Tamoxifen: a most unlikely pioneering medicine

For more than 25 years, tamoxifen has been the gold standard for the endocrine treatment of all stages of oestrogen-receptor-positive breast cancer, and the World Health Organization lists tamoxifen as an essential drug for the treatment of breast cancer. It is estimated that more than 400,000 women are alive today as a result of tamoxifen therapy, and millions more have benefited from palliation and extended disease-free survival. Interestingly, tamoxifen also became the first cancer chemopreventive approved by the Food and Drug Administration (FDA) for the reduction of breast-cancer incidence in both pre- and post-menopausal women at high risk. However, 40 years ago, it was hard to imagine that a non-toxic targeted treatment for breast cancer could be developed at all.

[1]  G. Beatson On the Treatment of Inoperable Cases of Carcinoma of the Mamma: Suggestions for a New Method of Treatment, with Illustrative Cases , 1896, Transactions. Medico-Chirurgical Society of Edinburgh.

[2]  Stanley Boyd,et al.  Oophorectomy for Cancer of the Breast , 1900, The Hospital.

[3]  A. Lathrop,et al.  Further investigations on the origin of tumors in mice. III. On the part played by internal secretion in the spontaneous development of tumors. , 1916, The Journal of cancer research.

[4]  A. Lacassagne,et al.  Hormonal Pathogenesis of Adenocarcinoma of the Breast , 1936 .

[5]  A. Haddow,et al.  Influence of Synthetic Oestrogens on Advanced Malignant Disease , 1944, British medical journal.

[6]  A. H. Harkness,et al.  Oral penicillin in gonorrhoea. , 1946, Lancet.

[7]  E. Paterson,et al.  SYNTHETIC ŒSTROGENS IN MAMMARY CANCER , 1949 .

[8]  E. Paterson,et al.  Synthetic oestrogens in mammary cancer. , 1949, Lancet.

[9]  L. Lerner,et al.  A non-steroidal estrogen antiagonist 1-(p-2-diethylaminoethoxyphenyl)-1-phenyl-2-p-methoxyphenyl ethanol. , 1958, Endocrinology.

[10]  A. Chobanian,et al.  The effects of triparanol (MER-29) in subjects with and without coronary artery disease. , 1960, JAMA.

[11]  L. Lerner,et al.  Gonadotrophin Inhibiting and Anti-Fecundity Effects of Chloramiphene. ∗ , 1960, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[12]  M. Thompson,et al.  Studies of cholesterol biosynthesis. I. The identification of desmosterol in serum and tissues of animals and man treated with MER-29. , 1960, The Journal of biological chemistry.

[13]  R. Greenblatt,et al.  Induction of ovulation with MRL/41. Preliminary report. , 1961, JAMA.

[14]  C. Huggins,et al.  Mammary Cancer Induced by a Single Feeding of Polynuclear Hydrocarbons, and its Suppression , 1961, Nature.

[15]  Kraft Ro Triparanol in the treatment of disseminated mammary carcinoma. , 1962 .

[16]  R. Laughlin,et al.  Cataracts in patients treated with triparanol. , 1962, JAMA.

[17]  R. Kraft Triparanol in the treatment of disseminated mammary carcinoma. , 1962, Cancer chemotherapy reports.

[18]  G. Duncan,et al.  Antifertility Activities of Two Diphenyl-Dihydronaphthalene Derivatives , 1963 .

[19]  C. Griffiths,et al.  CLOMIPHENE CITRATE (NSC-35770) IN DISSEMINATED MAMMARY CARCINOMA. , 1964, Cancer chemotherapy reports.

[20]  W. Herrmann [THE INDUCTION OF OVULATION]. , 1964, Gynakologische Rundschau.

[21]  Herbst Al,et al.  CLOMIPHENE CITRATE (NSC-35770) IN DISSEMINATED MAMMARY CARCINOMA. , 1964 .

[22]  G. R. Bedford,et al.  Preparation and Identification of cis and trans Isomers of a Substituted Triarylethylene , 1966, Nature.

[23]  M. Harper,et al.  Contrasting Endocrine Activities of cis and trans Isomers in a Series of Substituted Triphenylethylenes , 1966, Nature.

[24]  M. J. Whitelaw Clomiphene citrate: experience with 217 patients. Variation in response and unusual reactions. , 1966, Fertility and Sterility.

[25]  M. Harper,et al.  Mode of action of I.C.I. 46,474 in preventing implantation in rats. , 1967, Journal of Endocrinology.

[26]  Clomiphene citrate (Clomid) , 1967 .

[27]  K.,et al.  A new derivative of triphenylethylene: effect on implantation and mode of action in rats. , 1967, Journal of reproduction and fertility.

[28]  B. T. Kilbourn,et al.  Identification of isomers of a substituted triarylethylene: the crystal structure of 1-p-(2-dimethylaminoethoxyphenyl)-1,2-cis-diphenylbut-1-ene hydrobromide , 1968 .

[29]  A. P. Labhsetwar Role of estrogens in ovulation: A study using the estrogen-antagonist, I.C.I. 46,474. , 1970, Endocrinology.

