Tamoxifen 1269557 223560095 2008-07-04T16:49:59Z DOI bot 6652755 Citation maintenance. Removed redundant parameters. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. {{drugbox | IUPAC_name = (''Z'')-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-''N'',''N''-dimethyl-ethanamine | image = Tamoxifen.svg | image2 = Tamoxifen-3D-balls.png | CAS_number = 10540-29-1 | ATC_prefix = L02 | ATC_suffix = BA01 | PubChem = 5376 | DrugBank = APRD00123 | C = 26 |H = 29 |N = 1 |O = 1 | molecular_weight = 371.515 g/mol<br>563.638 g/mol ([[citrate]] salt) | bioavailability = | protein_bound = | metabolism = [[Liver|Hepatic]] ([[CYP3A4]], [[CYP2C9|2C9]] and [[CYP2D6|2D6]]) | elimination_half-life = 5–7 days | excretion = Fecal | pregnancy_category = B3 <small>([[Australia|Au]])</small> D <small>([[United States|US]])</small> | legal_UK = POM | legal_US = Rx-only | routes_of_administration = Oral }} '''Tamoxifen''' is an orally active [[selective estrogen receptor modulator]] (SERM) that is used in the treatment of [[breast cancer]] and is currently the world's largest selling drug for that purpose. Tamoxifen was discovered by [[Imperial Chemical Industries|ICI]] Pharmaceuticals<ref name="Jordan_2006">{{cite journal |author=Jordan VC|title=Tamoxifen (ICI46,474) as a targeted therapy to treat and prevent breast cancer|journal= Br J Pharmacol |volume= 147 |issue= Suppl 1 |pages= S269–76 |year= 2006 | doi = 10.1038/sj.bjp.0706399 |pmid= 16402113}}</ref> (now [[AstraZeneca]]) and is sold under the trade names '''Nolvadex''', '''Istubal''', and '''Valodex'''. However, the drug, even before its patent expiration, was and still is widely referred to by its generic name "tamoxifen." ==Breast cancer treatment== Tamoxifen is currently used for the treatment of both early and advanced ER+ (estrogen receptor positive) breast cancer in pre- and post-[[menopausal]] women.<ref name="Jordan_1993">{{cite journal |author=Jordan VC|title=Fourteenth Gaddum Memorial Lecture. A current view of tamoxifen for the treatment and prevention of breast cancer|journal= Br J Pharmacol |volume= 110 |issue= 2 |pages= 507–17 |year= 1993 | doi = |pmid= 8242225}}</ref> It is also approved by the [[Food and Drug Administration|FDA]] for the prevention of breast cancer in women at high risk of developing the disease.<ref name="FDA">{{cite web | url = http://www.fda.gov/cder/news/tamoxifen/| title = Tamoxifen Information: reducing the incidence of breast cancer in women at high risk | accessmonthday = July 3 | accessyear = 2007| author = Center for Drug Evaluation and Research | date = 03/08/2005 | publisher = U.S. Food and Drug Administration}}</ref> It has been further approved for the reduction of contralateral (in the opposite breast) cancer. In 2006, the large STAR clinical study concluded that [[raloxifene]] is equally effective in reducing the incidence of breast cancer, but after an average 4-year follow-up there were 36 % fewer [[uterine cancer]]s and 29 % fewer blood clots than in women taking tamoxifen.<ref name="NCI">{{cite web | url = http://www.cancer.gov/star| title = Study of Tamoxifen and Raloxifene (STAR) Trial | accessmonthday = July 3 | accessyear = 2007| author = National Cancer Institute | date = 04/26/2006 | publisher = U.S. National Institutes of Health}}</ref><ref name="STAR">{{cite web | url = http://www.nsabp.pitt.edu/STAR/Index.html| title = STAR Study of Tamoxifen and Raloxifen | accessmonthday = July 3 | accessyear = 2007| author = University of Pittsburgh | date = | publisher = }}</ref> In 2005, the [[ATAC]] trial showed that after average 68 months following a 5 year adjuvant treatment, the group that received [[anastrozole]] ([[Arimidex]]) had significantly better results than the tamoxifen group. Anastrozole vs tamoxifen: deaths - 575 vs 651, recurrences - 402 vs 498, distant metastases - 324 vs 375, second breast cancer - 35 vs 59 (42% reduction). The trial suggested that anastrozole should be the preferred medication for postmenopausal women with localized breast cancer that is [[estrogen receptor]] positive.