulating tumor growth as

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O. H. Pearson et al.

evidenced by the high incidence of response to antiestrogenused as a secondary therapy.

Other Endocrine Therapy after Antiestrogen Treatment

The question as to whether antiestrogen in the dosages usedtherapeutically (about 40 mg tamoxifen per day) can block allestrogen action in vivo has been approached by observationsin premenopausal women and by observations of the effects ofother endocrine therapy after antiestrogen treatment. It hasbeen noted above that antiestrogen as primary treatment inpremenopausal women with Stage IV breast cancer inducesremissions with an incidence and duration of remissions comparable to the results of surgical ovariectomy (13, 21). Thesetamoxifen-induced remissions occur despite the fact that the

patients continue to have cyclic menstrual bleeding, and escalation of the dosage of tamoxifen up to 120 mg/day sometimes failed to induce complete cessation of menstrual bleeding. These observations indicate that antiestrogen does notblock all estrogen action at least in the uterus of women withhigh circulating estrogen levels.

The results of surgical ovariectomy in premenopausal patients who were initially treated with tamoxifen also provideevidence that antiestrogen does not block all estrogen actionin the mammary cancers (12, 13). In these 2 reports, therewere 16 patients who failed to respond to initial tamoxifentherapy, all of whom failed to benefit from subsequent ovarianablation. Of 9 patients who responded to tamoxifen initially andfollowed by relapse, 7 women subsequently responded toovarian ablation. Thus, the response to tamoxifen seems highlypredictive of subsequent response to ovariectomy. Since response to ovariectomy is considered to be due to lowering ofserum estrogen levels, these results would suggest that antiestrogen therapy was not capable of blocking all estrogen actionat the tumor level in premenopausal patients.

Table 2

Results of tamoxifen therapy in 29 patients posthypophysectomy

Reproduced from Endocrinology of Cancer (12) by permission of CRC Press.

PatientsRemission

No progressionFailuresNo.8

615%27

2152Mean

duration3(mos.)19+

(4-63.5+)*

19.5+ (11-32 + )No.

stillin remis

sion1

1

' Median. 16.5 months (regression plus no progression).' Numbers in parentheses, range.

Surgical hypophysectomy has been carried out in 61 womenwith Stage IV breast cancer who were treated previously withtamoxifen (12). The results are shown in Table 3. Of 28postmenopausal women who initially responded to tamoxifen,16 (57%) obtained further remission from hypophysectomylasting for an average period of more than 1 year. Of 22patients who initially failed to benefit from tamoxifen, 6 (27%)obtained objective remissions following hypophysectomy lasting for an average period of 8.5 months. The mechanism bywhich hypophysectomy induced remissions in these patients isnot known, but, if antiestrogen therapy was capable of blockingall estrogen action in these postmenopausal women, it wouldseem likely that a pituitary factor was involved. There is newevidence (see below) that antiestrogen may not be capable ofblocking all estrogen action in postmenopausal women andthat the effects of hypophysectomy might be due at least inpart to reduction in circulating estrogen levels.

A recent report by Murray and Pitt (18) has evaluated theresponse of 53 women with Stage IV breast cancer, who werepreviously treated with antiestrogen, to aminoglutethimide-cor-tisone therapy ("medical adrenalectomy"). Of 16 patients who

initially responded to tamoxifen, 11 patients (69%) obtained aremission from aminoglutethimide. Of 32 patients who failed tobenefit from tamoxifen, 13 (35%) had objective remissions onaminoglutethimide therapy. The median duration of the ami-noglutethimide-induced remissions was 12 months. These re

sults are virtually identical to the results shown above forsurgical hypophysectomy after tamoxifen therapy. Additionalresults of aminoglutethimide therapy after tamoxifen are presented in this supplement (7). Santen ef al. (22) have shownthat aminoglutethimide not only suppresses adrenal steroidsynthesis but also inhibits extraglandular estrogen productionin postmenopausal women with breast cancer and thus lowerscirculating estrogen levels in postmenopausal women.

Androgen therapy (fluoxymesterone, 10 mg p.o. twice a day)was given to 33 women with Stage IV breast cancer who hadbeen treated previously with tamoxifen and 17 of whom hadalso undergone hypophysectomy (11 ). Objective remissionswere obtained in 13 patients (39%) with an average duration of11 + months. Of 17 patients who had previously been treatedwith tamoxifen and hypophysectomy, 7 obtained further remissions from fluoxymesterone for an average period of 10months.There was no correlation between the initial responseto tamoxifen (or hypophysectomy) and the subsequent response to androgen therapy. Although the mechanism by whichpharmacological doses of androgen induce remissions in somewomen with advanced breast cancer is unknown, these results

Table 3

Response to hypophysectomy after tamoxifen

Reproduced from Endocrinology of Cancer (12) by permission of CRC Press.