[30]  A. P. Labhsetwar Role of Oestrogen in Spontaneous Ovulation demonstrated by Use of an Antagonist of Oestrogen, ICI 46,474 , 1970, Nature.

[31]  A. Klopper,et al.  Medazepam Compared with Amylobarbitone in Treatment of Anxiety , 1971, British medical journal.

[32]  I. Todd,et al.  A New Anti-oestrogenic Agent in Late Breast Cancer: An Early Clinical Appraisal of ICI46474 , 1971, British Journal of Cancer.

[33]  E. Jensen,et al.  Estrogen receptors and breast cancer response to adrenalectomy. , 1971, National Cancer Institute monograph.

[34]  A. P. Labhsetwar Effects of an antioestrogen on the corpus luteum of rabbits and rats. , 1971, Journal of reproduction and fertility.

[35]  A. P. Labhsetwar Role of estrogens in spontaneous ovulation: evidence for the positive feedback in hamsters. , 1972, Endocrinology.

[36]  J. S. Beck,et al.  TREATMENT OF MENOMETRORRHAGIA WITH AN ANTI‐OESTROGEN , 1972, Clinical endocrinology.

[37]  J. Woodburn,et al.  Effect of some triphenylethylenes on oestradiol binding in vitro to macromolecules from uterus and anterior pituitary. , 1972, The Journal of endocrinology.

[38]  J. Williamson,et al.  THE INDUCTION OF OVULATION BY TAMOXIFEN , 1973, The Journal of obstetrics and gynaecology of the British Commonwealth.

[39]  H. Ward Anti-oestrogen Therapy for Breast Cancer: A Trial of Tamoxifen at Two Dose Levels , 1973, British medical journal.

[40]  D. Macourt,et al.  A NEW SYNTHETIC AGENT FOR THE INDUCTION OF OVULATION* , 1974, The Medical journal of Australia.

[41]  H. Bloom,et al.  Antioestrogens in Treatment of Breast Cancer: Value of Nafoxidine in 52 Advanced Cases , 1974, British medical journal.

[42]  M. Lippman,et al.  Oestrogen-responsive human breast cancer in long term tissue culture , 1975, Nature.

[43]  A. Klopper,et al.  ANTIOESTROGENS: A REVIEW , 1975, Clinical endocrinology.

[44]  V. Jordan,et al.  Tamoxifen (ICI 46,474) and the human carcinoma 8S oestrogen receptor. , 1975, European journal of cancer.

[45]  R. Nicholson,et al.  The effect of synthetic anti-oestrogens on the growth and biochemistry of rat mammary tumours. , 1975, European journal of cancer.

[46]  V. Jordan,et al.  Tamoxifen as an anti-tumour agent: oestrogen binding as a predictive test for tumour response. , 1976, The Journal of endocrinology.

[47]  S. Ernst,et al.  Stereochemistry of geometric isomers of clomiphene: a correction of the literature and a reexamination of structure-activity relationships. , 1976, Journal of pharmaceutical sciences.

[48]  D. Gordon WOODPECKERS' TONGUES , 1976, The Lancet.

[49]  V. Jordan,et al.  Tamoxifen as an anti-tumour agent: effect on oestrogen binding. , 1976, The Journal of endocrinology.

[50]  S. Legha,et al.  Nafoxidine–‐an antiestrogen for the treatment of breast cancer , 1976, Cancer.

[51]  V. Jordan Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. , 1976, European journal of cancer.

[52]  D A Chamberlain,et al.  The Brighton resuscitation ambulances: a continuing experiment in prehospital care by ambulance staff. , 1976, British medical journal.

[53]  J. Evans,et al.  The induction of ovulation. , 1976, American journal of obstetrics and gynecology.

[54]  V. Jordan,et al.  A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. , 1977, Journal of Endocrinology.

[55]  D. Kiang,et al.  Tamoxifen (antiestrogen) therapy in advanced breast cancer. , 1977, Annals of internal medicine.

[56]  I. Todd Adjuvant Therapy of Cancer , 1978, British Journal of Cancer.

[57]  V. Jordan,et al.  EVIDENCE FOR THE METABOLIC ACTIVATION OF NON‐STEROIDAL ANTIOESTROGENS: A STUDY OF STRUCTURE‐ACTIVITY RELATIONSHIPS , 1980, British journal of pharmacology.

[58]  V. Jordan,et al.  Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. , 1980, European journal of cancer.

[59]  J. deBoever,et al.  Oestrogen receptors in human breast cancer. , 1980 .

[60]  V. Jordan,et al.  Pharmacology of tamoxifen in laboratory animals. , 1980, Cancer treatment reports.

[61]  J. Ingle,et al.  Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. , 1981, The New England journal of medicine.

[62]  R. Deitch After the Trial at Leicester , 1981, The Lancet.

[63]  V. Kyle,et al.  PROSTAGLANDIN E1 AND PERIPHERAL VASCULAR DISEASE , 1983, The Lancet.

[64]  K. McPherson,et al.  Improved survival among patients treated with adjuvant tamoxifen after mastectomy for early breast cancer. , 1983, Lancet.