<ref name="pmid15639680">{{cite journal | author = Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS | title = Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer | journal = Lancet | volume = 365 | issue = 9453 | pages = 60–2 | year = 2005 | pmid = 15639680 | doi = 10.1016/S0140-6736(04)17666-6 }}</ref> ==Other uses== Tamoxifen is used to treat infertility in women with [[Anovulatory cycle|anovulatory]] disorders. A dose of 10–40 mg per day is administered in days 3–7 of a woman's cycle.<ref name="Steiner_2005">{{cite journal |author=Steiner AZ, Terplan M, Paulson RJ |title=Comparison of tamoxifen and clomiphene citrate for ovulation induction: a meta-analysis |journal=Hum. Reprod. |volume=20 |issue=6 |pages=1511–5 |year=2005 |pmid=15845599 |doi=10.1093/humrep/deh840}}</ref> In addition, a rare condition occasionally treated with tamoxifen is [[retroperitoneal fibrosis]].<ref name="pmid16418409">{{cite journal |author=van Bommel EF, Hendriksz TR, Huiskes AW, Zeegers AG |title=Brief communication: tamoxifen therapy for nonmalignant retroperitoneal fibrosis |journal=Ann. Intern. Med. |volume=144 |issue=2 |pages=101–6 |year=2006 |pmid=16418409 |doi= |issn=}}</ref> In men, tamoxifen is sometimes used to treat [[gynecomastia]] that arises for example as a side effect of [[antiandrogen]] [[prostate cancer]] treatment.<ref name="Ferraris_2005">{{cite journal |author=Boccardo F, Rubagotti A, Battaglia M, Di Tonno P, Selvaggi FP, Conti G, Comeri G, Bertaccini A, Martorana G, Galassi P, Zattoni F, Macchiarella A, Siragusa A, Muscas G, Durand F, Potenzoni D, Manganelli A, Ferraris V, Montefiore F|title=Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer|journal= J Clin Oncol |volume= 23 |issue= 4 |pages= 808–15 |year= 2005 | doi = 10.1200/JCO.2005.12.013 |pmid= 15681525}}</ref> Tamoxifen is also used by bodybuilders to prevent or reduce drug-induced gynecomastia caused by the [[estrogenic]] metabolites of [[anabolic steroids]].<ref name="pmid17098591">{{cite journal |author=Baker JS, Graham MR, Davies B |title=Steroid and prescription medicine abuse in the health and fitness community: A regional study |journal=Eur. J. Intern. Med. |volume=17 |issue=7 |pages=479–84 |year=2006 |pmid=17098591 |doi=10.1016/j.ejim.2006.04.010}}</ref> Tamoxifen is also sometimes used to treat or prevent gynecomastia in [[sex offender]]s undergoing treatment by temporary [[chemical castration]].<ref name="Guardian_chemical_castration">{{cite web |author=Sample, Ian |date=2007-06-13 |title=Q&A: Chemical castration |publisher=[[Guardian Unlimited]] |url=http://www.guardian.co.uk/theissues/article/0,,2102029,00.html |accessdate=2007-09-10}}</ref> Tamoxifen has been shown to be effective in the treatment of [[mania]] in patients with [[bipolar disorder]] by blocking [[protein kinase C]] (PKC), an [[enzyme]] that regulates [[neuron]] activity in the [[brain]]. Researchers believe PKC is over-active during the mania in bipolar patients.<ref name="nimh">{{cite web |publisher= [[National Institutes of Mental Health]] |title= Manic Phase of Bipolar Disorder Benefits from Breast Cancer Medication |url= http://www.nimh.nih.gov/science-news/2007/manic-phase-of-bipolar-disorder-benefits-from-breast-cancer-medication.shtml |date= September 12, 2007 |accessdate= 2008-03-10 }}</ref><ref name="pmid18316672">{{cite journal |author=Yildiz A, Guleryuz S, Ankerst DP, Ongür D, Renshaw PF |title=Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen |journal=Arch. Gen. Psychiatry |volume=65 |issue=3 |pages=255–63 |year=2008 |pmid=18316672 |doi=10.1001/archgenpsychiatry.2007.43}}</ref> Tamoxifen is one of three drugs in an [[angiogenesis inhibitor|anti-angiogenetic]] protocol developed by Dr. [[Judah Folkman]], a researcher at Children's Hospital at Harvard Medical School in Boston. Folkman discovered in the 1970s that [[angiogenesis]] – the growth of new blood vessels – plays a significant role in the development of cancer. Since his discovery, an entirely new field of cancer research has developed. Clinical trials on angiogenesis inhibitors have been underway since 1992 using a myriad of different drugs. The Harvard researchers developed a specific protocol for a golden retriever named Navy who was cancer-free after receiving the prescribed cocktail of [[celecoxib]], [[doxycycline]], and tamoxifen – the treatment subsequently became known as the Navy Protocol.