RemissionsRemissions

totamoxifenFailurestotamoxifenArrest

of diseaseontamoxifenTotalNo.28221161No.16"6224%57271839Duration3

(mos.)13+

(3-29)c8.5

(5-16)21+(20, 22 +)13

+No.

stillsion1012Failures1216937

Median, 11.5 months.6 In 3 patients, only arrest of disease was documented.c Numbers in parentheses, range.

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Antiestrogens in Breast Carcinoma

suggest that it is probably not an antiestrogen effect or anindirect effect mediated through the pituitary gland.

Estrogen therapy (diethylstilbestrol, 5 mg p.o. twice a day)has also been shown to induce remissions in a few patientsafter previous treatment with antiestrogen. Stewart ef al. (25)noted remissions in 4 of 17 patients who had previously beentreated with tamoxifen with a median duration of about 6months. Ingle ef al. (6) observed that 9 of 33 patients (22%)had a partial regression during secondary treatment with stil-

bestrol. This group included 5 of 11 (45%) with a prior responseto tamoxifen and 4 of 22 (18%) without a prior response totamoxifen. The duration of remissions was apparently rathershort since the "median time to treatment failure" was only 56

days.Virtually no information is available on the use of progestins

as secondary therapy after tamoxifen. We have observed objective remissions in 2 of 12 patients who received Megace (40mg 4 times a day p.o.) after previous treatment with tamoxifen.

These results of various endocrine treatments after tamoxifentherapy indicate that ovariectomy, hypophysectomy, and medical adrenalectomy can induce a high percentage of significantsecondary remissions, particularly in those patients who havehad an initial response to antiestrogen therapy. Thus, ovariectomy appears to be the secondary treatment of choice forpremenopausal patients who have responded to tamoxifen.The impressive results with medical adrenalectomy in postmen-

opausal patients after tamoxifen as reported by Murray and Pitt(18) appear to justify their conclusion that aminoglutethimideis the secondary treatment of choice in patients who haveinitially responded to antiestrogen. Further studies of surgicalhypophysectomy after antiestrogen and aminoglutethimide areneeded to determine whether there is any further role for thisprocedure in the management of women with advanced breastcancer. Of the responses to additive hormone therapy afterantiestrogen, the remissions induced by androgen appear tobe the most effective, and thus the drug constitutes the tertiaryendocrine therapy of choice.

Antiestrogen as Adjuvant Treatment in Women with Stage IIBreast Cancer

Tamoxifen is an ideal drug for systemic therapy in womenwith earlier stages of breast cancer (Stage I and II) because ofits high order of effectiveness and lack of significant sideeffects. Hubay ef al. (4, 5) have reported a prospective, randomized clinical trial of tamoxifen plus 3-drug chemotherapy(Cytoxan-methotrexate-5-fluorouracM) versus Cytoxan-metho-trexate-5-fluorouracil alone in 318 women with Stage II breastcancer. The results of this study indicate that tamoxifen pluschemotherapy was more effective than chemotherapy alone indelaying recurrence in women with estrogen receptor positivecancers. Fisher ef al. (3) have recently reported similar findingswith the use of tamoxifen plus 2-drug chemotherapy (L-phe-nylalanine mustard-5-fluorouracN) versus chemotherapy alonein women with estrogen receptor-positive Stage II breast cancer. Further follow-up periods are needed to determine whether

antiestrogen can prevent recurrence in some patients orwhether relapse is simply delayed. These results suggest thatantiestrogen has a significant role in the systemic treatment ofless advanced stages of this disease.

Combination of Antiestrogen with Other Modalities ofTreatment

There have been very few studies in which antiestrogen hasbeen combined with other modalities of endocrine therapy.Mouridsen ef al. (17) studied the effect of tamoxifen (30 mgdaily) versus tamoxifen plus diethylstilbestrol (3 mg daily) in122 postmenopausal patients with advanced breast cancer.They found no significant difference in the incidence or durationof remissions with these 2 regimens. Ward (28) reported thataddition of a prolactin-lowering agent to antiestrogen therapy

of patients refractory to tamoxifen resulted in further stabilization of the disease, and 2 of 45 patients had an objectiveresponse. In a small randomized study, Settatree ef al. (23)found no clear differences between tamoxifen versus tamoxifenplus bromocryptine. Tormey ef al. (26) studied the effects ofcombining antiestrogen and androgen therapy. Subsequentfollow-up of this study2 indicates that there was some additional

benefit from this combination, but the results did not suggesta synergistic effect or any advantage over the sequential useof these therapies.

