Antiestrogen Treatment of Breast Cancer: an Overview1

Home , Antiestrogen, Nafoxidine, Stilbestrol

(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 a into the target tissue rather than suppression of circulating highly effective, nontoxic endocrine therapy for women with estrogen levels. The antiestrogen tamoxifen has emerged as Stage IV and II estrogen receptor-positive breast cancer. Ta the favored drug because of its minimal toxicity, and a large moxifen appears to act by blocking endogenous estrogen number of clinical trials have been carried out with tamoxifen action at the target tissue level rather than by suppression of in women with Stage IV and II breast cancer which indicate that circulating estrogen levels. it is a highly effective therapeutic agent. The purpose of this In a series of 113 consecutive, selected patients with Stage report is to review some of the clinical studies with antiestro- IV breast cancer, tamoxifen induced objective remissions in gens which may help to evaluate their role in relationship to 50% lasting an average period of 21 + months and a median other modalities of endocrine therapy. period of 16 months. These results are comparable to previous Early studies showed that tamoxifen could induce objective results with surgical hypophysectomy. Recent randomized remissions in 30 to 40% of women with advanced breast studies comparing pharmacological doses of estrogen versus cancer most of whom had previously been treated with other tamoxifen in postmenopausal women with Stage IV breast endocrine and/or chemotherapeutic modalities (1, 27). The cancer have shown comparable results with these two treat results of our initial study in 113 consecutive, selected patients ment modalities. with Stage IV breast cancer (16), recently updated (15), are Antiestrogen therapy has been shown to be effective in some shown in Table 1. Fifty % of these patients obtained objective patients after prior endocrine additive therapy and, in particu tumor regression lasting for an average period of 21+ months lar, after ablative procedures, such as ovariectomy, adrenal- with a median duration of 16 months. Survival after the onset ectomy, and hypophysectomy. It has been shown that circulat of tamoxifen treatment was significantly longer in those patients ing estrogens are not completely eliminated following ablation who responded to treatment as compared to those who failed of these endocrine glands, which may account for the effec to benefit. Overall survival from the onset of metastasis was tiveness of antiestrogen in this setting. significantly prolonged in those patients who benefited from Other endocrine therapies have been shown to be effective antiestrogen therapy as compared to those who failed to re after prior treatment with antiestrogen. Hypophysectomy can spond (Chart 1). Tumor regression occurred in visceral, os induce remissions in 60% of patients who initially responded seous, and soft tissue sites with about equal frequencies. to tamoxifen and in 25% of patients who failed to benefit from Patients with estrogen receptor-positive tumors had a signifi tamoxifen. Recent studies have shown that aminoglutethimide cantly higher remission rate (63%) than did those in whom plus hydrocortisone may also induce remissions in some pa estrogen receptor measurements were not done (44%). tients after prior treatment with tamoxifen. This latter finding is Women who were more than 10 years postmenopausal had a of particular interest since aminoglutethimide is thought to work significantly higher remission rate (58%) than did those who by blocking estrogen production, and the finding suggests that were less than 10 years postmenopausal (41 %). These results tamoxifen does not completely block all endogenous estrogen of tamoxifen therapy in women with Stage IV breast cancer activity. Fluoxymesterone has been shown to induce remis indicate a high order of effectiveness, which are quite compa sions after tamoxifen or after tamoxifen plus hypophysectomy, rable to our results in 200 women with surgical hypophysec and there was no correlation between the response to anties tomy where the incidence of objective remissions was 42% trogen and subsequent response to androgen. with an average duration of 18+ months and a median of 16 Because of its effectiveness and minimal side effects, tamox months (14). Tamoxifen administration did not alter serum ifen is considered to be an initial endocrine therapy of choice estrogen levels in postmenopausal women but did induce a in women with breast cancer. However, it has its limitations, as slight decrease in serum gonadotrophin levels. Serum prolactin demonstrated by the results of secondary endocrine therapies and growth hormone levels were unaffected by antiestrogen such as hypophysectomy, medical adrenalectomy, and andro therapy (10). gen therapy. Tamoxifen induces remissions in premenopausal women with Stage IV breast cancer with an incidence and duration of remissions which appear to be comparable to those of surgical Nonsteroidal antiestrogen drugs were first reported to be ovariectomy (13, 21). It is of interest that tumor regression effective antitumor agents in women with advanced breast occurs despite continued cyclic menstrual bleeding in most of cancer a decade ago (1, 2). These drugs were novel in that the patients. This suggests that it is not necessary to eliminate their mechanism of action appeared to be competitive binding all estrogen action to obtain mammary tumor regression. Ta to the estrogen receptor and blocking the entry of estrogens moxifen has been shown to induce a marked increase in