<ref name="urlUSA_Today">{{cite web | url = http://www.usatoday.com/news/health/2002-07-24-cover-cancer_x.htm | title = Dog's tale of survival opens door in cancer research | author = Kirk E | authorlink = | coauthors = | date = 2002-07-24 | format = | work = Health and Behavior | publisher = USA Today | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-06-24}}</ref> Furthermore tamoxifen treatment alone has been shown to have anti-angiogenetic effects in animal models of cancer which appear to be, at least in part, independent of tamoxifen's [[estrogen receptor]] antagonist properties.<ref name="pmid11106254">{{cite journal | author = Blackwell KL, Haroon ZA, Shan S, Saito W, Broadwater G, Greenberg CS, Dewhirst MW | title = Tamoxifen inhibits angiogenesis in estrogen receptor-negative animal models | journal = Clin. Cancer Res. | volume = 6 | issue = 11 | pages = 4359–64 | year = 2000 | month = November | pmid = 11106254 | doi = | url = http://clincancerres.aacrjournals.org/cgi/content/abstract/6/11/4359 | issn = }}</ref> Finally tamoxifen is used as a research tool to trigger tissue selective gene expression in genetically modified animals using the [[Cre-Lox recombination]] technique.<ref name="pmid8855277">{{cite journal |author=Feil R, Brocard J, Mascrez B, LeMeur M, Metzger D, Chambon P |title=Ligand-activated site-specific recombination in mice |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue=20 |pages=10887–90 |year=1996 |pmid=8855277 |doi= 10.1073/pnas.93.20.10887}}</ref> ==Mechanism== [[Image:3ert.png|thumbnail|right|270px|Crystallographic structure ({{PDB|3ERT}}) of 4-hydroxytamoxifen (white sticks) complexed with the ligand binding domain of the estrogen receptor (cyan cartoon diagram).]] Tamoxifen competitively binds to estrogen receptors on tumors and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for [[Cell signaling|binding sites]] in breast and other tissues. Tamoxifen causes cells to remain in the G0 and G1 phases of the [[cell cycle]]. Because it prevents (pre)cancerous cells from dividing but does not cause cell death, tamoxifen is cytostatic rather than cytocidal. Tamoxifen itself is a [[prodrug]], having very little affinity for its target protein, the [[estrogen receptor]]. It must first be metabolized in the liver by the [[cytochrome P450]] isoform [[CYP2D6]] into the active metabolites 4-hydroxytamoxifen and des-N-methyl-4-hydroxytamoxifen (endoxifen).<ref name="Desta_2004">{{cite journal |author=Desta Z, Ward BA, Soukhova NV, Flockhart DA|title=Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6|journal= J Pharmacol Exp Ther |volume= 310 |issue= 3 |pages= 1062–75 |year= 2004 | doi = 10.1124/jpet.104.065607 |pmid= 15159443}}</ref> These active metabolites compete with estrogen in the body for binding to the [[estrogen receptor]]. In breast tissue, 4-hydroxytamoxifen acts as an estrogen receptor [[receptor antagonist|antagonist]] so that transcription of estrogen-responsive genes is inhibited.<ref name="Wang_2004">{{cite journal |author=Wang DY, Fulthorpe R, Liss SN, Edwards EA|title=Identification of estrogen-responsive genes by complementary deoxyribonucleic acid microarray and characterization of a novel early estrogen-induced gene: EEIG1|journal=Mol Endocrinol |volume= 18 |issue= 2 |pages= 402–11 |year= 2004 | doi = 10.1210/me.2003-0202 |pmid= 14605097}}</ref> ==Side effects== Tamoxifen is a selective estrogen receptor modulator.