A comparison of antiestrogen versus antiestrogen plus aminoglutethimide is reported in this supplement (7, 24).

A number of studies have combined antiestrogen therapywith cytotoxic chemotherapy, and the results of these studiesrecently have been reviewed by Patterson (20). The early trialssuggest that there is no apparent antagonism between these 2classes of agents. Other studies have suggested that there isno advantage in combining these agents and that sequentialuse of these modalities may enhance the quality of life. Osborn(19) has postulated that the apparent lack of synergism withcombined endocrine and cytotoxic chemotherapy could be dueto the effect of endocrine therapy on tumor cell kinetics, whichcould inhibit the activity of the cytotoxic drugs. He has proposed alternative designs for chemoendocrine therapy in whichhormones might be used as synchronizing or recruiting agentsto enhance the effectiveness of cytotoxic drugs.

Discussion

The nonsteroid antiestrogen tamoxifen has emerged as ahighly effective, nontoxic endocrine therapy for women withbreast cancer. At present, it is probably the initial endocrinetreatment of choice for both pre- and postmenopausal womenwith Stage IV breast cancer. It has also been shown to beuseful as adjuvant endocrine therapy for women with estrogenreceptor-positive Stage II breast cancer.

Clinical studies have shown that there are limitations to theeffectiveness of this antiestrogen in the endocrine managementof patients with breast cancer. The data suggest that tamoxifen,with the therapeutic dosages used, does not block all endogenous estrogen action in either premenopausal or postmenopausal patients. In premenopausal patients, although antiestrogen may induce tumor regression comparable to ovarian ablation, these patients may continue to have cyclic menstrualbleeding, and ovariectomy may induce further remissions inwomen who have initially responded to tamoxifen. These results suggest that optimal antiestrogen treatment in premenopausal patients may require ovarian ablation, aminoglutethimide, and antiestrogen. In postmenopausal patients, although

2 D. C. Tormey. personal communication.

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Discussion

tamoxifen may induce remissions comparable to those of surgical ablative procedures such as adrenalectomy or hypophy-sectomy, the aromatase inhibitor aminoglutethimide has beenshown to induce further remissions after initial antiestrogentherapy, particularly in those patients who initially respondedto antiestrogen. These results suggest that tamoxifen does notblock all estrogen action even in postmenopausal womenwhose circulating estrogen levels are lower than in the pre-menopausal patient. For the future, it seems possible that otherantiestrogen drugs, which bind with a higher affinity to theestrogen receptor, might prove to be more effective in blockingthe peripheral action of estrogens in vivo. Aromatase inhibitors,which could lower circulating estrogen levels to virtually nil,might also prove to be most effective. For the present, studieson the combination of aromatase inhibitors and antiestrogenswould be most interesting.

Clinical studies with antiestrogen have also provided someinsight into the endocrinology of human breast cancer. It seemsclear that estrogens play a major role in maintaining the growthof some breast cancers, and this action appears to be direct atthe level of the tumor. Whether other hormones, such aspituitary hormones, play a role in stimulating tumor growthremains to be established. The observation that androgentherapy may be effective after antiestrogen treatment andhypophysectomy suggests that other endocrine factors may beinvolved in tumor growth.

References

1. Cole. M. P., Jones, C. T. A., and Todd, I. D. H. A new antiestrogenic agentin late breast cancer. An early clinical appraisal of ICI 46474. Br. J. Cancer,25. 270-275, 1971.

2. European Breast Cancer Group. Clinical trial of Nafoxidine, an oestrogenantagonist in advanced breast cancer. Eur. J. Cancer. 8. 387-389, 1972.

3. Fisher. B., Redmond, C., Brown, A.. Wolmark, N., Wittliff, J., Fisher. E. R.,Plotkin, D., Bowman. D., Sachs. S., Wolter. J., Frelick, R., Desser, R..LiCalzi. N., Geggie, P., Campbell, T., Elias, E. G.. Prager, D., Koonyz, P.,Volk, H., Dimitrov, N., Gardner, B.. Lerner, H., Shibata H., and Other NSABPInvestigators. Treatment of primary breast cancer with chemotherapy andtamoxifen. N. Engl. J. Med., 305. 1-6, 1981.