[65]  Michael Baum,et al.  IMPROVED SURVIVAL AMONGST PATIENTS TREATED WITH ADJUVANT TAMOXIFEN AFTER MASTECTOMY FOR EARLY BREAST CANCER , 1983, The Lancet.

[66]  E. Bäumler,et al.  Paul Ehrlich, scientist for life , 1984 .

[67]  P. Satyaswaroop,et al.  Estrogen-like effects of tamoxifen on human endometrial carcinoma transplanted into nude mice. , 1984, Cancer research.

[68]  P. Draca,et al.  [Postcoital contraception]. , 1985, Medicinski pregled.

[69]  S. Robinson,et al.  Species-specific pharmacology of antiestrogens: role of metabolism. , 1987, Federation proceedings.

[70]  V. Jordan,et al.  Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. , 1987, Cancer research.

[71]  C. Osborne,et al.  Human breast cancer in the athymic nude mouse: cytostatic effects of long-term antiestrogen therapy. , 1987, European journal of cancer & clinical oncology.

[72]  S. Robinson,et al.  Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. , 1988, Cancer research.

[73]  G. Hortobagyi,et al.  Phase II evaluation of Ly156758 in metastatic breast cancer. , 1988, Oncology.

[74]  V. Jordan,et al.  Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. , 1988, Cancer research.

[75]  T. Powles,et al.  A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. , 1989, British Journal of Cancer.

[76]  Nils Wilking,et al.  ADJUVANT TAMOXIFEN IN EARLY BREAST CANCER: OCCURRENCE OF NEW PRIMARY CANCERS , 1989, The Lancet.

[77]  M. Gail,et al.  Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. , 1989, Journal of the National Cancer Institute.

[78]  Stephen E. Jones,et al.  Adjuvant Therapy of Cancer , 1990 .

[79]  A. Wakeling,et al.  A potent specific pure antiestrogen with clinical potential. , 1991, Cancer research.

[80]  D. DeMets,et al.  Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. , 1991, Annals of internal medicine.

[81]  V. Jordan,et al.  Suppression of mouse mammary tumorigenesis by long-term tamoxifen therapy. , 1991, Journal of the National Cancer Institute.

[82]  R B Mazess,et al.  Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. , 1992, The New England journal of medicine.

[83]  T. Orton,et al.  Two-year carcinogenicity study of tamoxifen in Alderley Park Wistar-derived rats. , 1993, Cancer research.

[84]  M. Carcangiu Re: Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. , 1994, Journal of the National Cancer Institute.

[85]  C. Redmond,et al.  Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. , 1994, Journal of the National Cancer Institute.

[86]  V. Jordan What if tamoxifen (ICI 46,474) had been found to produce rat liver tumors in 1973? A personal perspective. , 1995, Annals of oncology : official journal of the European Society for Medical Oncology.

[87]  Mike Clarke,et al.  Tamoxifen for early breast cancer: an overview of the randomised trials , 1998, The Lancet.

[88]  T. Powles,et al.  Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial , 1998, The Lancet.

[89]  C K Redmond,et al.  Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. , 1999, Journal of the National Cancer Institute.

[90]  V. Jordan Designer estrogens. , 1998, Scientific American.

[91]  W. Gradishar,et al.  Tamoxifen and contralateral breast cancer. , 1999, Journal of the American College of Surgeons.

[92]  T. Powles COMMENT ON: TAMOXIFEN FOR PREVENTION OF BREAST CANCER : REPORT OF THE NATIONAL SURGICAL ADJUVANT BREAST AND BOWEL PROJECT P-1 STUDY , 1999 .

[93]  S. Cummings,et al.  The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. , 1999, JAMA.

[94]  C C Glüer,et al.  Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. , 1999, JAMA.

[95]  S. Cummings,et al.  The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women: Results From the MORE Randomized Trial , 2000 .

[96]  V. Jordan,et al.  Selective estrogen receptor modulation: a personal perspective. , 2001, Cancer research.

[97]  J. Bryant,et al.  Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. , 2001, Journal of the National Cancer Institute.

[98]  C K Osborne,et al.  Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[99]  A. Howell,et al.  Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[100]  J. Mackay IBIS investigators. First results from the International Breast Cancer Intervention Study (IBIS-1) - a randomised prevention trial , 2002 .

[101]  Charles Kooperberg,et al.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. , 2002, JAMA.

[102]  J. Cuzick,et al.  Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial , 2002, The Lancet.

[103]  M Baum,et al.  First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial , 2002, The Lancet.

[104]  J. Andersen,et al.  Oestrogen receptors in human breast cancer , 1982, Virchows Archiv A.

[105]  M. Baum,et al.  Alternative mechanisms of action of anti-oestrogens , 2004, Breast Cancer Research and Treatment.

[106]  J. Lindgren,et al.  Effects of anti-estrogens on bone in castrated and intact female rats , 1987, Breast Cancer Research and Treatment.

[107]  V. Jordan,et al.  The development of tamoxifen for breast cancer therapy: A tribute to the late Arthur L. Walpole , 1988, Breast Cancer Research and Treatment.