1 Presented at the Conference "Aromatase: New Perspectives for Breast ovarian estrogen secretion, perhaps mediated by increased Cancer." December 6 to 9. 1981. Key Biscayne. Fla. Supported in part by pituitary gonadotropin secretion, which may counteract to USPHS Grant CA-05197 and American Cancer Society, Inc.. Grant PDT-48W. some extent the effects of the antiestrogen (10). Thus far, all

3424s CANCER RESEARCH VOL. 42

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

Median21+ 1623 (4-54+)a +0 40 39 +'15 changeFailuresNo.56849%50743Duration(9-45) 19remission5 +Survival a Numbers in parentheses, range 6 p < 0.0005 versus "failures" group.

1.0 ment) improved the chance of a second remission on antiestro gen to 31 of 46 (67%) (20). In 34 women who failed to respond to previous endocrine therapy, 5 (15%) achieved a remission ÃŒO.0.8 > on antiestrogen treatment. Similar findings were noted in our > ac initial study (16). When tamoxifen was used as a secondary D (/* treatment after stilbestrol, Stewart ef al. (25) noted the same Z0.6 g incidence and duration of remissions as when antiestrogen was used as a primary treatment. Two patients who failed on Oi 0.4 stilbestrol therapy responded to tamoxifen. Ingle ef al. (6) o. REMISSIONS + reported that, of 25 patients who had had objective tumor UJ > , NO CHANGE progression without a regression on stilbestrol, only 3 (12%) <0.2 had a partial regression with tamoxifen as secondary therapy. Of 6 patients in whom disease progression occurred during the FAILURES withdrawal phase after stilbestrol therapy, 4 patients re 1 23456789 sponded to tamoxifen treatment. Kiang ef al. (8) obtained YEARS remissions with tamoxifen as secondary treatment in 4 of 6 Chart 1. Life table plots of survival from onset of metastasis for patients who benefited from tamoxifen (remissions plus no change) and for those who failed to patients who had initially responded to stilbestrol therapy. In respond, p < 0.001 (generalized Wilcoxon test). Bars, 2 S.E. Reproduced from addition, 2 of 3 patients responded to tamoxifen after previous Breast Cancer Research and Treatment (15) by permission of Martinus Nijhoff remission on androgen therapy. Publishers. It has now been well documented that antiestrogens can patients who failed to benefit from tamoxifen have subsequently induce tumor regression in some patients after initial endocrine- failed to respond to ovariectomy. Although further studies are ablative procedures, such as ovariectomy, adrenalectomy, and needed, these preliminary results suggest that antiestrogen is hypophysectomy. In our study, 8 of 9 premenopausal women an effective initial endocrine treatment for premenopausal who obtained objective remissions following ovariectomy re women with Stage IV breast cancer. sponded to tamoxifen as a secondary therapy. Two of 4 pa tients who had undergone combined ovariectomy-adrenalec- Randomized Studies tomy subsequently responded to antiestrogen treatment. The results of tamoxifen therapy in 29 patients who had initially Kiang ef al. (8) compared the results of tamoxifen versus responded to surgical hypophysectomy followed by relapse hypophysectomy in 26 women who had previously responded are shown in Table 2. One-fourth of these patients obtained to ovariectomy or to additive hormone therapy (estrogen or objective tumor regression, and one-fourth had no progression androgen). In this small series of patients, the incidence and of disease on tamoxifen treatment with a median duration of duration of remission were similar for these 2 modalities of 16.5 months. The completeness of hypophysectomy was doc treatment. umented by finding undetectable levels of serum prolactin, Two studies comparing the effects of tamoxifen versus phar thyroid-stimulating hormone, and growth hormone after pro macological doses of estrogen in postmenopausal women with vocative stimuli. Nevertheless, serum estrone and estradiol advanced breast cancer have been reported (6, 25). In both were detectable at low levels (5 to 40 pg/ml) in these patients. studies, no prior endocrine therapy was used, and cross-over These results suggest that estrogens, even in small amounts, studies were attempted. No significant difference in incidence can directly stimulate tumor growth in the absence of the or duration of remission was found between estrogen versus pituitary gland and that antiestrogens can counteract this ef tamoxifen therapy in these 2 studies. The incidence of side fect. effects was much greater with estrogen therapy, and both From these studies, it is apparent that antiestrogens are very groups of investigators felt that antiestrogen was the preferred effective when used as a secondary form of endocrine therapy. initial therapy for postmenopausal patients. A response to initial, additive, hormonal therapy appears to Randomized trials of aminoglutethimide versus antiestrogen have predictive value for a response to antiestrogen as a are reported in this supplement (9). secondary therapy. It is now well documented that endocrine- Antiestrogen Therapy after Prior Endocrine Therapy ablative procedures such as ovariectomy, adrenalectomy, and hypophysectomy do not eliminate circulating estrogens and Early studies with tamoxifen indicated that a response to that low levels of circulating estrogens after endocrine gland previous endocrine therapy (usually additive hormonal treat ablations may be effective in stimulating tumor growth as