4. Hubay. C A.. Pearson. O. H.. Marshall. J. S.. Rhodes. R. S.. Debanne. S.M.. Mansour. E. G., Hermann. R. E.. Jones, J. C.. Flynn, W. J., Eckert, C.,and McGuire, W. L. Antiestrogen, cytotoxic chemotherapy, and BacillusCa/mette-Guerin vaccination in stage II breast cancer: a preliminary report.Surgery, 87: 494-501. 1980.

5. Hubay. C. A., Pearson, O. H.. Marshall, J. S. Stellato. T. A., Rhodes, R. S..DeBanne, S. M., Rosenblatt. J., Mansour, E. G., Hermann, R. E., Jones. J.C., Flynn, W. J., Eckert, C., McGuire, W. L., and 27 Participating Investigators. Adjuvant therapy of stage II breast cancer: 48-month follow-up of aprospective randomized clinical trial. Breast Cancer Res. Treat., 1: 77-82,

1981.6. Ingle, j. N.. Ahmann, D. L., Green, S. J., Edmonson, J. H., Bisel, H. F.,

Kvols, L. K., Nichols, W.C.. Creagan, E. T., Hahn, R. G., Rubin, J., andFrytak. S. Randomized clinical trial of diethylstilbestrol versus tamoxifen inpostmenopausal women with advanced breast cancer. N. Engl. J. Med. 304:16-21, 1981.

7. Ingle, J. N., Green, S. J., Ahmann, D. L., Edmonson, J. H.. Nichols, W. C.,Frytak, S., and Rubin, J. Progress report on two clinical trials in women withadvanced breast cancer. Trial I: tamoxifen versus tamoxifen plus aminoglutethimide; Trial II: aminoglutethimide in patients with prior tamoxifen exposure. Cancer Res. (Suppl.), 42: 3461s-3464s, 1982.

8. Kiang, D. T., Frenining, D.H., Vosika, G. J., and Kennedy. B. J. Comparison

of tamoxifen and hypophysectomy in breast cancer treatment. Cancer(Phila.), 45: 1322-1325, 1980.

9. Lipton, A., Harvey, H. A., Santen, R. J., Boucher, A.. White, D., Bernath, A.,Dixon, R., Richards, G., and Shafik, A. A randomized trial of aminoglutethimide versus tamoxifen in metastatic breast cancer. Cancer Res. (Suppl.)42: 3434S-3436S, 1982.

10. Manni, A., Arafah, B., and Pearson, O. H. Changes in endocrine statusfollowing antiestrogen administration to premenopausal and postmenopausal women. In: R. L. Sutherland and V. C. Jordon (eds.), Non-steroidalAntiestrogens, pp. 435-452, New York: Academic Press, Inc., 1981.

11. Manni, A., Arafah, B. M., and Pearson, O. H. Androgen-induced remissionsafter antiestrogen and hypophysectomy in stage IV breast cancer. Cancer(Phila.), 48: 2507-2509. 1981.

12. Manni, A., Arafah, B. M., and Pearson, O. H. Medical hypophysectomy inadvanced breast cancer. In: E. P. Rose (ed.). Endocrinology of Cancer, Vol.3. West Palm Beach, Fla.: CRC Press, in press, 1982.

13. Manni, A., and Pearson. O. H. Antiestrogen-induced remissions in premenopausal women with stage IV breast cancer: effects on ovarian function.Cancer Treat. Rep., 64. 779-785. 1980.

14. Manni, A., Pearson, O. H., Brodkey, J., and Marshall, J. S. Trans-sphenoidalhypophysectomy in breast cancer: evidence for an individual role of pituitaryand gonadal hormones in supporting tumor growth. Cancer (Phila.), 44:2330-2337, 1979.

15. Manni, A., Pearson, O. H., Marshall, J. S., and Arafah, B. M. Sequentialendocrine therapy and chemotherapy in metastatic breast cancer: effectson survival. Breast Cancer Res. Treat.. 1: 97-103, 1981.

16. Manni, A., Trujillo, J. E., Marshall, J. S., Brodkey, J., and Pearson, O. H.Antihormone treatment of stage IV breast cancer. Cancer (Phila.), 43: 444-

450, 1979.17. Mouridsen, H. T., Salimtschik, M., Dombernowsky, P., Gelshoj, K.. Palshof.