<ref name="Gallo_1997">{{cite journal |author=Gallo MA, Kaufman D|title=Antagonistic and agonistic effects of tamoxifen: significance in human cancer|journal= Semin Oncol |volume= 24 |issue= Suppl 1 |pages= S1–71–S1–80 |year= 1997 | doi = |pmid= 9045319}}</ref> Even though it is an [[receptor antagonist|antagonist]] in breast tissue it acts as [[partial agonist]] on the [[endometrium]] and has been linked to [[endometrial cancer]] in some women. Therefore endometrial changes, including cancer, are among tamoxifen's side effects.<ref name="Grilli_2006">{{cite journal |author=Grilli S|title=Tamoxifen (TAM): the dispute goes on|journal= Ann Ist Super Sanita |volume= 42 |issue= 2 |pages= 170–3 |year= 2006 | doi = |pmid= 17033137 | url = http://www.iss.it/publ/anna/2006/2/422170.pdf}}</ref> The [[American Cancer Society]] lists tamoxifen as a known carcinogen, stating that it increases the risk of some types of uterine cancer while lowering the risk of breast cancer recurrence.<ref name="ACS">{{cite web | url = http://www.cancer.org/docroot/PED/content/PED_1_3x_Known_and_Probable_Carcinogens.asp?sitearea=PED | title = Known and Probable Carcinogens | accessdate = 2008-03-21 | author = | authorlink = | coauthors = | date = 2006-02-03 | format = | work = | publisher = American Cancer Society | pages = | language = | archiveurl = | archivedate = | quote = }}</ref> The ACS states that its use should not be avoided in cases where the risk of breast cancer recurrence without the drug is higher than the risk of developing uterine cancer with the drug. For some women, tamoxifen can cause a rapid increase in [[triglyceride]] concentration in the blood. In addition there is an increased risk of [[thromboembolism]] especially during and immediately after major surgery or periods of immobility.<ref name="pmid15699284">{{cite journal |author=Decensi A, Maisonneuve P, Rotmensz N, Bettega D, Costa A, Sacchini V, Salvioni A, Travaglini R, Oliviero P, D'Aiuto G, Gulisano M, Gucciardo G, del Turco MR, Pizzichetta MA, Conforti S, Bonanni B, Boyle P, Veronesi U |title=Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial |journal=Circulation |volume=111 |issue=5 |pages=650–6 |year=2005 |pmid=15699284 |doi=10.1161/01.CIR.0000154545.84124.AC}}</ref> Tamoxifen is also a cause of [[fatty liver]], otherwise known as steatorrhoeic hepatosis or steatosis hepatis.<ref name="pmid17181445">{{cite journal |author=Khalid A Osman; Meissa M Osman; Mohamed H Ahmed |title=Tamoxifen-induced non-alcoholic steatohepatitis: where are we now and where are we going? |journal=Expert opinion on drug safety |volume=6 |issue=1 |pages=1–4 |year=2007 |pmid=17181445 |doi=10.1517/14740338.6.1.1}}</ref> A significant number of tamoxifen treated breast cancer patients experience a reduction of [[libido]].<ref name="pmid10334535">{{cite journal | author = Mortimer JE, Boucher L, Baty J, Knapp DL, Ryan E, Rowland JH | title = Effect of tamoxifen on sexual functioning in patients with breast cancer | journal = J. Clin. Oncol. | volume = 17 | issue = 5 | pages = 1488–92 | year = 1999 | pmid = 10334535 | doi = | issn = | url = http://jco.ascopubs.org/cgi/content/abstract/17/5/1488 | format = abstract}}</ref><ref name="pmid16944295">{{cite journal | author = Cella D, Fallowfield L, Barker P, Cuzick J, Locker G, Howell A | title = Quality of life of post-menopausal women in the ATAC ("Arimidex", tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for early breast cancer | journal = Breast Cancer Res. Treat. | volume = 100 | issue = 3 | pages = 273–84 | year = 2006 | pmid = 16944295 | doi = 10.1007/s10549-006-9260-6 }}</ref> A beneficial side effect of tamoxifen is that it prevents bone loss by inhibiting [[osteoclasts]] by acting as an estrogen receptor [[agonist]] (i.e., mimicking the effects of estrogen) in this cell type, and therefore it prevents [[osteoporosis]].