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evidenced by the high incidence of response to antiestrogen Surgical hypophysectomy has been carried out in 61 women used as a secondary therapy. with Stage IV breast cancer who were treated previously with tamoxifen (12). The results are shown in Table 3. Of 28 postmenopausal women who initially responded to tamoxifen, Other Endocrine Therapy after Antiestrogen Treatment 16 (57%) obtained further remission from hypophysectomy lasting for an average period of more than 1 year. Of 22 The question as to whether antiestrogen in the dosages used patients who initially failed to benefit from tamoxifen, 6 (27%) therapeutically (about 40 mg tamoxifen per day) can block all obtained objective remissions following hypophysectomy last estrogen action in vivo has been approached by observations ing for an average period of 8.5 months. The mechanism by in premenopausal women and by observations of the effects of which hypophysectomy induced remissions in these patients is other endocrine therapy after antiestrogen treatment. It has not known, but, if antiestrogen therapy was capable of blocking been noted above that antiestrogen as primary treatment in all estrogen action in these postmenopausal women, it would premenopausal women with Stage IV breast cancer induces seem likely that a pituitary factor was involved. There is new remissions with an incidence and duration of remissions com evidence (see below) that antiestrogen may not be capable of parable to the results of surgical ovariectomy (13, 21). These blocking all estrogen action in postmenopausal women and tamoxifen-induced remissions occur despite the fact that the that the effects of hypophysectomy might be due at least in patients continue to have cyclic menstrual bleeding, and es part to reduction in circulating estrogen levels. calation of the dosage of tamoxifen up to 120 mg/day some A recent report by Murray and Pitt (18) has evaluated the times failed to induce complete cessation of menstrual bleed response of 53 women with Stage IV breast cancer, who were ing. These observations indicate that antiestrogen does not previously treated with antiestrogen, to aminoglutethimide-cor- block all estrogen action at least in the uterus of women with tisone therapy ("medical adrenalectomy"). Of 16 patients who high circulating estrogen levels. initially responded to tamoxifen, 11 patients (69%) obtained a The results of surgical ovariectomy in premenopausal pa remission from aminoglutethimide. Of 32 patients who failed to tients who were initially treated with tamoxifen also provide benefit from tamoxifen, 13 (35%) had objective remissions on evidence that antiestrogen does not block all estrogen action aminoglutethimide therapy. The median duration of the ami- in the mammary cancers (12, 13). In these 2 reports, there noglutethimide-induced remissions was 12 months. These re were 16 patients who failed to respond to initial tamoxifen sults are virtually identical to the results shown above for therapy, all of whom failed to benefit from subsequent ovarian surgical hypophysectomy after tamoxifen therapy. Additional ablation. Of 9 patients who responded to tamoxifen initially and results of aminoglutethimide therapy after tamoxifen are pre followed by relapse, 7 women subsequently responded to sented in this supplement (7). Santen ef al. (22) have shown ovarian ablation. Thus, the response to tamoxifen seems highly that aminoglutethimide not only suppresses adrenal steroid predictive of subsequent response to ovariectomy. Since re synthesis but also inhibits extraglandular estrogen production sponse to ovariectomy is considered to be due to lowering of in postmenopausal women with breast cancer and thus lowers serum estrogen levels, these results would suggest that anties circulating estrogen levels in postmenopausal women. trogen therapy was not capable of blocking all estrogen action Androgen therapy (fluoxymesterone, 10 mg p.o. twice a day) at the tumor level in premenopausal patients. was given to 33 women with Stage IV breast cancer who had been treated previously with tamoxifen and 17 of whom had Table 2 also undergone hypophysectomy (11 ). Objective remissions Results of tamoxifen therapy in 29 patients posthypophysectomy were obtained in 13 patients (39%) with an average duration of Reproduced from Endocrinology of Cancer (12) by permission of CRC Press. 11 + months. Of 17 patients who had previously been treated PatientsRemission still with tamoxifen and hypophysectomy, 7 obtained further remis in remis (mos.)19+duration3 sions from fluoxymesterone for an average period of 10 sion1 (4-63.5+)* months.There was no correlation between the initial response to tamoxifen (or hypophysectomy) and the subsequent re No progression 6 2152Mean19.5+ (11-32 + )No. 1 FailuresNo.8 15%27 sponse to androgen therapy. Although the mechanism by which ' Median. 16.5 months (regression plus no progression). pharmacological doses of androgen induce remissions in some ' Numbers in parentheses, range. women 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 stillsion1012Failures1216937 (mos.)13+ (3-29)c8.5 tamoxifenFailuresto tamoxifenArrestto (5-16)21+ ontamoxifenTotalNo.28221161No.16"6224%57271839Duration3of disease )13 (20, 22 +

