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Will the Experience with Tamoxifen in Breast Cancer Help De®Ne the Role of Antiandrogens in Prostate Cancer?

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Will the Experience with Tamoxifen in Breast Cancer Help De®Ne the Role of Antiandrogens in Prostate Cancer? Prostate Cancer and Prostatic Diseases (2001) 4, 72±80 ß 2001 Nature Publishing Group All rights reserved 1365±7852/01 $15.00 www.nature.com/pcan Will the experience with tamoxifen in breast cancer help de®ne the role of antiandrogens in prostate cancer? GW Chodak1* & GJCM Kolvenbag2 1The Midwest Prostate and Urology Health Center, Chicago, IL, USA; and 2AstraZeneca, Wilmington, DE, USA Breast and prostate cancers are the two predominant hormone-responsive tumours. The use of the antioestrogen tamoxifen in the treatment of breast cancer has evolved over the past 30 y from treatment for advanced breast cancer to prevention. Tamoxifen is currently the endocrine treatment of choice for advanced breast cancer and for adjuvant therapy in a broad spectrum of women whose primary tumours have functional oestrogen receptors. It has also been shown to reduce the incidence of breast cancer in high-risk women. Non- steroidal antiandrogen therapy is used in the treatment of prostate cancer, but its role is still being de®ned. The clinical development of tamoxifen and that of the antiandrogens are reviewed and parallels are uncovered which provide insight into contemporary and future management of hormone-responsive prostate cancer. Prostate Cancer and Prostatic Diseases (2001) 4, 72±80. Keywords: hormone-responsive tumours; tamoxifen; prostate cancer; non-steroidal antiandrogens; bicalutamide Introduction than 100 years ago.1 Ablative endocrine surgery became a mainstay in the palliative treatment of metastatic breast In the battle against advanced breast and prostate can- cancer, providing tumour control in approximately 30% cers, the use of endocrine manipulation has been accepted of unselected women. It was not until the mid-1940s that as ®rst-line treatment. Non-steroidal antiandrogen ther- a medical treatment, diethylstilbestrol (DES), was devel- apy is used in the treatment of prostate cancer, but its role oped for postmenopausal women.2 is still being de®ned. This paper draws parallels between Development of non-steroidal antioestrogens, particu- the clinical development of tamoxifen and that of the larly tamoxifen, provided the next advance in hormonal antiandrogens to provide insights into the potential role therapy for breast cancer. Tamoxifen was developed of the antiandrogens in the therapy of prostate cancer. initially in 1969 as a possible oral contraceptive, but preliminary trials in humans showed that the compound failed to work as an antifertility drug.3 At about the same Tamoxifen in the treatment of breast time, tamoxifen was shown to inhibit the growth of experimental hormone-dependent tumours.4 The parallel cancer discovery that the presence of oestrogen receptors in History and development tumour tissue might predict the hormone responsiveness of advanced breast cancer5 led to an evaluation of tamox- Regression of breast cancer as the result of endocrine ifen's ability to control tumour growth. Early trials with therapy (ie oophorectomy) was ®rst described more tamoxifen demonstrated that it was effective in the treat- ment of advanced breast cancer and had lower toxicity compared with other endocrine treatments.6,7 *Correspondence: G Chodak, The Midwest Prostate and Urology Oestrogen receptors reside in the nucleus of the cell. Health Center, 4646 N. Marine Drive, Suite A2400, Chicago, IL 60640, USA. When bound by oestrogen the receptor molecules dimer- Received 12 October 2000; revised 31 January 2001; ise to form functional transcription factors, which are accepted 26 February 2001 able to bind and activate promotor regions of The role of antiandrogens in prostate cancer GW Chodak & GJCM Kolvenbag oestrogen-activated genes. Tamoxifen is a type I antioes- of age, menopausal status, or adjuvant tamoxifen treat- 73 trogen that binds to the oestrogen receptor, blocking the ment. Although there was some bene®t in patients with binding of oestrogen and causing a change in the shape of truly oestrogen-receptor negative tumours, the certainty the receptor complex, which prevents it functioning as a of bene®t for these patients was less clear and remains a transcription factor. The oestrogen-activated genes that matter for research. mediate breast cancer cell replication are thus inactivated. The optimal duration of adjuvant tamoxifen therapy In addition to oestrogen, adrenal androgens are remains controversial and continues to be the subject of thought to play a role in the development of breast evaluation in ongoing clinical studies. In the mid-1990s, cancer. Postmenopausal women with breast cancer have analyses of several trials indicated that 5 y of adjuvant been found to have elevated plasma levels of adrenal tamoxifen produced greater reductions in the risk of androgens,8 and these elevated levels have also been seen recurrence and death than did 1 or 2 y of treatment.40,42,43 in women who later developed breast cancer.9 Results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-14; which