<ref name="pmid17803905">{{cite journal | author = Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, Harada Y, Azuma Y, Krust A, Yamamoto Y, Nishina H, Takeda S, Takayanagi H, Metzger D, Kanno J, Takaoka K, Martin TJ, Chambon P, Kato S | title = Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts | journal = Cell | volume = 130 | issue = 5 | pages = 811–23 | year = 2007 | pmid = 17803905 | doi = 10.1016/j.cell.2007.07.025 }}</ref><ref name="pmid18219273">{{cite journal | author = Krum SA, Miranda-Carboni GA, Hauschka PV, Carroll JS, Lane TF, Freedman LP, Brown M | title = Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival | journal = EMBO J. | volume = 27 | issue = 3 | pages = 535–45 | year = 2008 | pmid = 18219273 | doi = 10.1038/sj.emboj.7601984 }}</ref> When tamoxifen was launched as a drug, it was thought that tamoxifen would act as an estrogen receptor antagonist in all tissue, including bone, and therefore it was feared that it would contribute to osteoporosis. It was therefore very surprising that the opposite effect was observed clinically. Hence tamoxifen's tissue selective action directly lead to the formulation of the concept of selective estrogen receptor modulators (SERMs).<ref name="Mincey_2000">{{cite journal |author=Mincey BA, Moraghan TJ, Perez EA|title = Prevention and treatment of osteoporosis in women with breast cancer|journal= Mayo Clin Proc |volume= 75 |issue= 8 |pages= 821–9 |year= 2000 | doi = |pmid= 10943237 | url = http://www.mayoclinicproceedings.com/inside.asp?ref=7508r}}</ref> ==Pharmacogenetics== Patients with variant forms of the gene [[CYP2D6]] (also called simply 2D6) may not receive full benefit from tamoxifen because of too slow metabolism of the tamoxifen prodrug into its active metabolite 4-hydroxytamoxifen.<ref name="Goetz_2005">{{cite journal |author=Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN |title=Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes|journal= J Clin Oncol |volume= 23 |issue= 36 |pages= 9312–8 |year= 2005 | doi = 10.1200/JCO.2005.03.3266 |pmid= 16361630 }}</ref><ref name="Beverage_2007">{{cite journal |author=Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD |title=CYP2D6 polymorphisms and the impact on tamoxifen therapy|journal= J Pharm Sci |volume= 96 |issue= 9 |pages= Epub ahead of print |year= 2007 | doi = 10.1002/jps.20892 |pmid= 17518364 }}</ref> On Oct 18, 2006 the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert.<ref>[http://talk.dnadirect.com/2006/10/19/genetic-test-for-response-to-tamoxifen/ Information about CYP2D6 and tamoxifen from DNADirect's website]</ref> Recent studies suggest that taking selective serotonin reuptake inhibitor (SSRI) antidepressants such as Paxil, Prozac, etc., can decrease the effectiveness of tamoxifen, because these drugs compete for the CYP2D6 enzyme which is needed to metabolize tamoxifen into the active form endoxifen.<ref name="Jin_2005">{{cite journal |author=Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA |title=CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment|journal= J Natl Cancer Inst |volume= 97 |issue= 1 |pages= 30–9 |year= 2005 | doi = 10.1093/jnci/dji005 |pmid= 15632378}}</ref> ==Market== Global sales of tamoxifen in 2001 were $1,024 million.<ref>{{cite web|title=Cancer: the generic impact|url=http://www.bioportfolio.com/news/datamonitor_16.htm|accessdate = 2007-08-02}}</ref> Since the expiration of the patent, it is now widely available as a [[generic drug]] around the world. ==Discovery== In the late 1950s, pharmaceutical companies were actively researching a newly discovered class of anti-estrogen compounds in the hope of developing a morning-after contraceptive pill. [[Arthur L Walpole]] was a reproductive [[endocrinologist]] who led such a team at the [[Alderley Park]] research laboratories of [[ICI Pharmaceuticals]]. It was there in 1962 that Dora Richardson first synthesised tamoxifen, known then as ICI-46,474.