+No. Median, 11.5 months. 6 In 3 patients, only arrest of disease was documented. c Numbers in parentheses, range.

3426s CANCER RESEARCH VOL. 42

Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1982 American Association for Cancer Research. Antiestrogens in Breast Carcinoma suggest that it is probably not an antiestrogen effect or an Combination of Antiestrogen with Other Modalities of indirect effect mediated through the pituitary gland. Treatment Estrogen therapy (diethylstilbestrol, 5 mg p.o. twice a day) has also been shown to induce remissions in a few patients There have been very few studies in which antiestrogen has after previous treatment with antiestrogen. Stewart ef al. (25) been combined with other modalities of endocrine therapy. noted remissions in 4 of 17 patients who had previously been Mouridsen ef al. (17) studied the effect of tamoxifen (30 mg treated with tamoxifen with a median duration of about 6 daily) versus tamoxifen plus diethylstilbestrol (3 mg daily) in 122 postmenopausal patients with advanced breast cancer. months. Ingle ef al. (6) observed that 9 of 33 patients (22%) had a partial regression during secondary treatment with stil- They found no significant difference in the incidence or duration bestrol. This group included 5 of 11 (45%) with a prior response of remissions with these 2 regimens. Ward (28) reported that addition of a prolactin-lowering agent to antiestrogen therapy to tamoxifen and 4 of 22 (18%) without a prior response to tamoxifen. The duration of remissions was apparently rather of patients refractory to tamoxifen resulted in further stabiliza short since the "median time to treatment failure" was only 56 tion of the disease, and 2 of 45 patients had an objective response. In a small randomized study, Settatree ef al. (23) days. Virtually no information is available on the use of progestins found no clear differences between tamoxifen versus tamoxifen as secondary therapy after tamoxifen. We have observed ob plus bromocryptine. Tormey ef al. (26) studied the effects of combining antiestrogen and androgen therapy. Subsequent jective remissions in 2 of 12 patients who received Megace (40 follow-up of this study2 indicates that there was some additional mg 4 times a day p.o.) after previous treatment with tamoxifen. These results of various endocrine treatments after tamoxifen benefit from this combination, but the results did not suggest therapy indicate that ovariectomy, hypophysectomy, and med a synergistic effect or any advantage over the sequential use ical adrenalectomy can induce a high percentage of significant of these therapies. secondary remissions, particularly in those patients who have A comparison of antiestrogen versus antiestrogen plus ami had an initial response to antiestrogen therapy. Thus, ovariec noglutethimide is reported in this supplement (7, 24). tomy appears to be the secondary treatment of choice for A number of studies have combined antiestrogen therapy premenopausal patients who have responded to tamoxifen. with cytotoxic chemotherapy, and the results of these studies The impressive results with medical adrenalectomy in postmen- recently have been reviewed by Patterson (20). The early trials opausal patients after tamoxifen as reported by Murray and Pitt suggest that there is no apparent antagonism between these 2 (18) appear to justify their conclusion that aminoglutethimide classes of agents. Other studies have suggested that there is is the secondary treatment of choice in patients who have no advantage in combining these agents and that sequential initially responded to antiestrogen. Further studies of surgical use of these modalities may enhance the quality of life. Osborn hypophysectomy after antiestrogen and aminoglutethimide are (19) has postulated that the apparent lack of synergism with needed to determine whether there is any further role for this combined endocrine and cytotoxic chemotherapy could be due procedure in the management of women with advanced breast to the effect of endocrine therapy on tumor cell kinetics, which cancer. Of the responses to additive hormone therapy after could inhibit the activity of the cytotoxic drugs. He has pro antiestrogen, the remissions induced by androgen appear to posed alternative designs for chemoendocrine therapy in which be the most effective, and thus the drug constitutes the tertiary hormones might be used as synchronizing or recruiting agents endocrine therapy of choice. to enhance the effectiveness of cytotoxic drugs. Discussion

