Tamoxifen

Tamoxifen is an antagonist of the estrogen receptor in breast tissue. It has been the standard endocrine (anti-estrogen) therapy for hormone-positive early breast cancer in post-menopausal women, although aromatase inhibitors have been proposed.[1]

Some breast cancer cells require estrogen to grow. Estrogen binds to and activates the estrogen receptor in these cells. Tamoxifen is metabolized into compounds that also bind to the estrogen receptor but do not activate it. Because of this competitive antagonism, tamoxifen acts like a key broken off in the lock that prevents any other key from being inserted, preventing estrogen from binding to its receptor. Hence breast cancer cell growth is blocked.

Tamoxifen was discovered by ICI Pharmaceuticals[2] (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

Bottle and pills of tamoxifen

Tamoxifen is currently used for the treatment of both early and advanced ER+ (estrogen receptor positive) breast cancer in pre- and post-menopausal women.[3] Additionally, it is the most common hormone treatment for male breast cancer.[4] It is also approved by the FDA for the prevention of breast cancer in women at high risk of developing the disease.[5] It has been further approved for the reduction of contralateral (in the opposite breast) cancer.

Comparative studies

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 cancers and 29% fewer blood clots in women taking raloxifene than in women taking tamoxifen, although the difference is not statistically significant.[6][7][8]

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 in measures like disease free survival, but no overall mortality benefit.[9] Data from the trial suggest that anastrozole should be the preferred medication for postmenopausal women with localized breast cancer that is estrogen receptor (ER) positive.[10] Another study found that the risk of recurrence was reduced 40% (with some risk of bone fracture) and that ER negative patients also benefited from switching to anastrozole.[11][12]

Other uses

Infertility

Tamoxifen is used to treat infertility in women with anovulatory disorders. A dose of 10–40 mg per day is administered in days 3–7 of a woman’s cycle.[13] In addition, a rare condition occasionally treated with tamoxifen is retroperitoneal fibrosis.[14]

Gynecomastia

In men, tamoxifen “Nolvadex” is sometimes used by steroid-taking, weight-training athletes. An alternative and highly similar compound is clomiphene citrate “Clomid”. These drugs are used as anti-estrogen therapy. In this regard, the drug is used for three purposes. The first purpose, is to reduce the effect of circulating estrogens even if Tamoxifen itself increase the circulating level of estrogens since they are not bound to the estrogen receptors. Abnormally high levels of estrogen in men, can be caused by taking highly aromatizing anabolic steroids e.g. Dianabol, Anadrol or Testosterone. In dosing with a dosing with 20 mg of Novaldex (Tamoxifen) for the duration of a steroid cycle, a reduction in water retention can be achieved. This prevents large fluctuations in water weight within the muscle.

Using Tamoxifen for the duration of a steroid cycle may or may not promote a preferable outcome for a weight training athlete, as the temporary increase in water weight within the muscle increases strength and allows larger weights to be used for the duration of the steroid cycle. Said water will dissipate once usage of steroids has ceased, and a dramatic loss in weight can be observed. Tamoxifen is also used to prevent estrogen related gynecomastia, resulting from elevated estrogenic levels. It can be taken as a preventative measure in small doses, or used at the onset of any symptoms e.g. nipple soreness/sensitivity. In the latter case, dosing reverses the affliction.

Anti-aromatase drugs (such as Arimidex or Letrozole) are used at the cessation of a steroid cycle. The half life of the steroids used within a cycle must be considered, so as to calculate the length of time before levels of testosterone have returned to a baseline level. Quick recovery of natural levels of testosterone production is highly important for the maintenance of muscle tissue. This is not possible unless the hypothalamus and Leydig cells sense a below baseline level of testosterone, due to the body’s natural negative feedback loop. Levels of testosterone production from the testes can be totally inhibited upon cessation of steroid intake, although this inhibition is dependent upon the amount, type ( hence relative anabolic and androgenic strength)and the length of time that the steroids have been used for. Tamoxifen has also been shown to have liver protecting/regenerative properties, hence another reason why a steroid taking athlete might wish to use it. Tamoxifen citrate and clomiphene citrate are both commonly used at this point, although the latter has been shown to aggravate depressive mood.

Tamoxifen is also sometimes used to treat or prevent gynecomastia in sex offenders undergoing treatment by temporary chemical castration.[15]

Bipolar disorder

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.[16][17]

Angiogenesis and cancer

Tamoxifen is one of three drugs in an 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.[18] 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.[19]

Control of gene expression

Tamoxifen is used as a research tool to trigger tissue specific gene expression in many conditional expression constructs in genetically modified animals including a version of the Cre-Lox recombination technique.[20]

Mechanism of action

X-ray crystal 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 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 relatively little affinity for its target protein, the estrogen receptor. It is metabolized in the liver by the cytochrome P450 isoform CYP2D6 and CYP3A4 into active metabolites such as 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen (endoxifen)[21] which have 30-100 times more affinity with the estrogen receptor than tamoxifen itself. 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 antagonist so that transcription of estrogen-responsive genes is inhibited.[22]