<ref name="isbn0-471-89979-8">{{cite book | author = Sneader, Walter | title = Drug discovery: a history | publisher = Wiley | location = New York | year = 2005 | pages = 472 pages | isbn = 0-471-89979-8 | oclc = | doi = }}</ref> Walpole and his colleagues filed a UK patent covering this compound in 1962, but patent protection on this compound was repeatedly denied in the US until the 1980s.<ref name="Jordan_2003">{{cite journal | author = Jordan VC | title = Tamoxifen: a most unlikely pioneering medicine | journal = Nature reviews. Drug discovery | volume = 2 | issue = 3 | pages = 205–13 | year = 2003 | pmid = 12612646 | doi = 10.1038/nrd1031 }}</ref> Tamoxifen did eventually receive marketing approval as a fertility treatment, but the class of compounds never proved useful in human contraception. A link between estrogen and breast cancer had been known for many years, but cancer treatments were not a corporate priority at the time, and Walpole's personal interests were important in keeping support for the compound alive in the face of this and the lack of patent protection.<ref name="Jordan_2006"/> The first clinical study took place at the [[Christie Hospital]] in 1971, and showed a convincing effect in advanced breast cancer,<ref name="Cole_1971">{{cite journal | author = Cole MP, Jones CT, Todd ID | title = A new anti-estrogenic agent in late breast cancer. An early clinical appraisal of ICI46474 | journal = Br. J. Cancer | volume = 25 | issue = 2 | pages = 270–5 | year = 1971 | pmid = 5115829 | doi = | issn = }}</ref> but nevertheless ICI's development programme came close to termination when it was reviewed in 1972. It appears to have been Walpole again who convinced the company to market tamoxifen for late stage breast cancer in 1973.<ref name="Jordan_2003"/> He was also instrumental in funding [[V. Craig Jordan]] to work on tamoxifen. Approval in the US followed in 1977, but the drug was competing against other hormonal agents in a relatively small marketplace and was not at this stage either clinically or financially remarkable. 1980 saw the publication of the first trial to show that tamoxifen given in addition to chemotherapy improved survival for patients with early breast cancer.<ref name="Baum_2003">{{cite journal | author = Baum M, Brinkley DM, Dossett JA, McPherson K, Patterson JS, Rubens RD, Smiddy FG, Stoll BA, Wilson A, Lea JC, Richards D, Ellis SH | title = Improved survival among patients treated with adjuvant tamoxifen after mastectomy for early breast cancer | journal = Lancet | volume = 2 | issue = 8347 | pages = 450 | year = 1983 | pmid = 6135926 | doi = | issn = }}</ref> In advanced disease, tamoxifen is now only recognised as effective in [[estrogen receptor]] positive (ER+) patients, but the early trials did not select ER+ patients, and by the mid 1980s the clinical trial picture was not showing a major advantage for tamoxifen.<ref name="FURR_1984">{{cite journal | author = Furr BJ, Jordan VC | title = The pharmacology and clinical uses of tamoxifen | journal = Pharmacol. Ther. | volume = 25 | issue = 2 | pages = 127–205 | year = 1984 | pmid = 6438654 | doi = 10.1016/0163-7258(84)90043-3 }}</ref> Nevertheless, tamoxifen had a relatively mild side-effect profile, and a number of large trials continued. It was not until 1998 that the meta-analysis of the Oxford based Early Breast Cancer Trialists' Collaborative Group showed definitively that tamoxifen saved lives in early breast cancer.<ref name="pmid9605801">{{cite journal | author = Early Breast Cancer Trialists' Collaborative Group | title = Tamoxifen for early breast cancer: an overview of the randomised trials | journal = Lancet | volume = 351 | issue = 9114 | pages = 1451–67 | year = 1998 | pmid = 9605801 | doi = 10.1016/S0140-6736(97)11423-4 }}</ref> ==References== {{Reflist|2}} {{Sex hormones}} [[Category:Selective estrogen receptor modulators]] [[Category:Chemopreventive agents]] [[Category:AstraZeneca]] [[Category:Cancer treatments]] [[de:Tamoxifen]] [[fr:Tamoxifène]] [[it:Tamoxifene]] [[he:טמוקסיפן]] [[nl:Tamoxifen]] [[ja:タモキシフェンクエン酸塩]] [[pl:Tamoksyfen]] [[pt:Tamoxifeno]]