tamoxifen

A nonsteroidal estrogen antagonist used in the treatment of advanced breast cancer in women whose tumors are estrogen-dependent and also used prophylactically by some women at risk for breast cancer.

[T(RANS)- + AM(INO)- + alteration of OXY- + alteration of PHEN(OL).]

Key Terms: Anticoagulant, Apoptosis, Double-blind study, Oncogene.

Definition

Tamoxifen (also known as Nolvadex) is a synthetic compound similar to estrogen. It mimics the action of estrogen on the bones and uterus, but blocks the effects of estrogen on breast tissue.

Purpose

Tamoxifen is used as adjuvant hormonal therapy immediately after surgery in early stages of breast cancer and in advanced metastatic breast cancer (stages III and above) in women and men. Adjuvant therapy is treatment added to curative procedures (such as surgery) to prevent the recurrence of cancer. Although tamoxifen is also used to treat malignant melanoma, brain tumors and uterine cancer, these uses are not indicated on the product label. According to U.S. Food and Drug Administration (FDA) guidelines, women who are at high risk of developing breast cancer may take tamoxifen to reduce their risk; however, prolonged use may increase the risk of developing endometrial cancer (also called uterine cancer).

In 2003, researchers described the use of high-dose tamoxifen, along with follicle-stimulating hormone (FSH) in stimulating ovary production for women who have had breast cancer who want to undergo in vitro fertilization. Standard in vitro therapies can increase estrogen and risk of breast cancer recurrence. The combination of tamoxifene and FSH may offer some breast cancer protection and hope for pregnancy.

Description

First synthesized in 1966 in Great Britain as an anti-fertility drug, tamoxifen was evaluated to treat cancer in 1970. In 1998, the FDA approved tamoxifen to reduce the risk of breast cancer. While tamoxifen can be given to patients alone, it is often given in combination with other chemotherapeutic drugs such as 5-fluorouracil (5-FU, or fluorouracil).

Tamoxifen belongs to a family of compounds called antiestrogens. Antiestrogens are used in cancer therapy to inhibit the effects of estrogen on target tissues. Estrogen is a steroid hormone secreted by the female ovary. Depending on the target tissue, estrogen can stimulate the growth of female reproductive organs and breast tissue, play a role in the female menstrual cycle, and protect against bone loss by binding to estrogen receptors on the outside of cells within the target tissue. Antiestrogens act selectively against the effects of estrogen on target cells in a variety of ways, thus they are called selective estrogen receptor modulators (SERMs).

Tamoxifen selectively inhibits the effects of estrogen on breast tissue, while selectively mimicking the effects of estrogen on bone (by increasing bone mineral density) and uterine tissues. These qualities make tamoxifen an excellent therapeutic agent against breast cancer. Although researchers are unclear about precisely how tamoxifen kills breast cancer cells, it is known to compete with estrogen by binding to estrogen receptors on the membrane of target cells. This limits the effects of estrogen on breast tissue. Tamoxifen also may be involved in other anti-tumor activities affecting oncogene expression, promotion of apoptosis (cancer cell death) and growth factor secretion. (Growth factors are hormones that influence cell division and proliferation, and these hormones can encourage cancers to grow.)

In 2000, the STAR (Study of Tamoxifen and Raloxifene) study began. The purpose of this double-blind study is to evaluate the use of tamoxifen and raloxifene (another type of SERM) over a five-year period in 22,000 postmenopausal women 35 years or older who are at high risk for developing breast cancer. The study will evaluate both the effectiveness and degree of side effects to determine which drug is most beneficial.

Another National Cancer Institute study that is relevant to the discussion of tamoxifen is the Breast Cancer Prevention Trial. This trial began in 1992 and was designed to see if tamoxifen was effective as a preventive against breast cancer. The study also was a double-blind study, and participants were receiving either tamoxifen or a placebo (an inactive pill that looks like tamoxifen). About four years into the study, in 1998, researchers reported that the women receiving tamoxifen:

• had 49% fewer diagnoses of invasive breast cancer
• had 50% fewer diagnoses of noninvasive breast cancer (such as ductal carcinoma in situ)
• had fewer fractures of the hip, wrist, and spine
• had more than twice the chance of developing endometrial cancer, and
• had increased chance of developing blood clots, both in the lung and in major veins when compared to the women receiving the placebo. Because of these findings, in 1998, the FDA approved the use of tamoxifen as a breast cancer preventive for high-risk women, as mentioned above.