Tamoxifen binds to estrogen receptor (ER) which in turn interacts with DNA. The ER/tamoxifen complex recruits other proteins known as co-repressors to stop genes being switched on by estrogen. Some of these proteins include NCoR and SMRT.[23] Tamoxifen function can be regulated by a number of different variables including growth factors.[24] Tamoxifen needs to block growth factor proteins such as ErbB2/HER2[25] because high levels of ErbB2 have been shown to occur in tamoxifen resistant cancers.[26] Tamoxifen seems to require a protein PAX2 for its full anticancer effect.[25][27] In the presence of high PAX2 expression, the tamoxifen/estrogen receptor complex is able to suppress the expression of the pro-proliferative ERBB2 protein. In contrast, when AIB-1 expression is higher than PAX2, tamoxifen/estrogen receptor complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth.[25][28]

Side effects

A report in September 2009 from Health and Human Services’ Agency for Healthcare Research and Quality suggests that tamoxifen, raloxifene, and tibolone used to treat breast cancer significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.[29]

Bone

A beneficial side effect of tamoxifen is that it prevents bone loss by acting as an estrogen receptor agonist (i.e., mimicking the effects of estrogen) in this cell type. Therefore, by inhibiting osteoclasts, it prevents osteoporosis.[30][31] 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 led to the formulation of the concept of selective estrogen receptor modulators (SERMs).[32] In contrast tamoxifen appears to be associated with bone loss in premenopausal women who continue to menstruate after adjuvant chemotherapy.[33]

Endometrial cancer

Tamoxifen is a selective estrogen receptor modulator.[34] Even though it is an 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.[35] With time, risk of endometrial cancer may be doubled to quadrupled, which is a reason tamoxifen is typically only used for 5 years.[36]

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.[37] 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.

Cardiovascular and metabolic

Tamoxifen treatment of postmenopausal women is associated with beneficial effects on serum lipid profiles. However, long-term data from clinical trials have failed to demonstrate a cardioprotective effect.[38] For some women, tamoxifen can cause a rapid increase in triglyceride concentration in the blood.[citation needed] In addition there is an increased risk of thromboembolism especially during and immediately after major surgery or periods of immobility.[39] Tamoxifen is also a cause of fatty liver, otherwise known as steatorrhoeic hepatosis or steatosis hepatis.[40]

Central nervous system

Tamoxifen treated breast cancer patients show evidence of reduced cognition[41] and semantic memory scores.[42] However memory impairment in patients treated with tamoxifen was less severe compared with those treated with anastrozole (an aromatase inhibitor).[43]

A significant number of tamoxifen treated breast cancer patients experience a reduction of libido.[44][45]

Pre-mature growth plate fusion

While tamoxifen has been shown to antagonize the actions of estrogen in tissues such as the breast, its effects in other tissues such as bones has not been documented fully. There have been studies done in mice showing tamoxifen mimic the effects of estrogen on bone metabolism and skeletal growth. Thus increasing the possibility of pre-mature bone fusion. This effect would be less of a concern in adults who have stopped growing.[46]

Pharmacogenetics and drug interactions

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.[47][48] On Oct 18, 2006 the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert.[49]

Certain CYP2D6 variations in breast cancer patients leads to a worse clinical outcome for tamoxifen treatment.[50] Genotyping therefore has the potential for identification of women who have these CYP2D6 phenotypes and for whom the use of tamoxifen is associated with poor outcomes.

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.[51] A U.S study presented at the American Society of Clinical Oncology’s annual meeting in 2009 found that after two years, 7.5 percent of women who took only tamoxifen had a recurrence, compared with 16 percent who took Paxil, Prozac, or Zoloft—drugs considered to be the most potent CYP2D6 inhibitors. That difference translates to a 120 percent increase in the risk of breast cancer recurrence. Patients taking the so-called weaker antidepressants, Celexa (citalopram), Lexapro (escitalopram), and Luvox (fluvoxamine), did not have an increased risk of recurrence.[52]

Recent research has shown that 7-10% of women with breast cancer may not receive the full medical benefit from taking tamoxifen due to their unique genetic make-up. DNA Drug Safety Testing can examine DNA variations in the CYP2D6 and other important drug processing pathways. More than 20% of all clinically used medications are metabolized by CYP2D6 and knowing the CYP2D6 status of a person can help the doctor with the future selection of medications.[53]

Market

Global sales of tamoxifen in 2001 were $1,024 million.[54] Since the expiration of the patent in 2002, it is now widely available as a generic drug around the world. Barr Labs Inc had challenged the patent (which in 1992 was ruled unenforcable) but later came to an agreement with Zeneca to licence the patent and sell tamoxifen at close to Zeneca’s price.[55] As of 2004, tamoxifen was the world’s largest selling hormonal drug for the treatment of breast cancer.[56]

In the US, 20 mg tamoxifen tablets cost under $20 per month in quantity.[57] In the UK, the NHS pays £1.90 a month (patients receive them either free or for the standard prescription charge of £7.10 in England, £4 in Scotland[58], £3 in Northern Ireland[59] and free in Wales). In Estonia tamoxifen costs less than $2 for 30 tablets of 20mg when used for treatment of a neoplasm or lymphangioma.[60] Other countries report similar prices.[citation needed]

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.[61] 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.[62] 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.[2]

The first clinical study took place at the Christie Hospital in 1971, and showed a convincing effect in advanced breast cancer,[63] 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.[62] 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.[64] 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.[65] 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.[66]