T., Rorth, M., Daennfeldt, J. L., and Rose, C. Therapeutic effect of tamoxifenversus combined tamoxifen and diethylstilbestrol in advanced breast cancerin postmenopausal women. In: H. T. Mouridsen and T. Palshof (eds.). BreastCancer: Experimental and Clinical Aspects, pp. 107-110. Elmsford, N. Y.:Pergamon Press, 1980.

18. Murray, R. M. L., and Pitt, P. Medical adrenalectomy in patients withadvanced breast cancer resistant to anti-oestrogen treatment. Breast CancerRes. Treat., Õ.91-95, 1981.

19. Osborn, C. K. Combined chemo-hormonal therapy in breast cancer: ahypothesis. Breast Cancer Res. Treat. ). 121-123, 1981.

20. Patterson, J. S. "Nolvadex" (tamoxifen) as an anti-cancer agent in humans.

In: R. L. Sutherland and V. C. Jordan (eds.), Non-steroidal Antiestrogens,pp. 453-472. New York: Academic Press, Inc., 1981.

21. Pritchard, K. I., Thomson, D. B., Myers, R. E.. Sutherland, D. J. A., Mobbs,B. G., and Meakin, J. W. Tamoxifen therapy in premenopausal patients withmetastatic breast cancer. Cancer Treat. Rep., 64: 787-796. 1980.

22. Santen, R. J., Santner, S. J., Davis, B., Veldhuis, J., Samojlik, E., and Ruby,E. Aminoglutethimide inhibits extraglandular estrogen production in postmenopausal women with breast cancer. J. Clin. Endocrinol. Metab., 47:1257-1265, 1978.

23. Settatree, R. S., Butt, W. P.. London, D. R., Holme, G. M., and Morrison, J.M. Tamoxifen and bromocriptine combination in advanced breast cancer.In: Proceedings of the Twelfth International Congress on Cancer, BuenosAires, pp. 3-79, 1978.

24. Smith, I. E., Harris. A. L., Morgan, M., Gazet, J.-C.. and McKinna. J. A.Tamoxifen versus aminoglutethimide versus combined tamoxifen and aminoglutethimide in the treatment of advanced breast carcinoma. Cancer Res.(Suppl.), 42: OOOOs-OOOOs,1982.

25. Stewart, H. J., Forrest, A. P. M., Gunn, J. M., Hamilton, T., Langland, A. O.,McFadyen, I. J., Raab, G., and Roberts, M. M. The tamoxifen trial. A doubleblind comparison with stilbesterol in postmenopausal women with advancedbreast cancer. In: H. T. Mouridsen and T. Palshof (eds.), Breast Cancer—Experimental and Clinical Aspects, pp. 83-88. Elmsford. N. Y.: Pergamon

Press, 1980.26. Tormey, D. C., Simon, R. M., Lippman, M. E. Bull, J. M., and Myers, C. E.

Evaluation of tamoxifen dose in advanced breast cancer: a progress report.Cancer Treat. Rep., 60. 1451-1459, 1976.

27. Ward, H. W. C. Anti-oestrogenic therapy for breast cancer: a trial of tamoxifen at two dose levels. Br. Med. J.. 1:13-14, 1973.

28. Ward, H. W. C. Combined anti-prolactin and anti-oestrogen therapy forbreast carcinoma. Clin. Oncol.. 3. 91-95, 1977.

Discussion

Dr. Naftolin: Dr. Pearson, the rate at which these lesions repairthemselves in the bone is very impressive. We have not heard aboutthe effects of depleting estrogen, either by binding receptors or bypreventing its manufacture, with regard to bone and bone mass. Iwonder whether in any of your studies you looked at bone turnover?

Dr. Pearson: We have not done special calcium studies. We simply

3428s

observed that the bone heals, can remodel itself, and can return tonormal. Results in bone are about the same as in visceral lesions andsoft tissue lesions with the antiestrogens.

Dr. Naftolin: When people are on TAM' tor years at a time, do they

show any evidence of osteoporosis?

1The abbreviations used are: TAM. tamoxifen; ER, estrogen receptor.

CANCER RESEARCH VOL. 42

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1982;42:3424s-3428s. Cancer Res   Olof H. Pearson, Andrea Manni and Baha'uddin M. Arafah  Antiestrogen Treatment of Breast Cancer: An Overview

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Research. on February 18, 2020. © 1982 American Association for Cancercancerres.aacrjournals.org Downloaded from