Recommended Dosage

Tamoxifen is taken orally and is available in 10- and 20-milligram (mg) tablets. Although it can be given within the range of 10 mg to 80 mg, the typical dosage is 20 to 40 mg daily for both adult females and males using tamoxifen for treatment of advanced breast cancer. At this dosage, there is an observed 30% response rate with complete remission in 10% of patients. It appears that patients 60 years and older have higher response rates. For patients using tamoxifen for adjuvant therapy after surgery, the typical dosage is 20 mg once daily for two to five years following surgery. Women at high risk for developing breast cancer usually take 20 mg daily for five years. If a dosage is missed, patients should not double the next dosage. Instead, they should go back to their regular schedule and contact their doctor.

Tamoxifen doesn't work for everyone. In 2003, scientists announced development of a new test that may predict whether patients' tumors are responding to tamoxifen treatment and warn clinicians if the tumor becomes resistant to the drugs.

Precautions

Tamoxifen is not recommended for use in children. Women who are pregnant or nursing should not use this drug since it has several side effects that, although rare, can be severe. It is known to cause miscarriages and birth defects. Women are encouraged to use birth control while taking tamoxifen. However, oral contraceptives can negatively alter the effects of tamoxifen. Therefore, patients should explore other, nonhormonal birth control options.

Great care should be exercised when tamoxifen is used with warfarin, an anticoagulant, because tamoxifen can interfere with the effects of warfarin, and dose adjustments may be necessary. Patients who are predisposed to the formation of thromboembolisms, or blood clots, should use tamoxifen with caution. It should be noted that smokers are at a higher risk for thromboembolism than nonsmokers.

In late 2003, cancer experts were beginning to recommend a new group of drugs called aromatase inhibitors (Arimidex, common name anastrozole or Femara and Novartis, common name letrozole) as an alternative to tamoxifen or following tamoxifen therapy. These drugs fight breast cancer differently, but early research shows they fight it as effectively and with fewer side effects. However, these drugs also may be added after a course of tamoxifen to improve overall treatment results.

Side Effects

Although tamoxifen is usually well tolerated by patients, there are some side effects. About 25% of patients experience side effects such as mild nausea, vomiting, hot flashes, weight gain, bone pain, and hair thinning. These side effects are usually not severe enough to stop therapy. Patients using tamoxifen for long periods of adjuvant therapy may face unwanted effects years into therapy, which warrant discontinued use of the drug. Some of these effects include possible increased risk of developing liver adenoma as well as increased risk of uterine (endometrial) cancer; eye problems such as retinal lesions, macular edema and corneal changes (most resolve after use is discontinued); neurological problems such as depression, dizziness, confusion, and fatigue; and genital problems such as vaginal bleeding, vaginal discharge, and endometriosis.

Interactions

Tamoxifen can interfere with the anticoagulant drug warfarin, and if these two drugs are used together, patients will need to be monitored very closely. Oral contraceptives can also interfere with the action of tamoxifen. In 2003, researchers discovered that paroxetine, an antidepressant used to ease hot flashes that accompany treatment with tamoxifene, was interfering with tamoxifene's effectiveness.

Resources

Periodicals

"Breast Cancer Guidelines Suggest Alternative to Standard Therapy." Drug Topics August 18, 2003: 22.

"Drug that Eases Tamoxifen Side Effect May also Hinder its Effectiveness." Drug Week December 26, 2003: 54.

Johnson, Kate. "High-dose Tamoxifen for IVF in Breast Cancer Survivors: Combine with FSH." OB GYN News December 15, 2003: 8–11.

MacReady, Nora. "Post-tamoxifen Letrozole May Cut Breast Ca Risk: More than 5,000 Women Studied." Internal Medicine News November 15, 2003: 18–19.

"New Test Could Predict Response to Tamoxifen and Anastrozole." Drug Week November 28, 2003: 64.

—Sally C. McFarlane-Parrott; Teresa G. Odle

Brand names: Nolvadex®Soltamox™

Chemical formula:

Drug Forms:
• Tamoxifen Citrate Oral tablet (below)
• Tamoxifen oral solution
• Tamoxifen Citrate Oral solution

Español:
• Tamoxifeno Citrato, Tableta oral
• Tamoxifeno Citrato, Solución oral

Tamoxifen Citrate Oral tablet

What is this medicine?

TAMOXIFEN blocks the effects of estrogen. It is commonly used to treat breast cancer. It is also used to decrease the chance of breast cancer coming back in women who have received treatment for the disease. It may also help prevent breast cancer in women who have a high risk of developing breast cancer.

This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
•blood clots
•blood disease
•cataracts or impaired eyesight
•endometriosis
•high calcium levels
•high cholesterol
•irregular menstrual cycles
•liver disease
•stroke
•uterine fibroids
•an unusual or allergic reaction to tamoxifen, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding

How should I use this medicine?

Take this medicine by mouth with a glass of water. Follow the directions on the prescription label. You can take it with or without food. Take your medicine at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your doctor's advice.