Antiestrogen as Adjuvant Treatment in Women with Stage II The nonsteroid antiestrogen tamoxifen has emerged as a Breast Cancer highly effective, nontoxic endocrine therapy for women with breast cancer. At present, it is probably the initial endocrine treatment of choice for both pre- and postmenopausal women Tamoxifen is an ideal drug for systemic therapy in women with earlier stages of breast cancer (Stage I and II) because of with Stage IV breast cancer. It has also been shown to be its high order of effectiveness and lack of significant side useful as adjuvant endocrine therapy for women with estrogen receptor-positive Stage II breast cancer. effects. Hubay ef al. (4, 5) have reported a prospective, ran domized clinical trial of tamoxifen plus 3-drug chemotherapy Clinical studies have shown that there are limitations to the (Cytoxan-methotrexate-5-fluorouracM) versus Cytoxan-metho- effectiveness of this antiestrogen in the endocrine management trexate-5-fluorouracil alone in 318 women with Stage II breast of patients with breast cancer. The data suggest that tamoxifen, cancer. The results of this study indicate that tamoxifen plus with the therapeutic dosages used, does not block all endog chemotherapy was more effective than chemotherapy alone in enous estrogen action in either premenopausal or postmeno delaying recurrence in women with estrogen receptor positive pausal patients. In premenopausal patients, although antiestro cancers. Fisher ef al. (3) have recently reported similar findings gen may induce tumor regression comparable to ovarian abla with the use of tamoxifen plus 2-drug chemotherapy (L-phe- tion, these patients may continue to have cyclic menstrual nylalanine mustard-5-fluorouracN) versus chemotherapy alone bleeding, and ovariectomy may induce further remissions in in women with estrogen receptor-positive Stage II breast can women who have initially responded to tamoxifen. These re cer. Further follow-up periods are needed to determine whether sults suggest that optimal antiestrogen treatment in premeno antiestrogen can prevent recurrence in some patients or pausal patients may require ovarian ablation, aminoglutethim whether relapse is simply delayed. These results suggest that ide, and antiestrogen. In postmenopausal patients, although antiestrogen has a significant role in the systemic treatment of less advanced stages of this disease. 2 D. C. Tormey. personal communication.