evaluated 5yvs 10 y of adjuvant tamoxifen treatment for early-stage breast cancer, indicated no advantage for continuation of Study results tamoxifen beyond 5 y in women with node-negative, oestrogen-receptor positive breast cancers.44 However, Tamoxifen, like other endocrine treatments, produced the results of a randomized trial conducted by the Eastern an objective response in approximately one-third of un- Cooperative Oncology Group (ECOG)45 indicated that selected women with advanced breast cancer. The obser- women with node-positive, oestrogen-receptor positive vation of the predictive value of the oestrogen receptor tumours experienced a longer time to relapse with tamox- for responsiveness to endocrine therapy in a subset of ifen therapy continued beyond 5 y (P 0.014), but the patients with breast cancers5,10 prompted oestrogen survival difference for this subgroup was not statistically receptor measurements in several clinical studies11 ± 14 signi®cant (P 0.81). and provided the basis for a predictive test to select patients who would be more likely to respond to tamox- ifen therapy. Results showed approximately 50 ± 60% of patients with oestrogen-receptor positive tumours Breast cancer prevention responded to tamoxifen therapy. It was also demon- strated that, by measuring progesterone receptor levels, The ®nding of a decrease in contralateral breast cancer response to endocrine treatment could be further incidence after adjuvant tamoxifen therapy con®rmed a improved.15 Women with oestrogen and progesterone large amount of preclinical evidence that tamoxifen could receptor-positive tumours have a 70% probability of block both the initiation and the progression of breast response to tamoxifen, whereas only 10% of women cancer in animal models.4,46 These data led to the theory lacking these markers will respond.16 that the drug might play a role in breast cancer preven- Various studies compared tamoxifen treatment for tion, and studies were undertaken to test this hypothesis. advanced breast cancer with other types of endocrine Proving the value of tamoxifen in the prevention of therapy including oestrogens,17 androgens,18 proges- breast cancer required very large (13 000 ± 20 000 subjects), tins,19,20 aminoglutethimide,21,22 oophorectomy,23,24 and randomized, placebo-controlled, double-blind clinical adrenalectomy.25 Generally, tamoxifen achieved response trials; three trials were started in Europe and North rates similar to those seen with other endocrine therapies America.47 The initial results of one trial, the Breast but was associated with considerably less toxicity. The Cancer Prevention Trial, conducted by the NSABP, high objective response rate combined with low acute became available in 1998.48 The study showed that toxicity established tamoxifen as the treatment of choice tamoxifen (n 6681), when compared with placebo for advanced relapsed metastatic breast cancer, parti- (n 6707), lowered the incidence of breast cancer by cuarly in patients with oestrogen-receptor positive 49% (two-sided P < 0.00001) in high-risk women (eg tumours and those with non-life-threatening visceral those aged 60 y; those aged 35 ± 59 y with a 5-year disease in which a rapid response is not essential. predicted risk for breast cancer of at least 1.66%; or Many multicentre trials of tamoxifen as adjuvant ther- those with a history of lobular carcinoma in situ). The apy were begun between 1975 and 1982.13,26 ± 37 These risk decreased in women aged 49 y (44%), 50 ± 59 y trials varied considerably in design and in the dosage and (51%), and 60 y (55%). The incidence of breast cancer duration of treatment. Generally, the results of these trials was reduced in women with a history of lobular carci- tended to point in the same direction: a reduction in the noma in situ or atypical hyperplasia. Tamoxifen also risk of relapse and death for patients receiving tamoxifen reduced the incidence of non-invasive breast cancer by compared with those receiving placebo. By the early 50%. Tamoxifen administration did not alter the average 1990s, 10-y data from adjuvant trials had become avail- annual rate of ischaemic heart disease, but hip, radius able.38 ± 41 Analysis of the ®ndings indicated that tamox- (Colles'), and spine fractures were reduced. The rate of ifen 20 mg/day given as adjuvant therapy for 2 ± 5 y after endometrial cancer increased in the tamoxifen group primary treatment reduced the odds of recurrence and predominantly in women aged 50 y. All endometrial death each year for at least 10 y in most patient subsets. cancers in the tamoxifen group were stage I (localized Speci®cally, this bene®t was observed in women with disease); no endometrial cancer deaths have occurred in breast cancer that was oestrogen-receptor positive and this group. No cases of liver cancer or increases in the also in women with breast cancer for whom no oestrogen incidences of colon, rectal, ovarian, or other tumours were receptor measurement was available; it was independent observed in the tamoxifen group. The rates of stroke, Prostate Cancer and Prostatic Diseases The role of antiandrogens in prostate cancer GW Chodak & GJCM Kolvenbag 74 pulmonary embolism, and deep vein thrombosis were oestrogen receptors.
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