A special MedGuide will be given to you by the pharmacist with each prescription and refill. Be sure to read this information carefully each time.

Talk to your pediatrician regarding the use of this medicine in children. While this drug may be prescribed for selected conditions, precautions do apply.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.

What may interact with this medicine?

•aminoglutethimide
•bromocriptine
•chemotherapy drugs
•female hormones, like estrogens and birth control pills
•letrozole
•medroxyprogesterone
•phenobarbital
•rifampin
•warfarin

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medicine?

Visit your doctor or health care professional for regular checks on your progress. You will need regular pelvic exams, breast exams, and mammograms. If you are taking this medicine to reduce your risk of getting breast cancer, you should know that this medicine does not prevent all types of breast cancer. If breast cancer or other problems occur, there is no guarantee that it will be found at an early stage.

Do not become pregnant while taking this medicine or for 2 months after stopping this medicine. Stop taking this medicine if you get pregnant or think you are pregnant and contact your doctor. This medicine may harm your unborn baby. Women who can possibly become pregnant should use birth control methods that do not use hormones during tamoxifen treatment and for 2 months after therapy has stopped. Talk with your health care provider for birth control advice.

Do not breast feed while taking this medicine.

What side effects may I notice from receiving this medicine?

Side effects that you should report to your doctor or health care professional as soon as possible:
•changes in vision (blurred vision)
•changes in your menstrual cycle
•difficulty breathing or shortness of breath
•difficulty walking or talking
•new breast lumps
•numbness
•pelvic pain or pressure
•redness, blistering, peeling or loosening of the skin, including inside the mouth
•skin rash or itching (hives)
•sudden chest pain
•swelling of lips, face, or tongue
•swelling, pain or tenderness in your calf or leg
•unusual bruising or bleeding
•vaginal discharge that is bloody, brown, or rust
•weakness
•yellowing of the whites of the eyes or skin

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
•fatigue
•hair loss, although uncommon and is usually mild
•headache
•hot flashes
•impotence (in men)
•nausea, vomiting (mild)
•vaginal discharge (white or clear)

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medicine?

Keep out of the reach of children.

Store at room temperature between 20 and 25 degrees C (68 and 77 degrees F). Protect from light. Keep container tightly closed. Throw away any unused medicine after the expiration date.

Last updated: 7/6/2006 9:54:00 AM

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

Tamoxifen, a selective estrogen-receptor modulator, is an oral medication exhibiting both estrogen agonist and antagonist effects. Tamoxifen can be used to treat advanced breast cancer, to decrease the risk of recurrence of early-stage breast cancer, and for breast cancer prevention. Patients with an early-stage breast cancer with expression of the estrogen or progesterone receptors, or for whom no receptor result is known, benefit from five years of tamoxifen treatment. This treatment has been shown to decrease the annual risk of recurrence of breast cancer, and to decrease the risk of contralateral breast cancer by 47 percent. Tamoxifen has been studied as breast cancer prevention in patients at elevated risk of developing breast cancer (five-year risk of 1.66% or higher), decreasing the chance of developing an invasive or noninvasive breast cancer by approximately 50 percent. Newer antiestrogens, such as raloxifene, may have fewer side effects and similar effectiveness. Studies are underway to determine their effectiveness.

(SEE ALSO: Breast Cancer; Breast Cancer Screening; Preventive Medicine)

Bibliography

Osborne, C. K. (1998). "Tamoxifen in the Treatment of Breast Cancer." New England Journal of Medicine 339:1609–1618.

— CLIFFORD HUDIS; ARTI HURRIA

For more information on tamoxifen, visit Britannica.com.

An antiestrogen used as the citrate in the treatment of disseminated mammary cancer.

Tamoxifen
Systematic (IUPAC) name
(Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethyl-ethanamine
Identifiers
CAS number	10540-29-1
ATC code	L02BA01
PubChem	5376
DrugBank	APRD00123
ChemSpider	2015313
Chemical data
Formula	C26H29NO
Mol. mass	371.515 g/mol 563.638 g/mol (citrate salt)
Pharmacokinetic data
Bioavailability	?
Metabolism	Hepatic (CYP3A4, 2C9 and 2D6)
Half life	5–7 days
Excretion	Fecal
Therapeutic considerations
Pregnancy cat.	B3 (Au) D (US)
Legal status	POM(UK) ℞-only(US)
Routes	Oral
Y(what is this?)  (verify)

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, although aromatase inhibitors have been proposed for postmenopausal women.^[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. Furthermore tamoxifen prevents 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."