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tamoxifen may induce remissions comparable to those of sur of tamoxifen and hypophysectomy in breast cancer treatment. Cancer gical ablative procedures such as adrenalectomy or hypophy- (Phila.), 45: 1322-1325, 1980. 9. Lipton, A., Harvey, H. A., Santen, R. J., Boucher, A.. White, D., Bernath, A., sectomy, the aromatase inhibitor aminoglutethimide has been Dixon, R., Richards, G., and Shafik, A. A randomized trial of aminogluteth shown to induce further remissions after initial antiestrogen imide versus tamoxifen in metastatic breast cancer. Cancer Res. (Suppl.) 42: 3434S-3436S, 1982. therapy, particularly in those patients who initially responded 10. Manni, A., Arafah, B., and Pearson, O. H. Changes in endocrine status to antiestrogen. These results suggest that tamoxifen does not following antiestrogen administration to premenopausal and postmenopau block all estrogen action even in postmenopausal women sal women. In: R. L. Sutherland and V. C. Jordon (eds.), Non-steroidal Antiestrogens, pp. 435-452, New York: Academic Press, Inc., 1981. whose circulating estrogen levels are lower than in the pre- 11. Manni, A., Arafah, B. M., and Pearson, O. H. Androgen-induced remissions menopausal patient. For the future, it seems possible that other after antiestrogen and hypophysectomy in stage IV breast cancer. Cancer antiestrogen drugs, which bind with a higher affinity to the (Phila.), 48: 2507-2509. 1981. 12. Manni, A., Arafah, B. M., and Pearson, O. H. Medical hypophysectomy in estrogen receptor, might prove to be more effective in blocking advanced breast cancer. In: E. P. Rose (ed.). Endocrinology of Cancer, Vol. the peripheral action of estrogens in vivo. Aromatase inhibitors, 3. West Palm Beach, Fla.: CRC Press, in press, 1982. 13. Manni, A., and Pearson. O. H. Antiestrogen-induced remissions in premen which could lower circulating estrogen levels to virtually nil, opausal women with stage IV breast cancer: effects on ovarian function. might also prove to be most effective. For the present, studies Cancer Treat. Rep., 64. 779-785. 1980. on the combination of aromatase inhibitors and antiestrogens 14. Manni, A., Pearson, O. H., Brodkey, J., and Marshall, J. S. Trans-sphenoidal hypophysectomy in breast cancer: evidence for an individual role of pituitary would be most interesting. and gonadal hormones in supporting tumor growth. Cancer (Phila.), 44: Clinical studies with antiestrogen have also provided some 2330-2337, 1979. insight into the endocrinology of human breast cancer. It seems 15. Manni, A., Pearson, O. H., Marshall, J. S., and Arafah, B. M. Sequential endocrine therapy and chemotherapy in metastatic breast cancer: effects clear that estrogens play a major role in maintaining the growth on survival. Breast Cancer Res. Treat.. 1: 97-103, 1981. of some breast cancers, and this action appears to be direct at 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- the level of the tumor. Whether other hormones, such as 450, 1979. pituitary hormones, play a role in stimulating tumor growth 17. Mouridsen, H. T., Salimtschik, M., Dombernowsky, P., Gelshoj, K.. Palshof. remains to be established. The observation that androgen T., Rorth, M., Daennfeldt, J. L., and Rose, C. Therapeutic effect of tamoxifen versus combined tamoxifen and diethylstilbestrol in advanced breast cancer therapy may be effective after antiestrogen treatment and in postmenopausal women. In: H. T. Mouridsen and T. Palshof (eds.). Breast hypophysectomy suggests that other endocrine factors may be Cancer: Experimental and Clinical Aspects, pp. 107-110. Elmsford, N. Y.: involved in tumor growth. Pergamon Press, 1980. 18. Murray, R. M. L., and Pitt, P. Medical adrenalectomy in patients with advanced breast cancer resistant to anti-oestrogen treatment. Breast Cancer References Res. Treat., Ã•.91-95, 1981. 1. Cole. M. P., Jones, C. T. A., and Todd, I. D. H. A new antiestrogenic agent 19. Osborn, C. K. Combined chemo-hormonal therapy in breast cancer: a in late breast cancer. An early clinical appraisal of ICI 46474. Br. J. Cancer, hypothesis. Breast Cancer Res. Treat. ). 121-123, 1981. 25. 270-275, 1971. 20. Patterson, J. S. "Nolvadex" (tamoxifen) as an anti-cancer agent in humans. 2. European Breast Cancer Group. Clinical trial of Nafoxidine, an oestrogen In: R. L. Sutherland and V. C. Jordan (eds.), Non-steroidal Antiestrogens, antagonist in advanced breast cancer. Eur. J. Cancer. 8. 387-389, 1972. pp. 453-472. New York: Academic Press, Inc., 1981. 3. Fisher. B., Redmond, C., Brown, A.. Wolmark, N., Wittliff, J., Fisher. E. R., 21. Pritchard, K. I., Thomson, D. B., Myers, R. E.. Sutherland, D. J. A., Mobbs, Plotkin, D., Bowman. D., Sachs. S., Wolter. J., Frelick, R., Desser, R.. B. G., and Meakin, J. W. Tamoxifen therapy in premenopausal patients with LiCalzi. N., Geggie, P., Campbell, T., Elias, E. G.. Prager, D., Koonyz, P., metastatic breast cancer. Cancer Treat. Rep., 64: 787-796. 1980. Volk, H., Dimitrov, N., Gardner, B.. Lerner, H., Shibata H., and Other NSABP 22. Santen, R. J., Santner, S. J., Davis, B., Veldhuis, J., Samojlik, E., and Ruby, Investigators. Treatment of primary breast cancer with chemotherapy and E. Aminoglutethimide inhibits extraglandular estrogen production in post tamoxifen. N. Engl. J. Med., 305. 1-6, 1981. menopausal women with breast cancer. J. Clin. Endocrinol. Metab., 47: 4. Hubay. C A.. Pearson. O. H.. Marshall. J. S.. Rhodes. R. S.. Debanne. S. 1257-1265, 1978. M.. Mansour. E. G., Hermann. R. E.. Jones, J. C.. Flynn, W. J., Eckert, C., 23. Settatree, R. S., Butt, W. P.. London, D. R., Holme, G. M., and Morrison, J. and McGuire, W. L. Antiestrogen, cytotoxic chemotherapy, and Bacillus M. Tamoxifen and bromocriptine combination in advanced breast cancer. Ca/mette-Guerin vaccination in stage II breast cancer: a preliminary report. In: Proceedings of the Twelfth International Congress on Cancer, Buenos Surgery, 87: 494-501. 1980. Aires, pp. 3-79, 1978. 5. Hubay. C. A., Pearson, O. H.. Marshall, J. S. Stellato. T. A., Rhodes, R. S.. 24. Smith, I. E., Harris. A. L., Morgan, M., Gazet, J.-C.. and McKinna. J. A. DeBanne, S. M., Rosenblatt. J., Mansour, E. G., Hermann, R. E., Jones. J. Tamoxifen versus aminoglutethimide versus combined tamoxifen and ami C., Flynn, W. J., Eckert, C., McGuire, W. L., and 27 Participating Investi noglutethimide in the treatment of advanced breast carcinoma. Cancer Res. gators. Adjuvant therapy of stage II breast cancer: 48-month follow-up of a (Suppl.), 42: OOOOs-OOOOs,1982. prospective randomized clinical trial. Breast Cancer Res. Treat., 1: 77-82, 25. Stewart, H. J., Forrest, A. P. M., Gunn, J. M., Hamilton, T., Langland, A. O., 1981. McFadyen, I. J., Raab, G., and Roberts, M. M. The tamoxifen trial. A double 6. Ingle, j. N.. Ahmann, D. L., Green, S. J., Edmonson, J. H., Bisel, H. F., blind comparison with stilbesterol in postmenopausal women with advanced Kvols, L. K., Nichols, W.C.. Creagan, E. T., Hahn, R. G., Rubin, J., and breast cancer. In: H. T. Mouridsen and T. Palshof (eds.), Breast Cancerâ€” Frytak. S. Randomized clinical trial of diethylstilbestrol versus tamoxifen in Experimental and Clinical Aspects, pp. 83-88. Elmsford. N. Y.: Pergamon postmenopausal women with advanced breast cancer. N. Engl. J. Med. 304: Press, 1980. 16-21, 1981. 26. Tormey, D. C., Simon, R. M., Lippman, M. E. Bull, J. M., and Myers, C. E. 7. Ingle, J. N., Green, S. J., Ahmann, D. L., Edmonson, J. H.. Nichols, W. C., Evaluation of tamoxifen dose in advanced breast cancer: a progress report. Frytak, S., and Rubin, J. 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Discussion observed that the bone heals, can remodel itself, and can return to normal. Results in bone are about the same as in visceral lesions and Dr. Naftolin: Dr. Pearson, the rate at which these lesions repair soft tissue lesions with the antiestrogens. themselves in the bone is very impressive. We have not heard about Dr. Naftolin: When people are on TAM' tor years at a time, do they the effects of depleting estrogen, either by binding receptors or by show any evidence of osteoporosis? preventing its manufacture, with regard to bone and bone mass. I wonder whether in any of your studies you looked at bone turnover? Dr. Pearson: We have not done special calcium studies. We simply 1The abbreviations used are: TAM. tamoxifen; ER, estrogen receptor.

3428s CANCER RESEARCH VOL. 42

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

Cancer Res 1982;42:3424s-3428s.

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