Contents 1 Breast cancer treatment 1.1 Comparative studies 2 Other uses 2.1 Infertility 2.2 Gynecomastia 2.3 Bipolar disorder 2.4 Angiogenesis and cancer 2.5 Control of gene expression 3 Mechanism of action 4 Side effects 4.1 Bone 4.2 Endometrial cancer 4.3 Cardiovascular and metabolic 4.4 Central nervous system 4.5 Pre-mature growth plate fusion 5 Pharmacogenetics 6 Market 7 Discovery 8 References 9 External links

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.^[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. 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.^[9] 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.^[10][11]

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.^[12] In addition, a rare condition occasionally treated with tamoxifen is retroperitoneal fibrosis.^[13]

Gynecomastia

In men, tamoxifen is sometimes used to treat gynecomastia that arises for example as a side effect of antiandrogen prostate cancer treatment.^[14] Tamoxifen is also used by bodybuilders^[15] to prevent or reduce drug-induced gynecomastia caused by the estrogenic metabolites of anabolic steroids.^[16] Tamoxifen is also sometimes used to treat or prevent gynecomastia in sex offenders undergoing treatment by temporary chemical castration.^[17]

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.^[18][19]

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.^[20] 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.^[21]

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.^[22]

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)^[23] 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.^[24]

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.^[25] Tamoxifen function can be regulated by a number of different variables including growth factors.^[26] Tamoxifen needs to block growth factor proteins such as ErbB2/HER2^[27] because high levels of ErbB2 have been shown to occur in tamoxifen resistant cancers.^[28] Tamoxifen seems to require a protein PAX2 for its full anticancer effect.^[27][29] 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.^[27][30]

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.^[31]

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.^[32][33] 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).^[34] In contrast tamoxifen appears to be associated with bone loss in premenopausal women who continue to menstruate after adjuvant chemotherapy.^[35]

Endometrial cancer

Tamoxifen is a selective estrogen receptor modulator.^[36] 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.^[37] The risk, however, is minute.

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.^[38] 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.^[39] 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.^[40] Tamoxifen is also a cause of fatty liver, otherwise known as steatorrhoeic hepatosis or steatosis hepatis.^[41]

Central nervous system

Tamoxifen treated breast cancer patients show evidence of reduced cognition^[42] and semantic memory scores.^[43] However memory impairment in patients treated with tamoxifen was less severe compared with those treated with anastrozole (an aromatase inhibitor).^[44]

A significant number of tamoxifen treated breast cancer patients experience a reduction of libido.^[45][46]

Pre-mature growth plate fusion

While tamoxifen has been shown to antagonize the actions of estrogen in tissue's such as the breast, it's 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.^[47]

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.^[48][49] On Oct 18, 2006 the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert.^[50]

Certain CYP2D6 variations in breast cancer patients leads to a worse clinical outcome for tamoxifen treatment.^[51] 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.^[52] 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.^[53]

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.^[54]

Market

Global sales of tamoxifen in 2001 were $1,024 million.^[55] 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.^[56] As of 2004, tamoxifen was the world's largest selling hormonal drug for the treatment of breast cancer.^[57]

In the US, 20 mg tamoxifen tablets cost under $20 per month in quantity.^[58] 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^[59] and free in Wales). 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.^[60] 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.^[61] 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,^[62] 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.^[61] 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.^[63] 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.^[64] 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.^[65]

References

1. ^ Letrozole Therapy Alone or in Sequence with Tamoxifen in Women with Breast Cancer, The BIG 1-98 Collaborative Group, N Engl J Med, 361:766 Aug. 20, 2009
2. ^ ^{a b} Jordan VC (2006). "Tamoxifen (ICI46,474) as a targeted therapy to treat and prevent breast cancer". Br J Pharmacol 147 (Suppl 1): S269–76. doi:10.1038/sj.bjp.0706399. PMID 16402113. 
3. ^ Jordan VC (1993). "Fourteenth Gaddum Memorial Lecture. A current view of tamoxifen for the treatment and prevention of breast cancer". Br J Pharmacol 110 (2): 507–17. PMID 8242225. 
4. ^ "Breast cancer in men". CancerHelp UK. Cancer Research UK. 2007-09-28. http://www.cancerhelp.org.uk/help/default.asp?page=5075. Retrieved 2009-03-22. 
5. ^ Center for Drug Evaluation and Research (03/08/2005). "Tamoxifen Information: reducing the incidence of breast cancer in women at high risk". U.S. Food and Drug Administration. http://www.fda.gov/cder/news/tamoxifen/. Retrieved July 3 2007. 
6. ^ National Cancer Institute (2006-04-26). "Study of Tamoxifen and Raloxifene (STAR) Trial". U.S. National Institutes of Health. http://www.cancer.gov/star. Retrieved July 3 2007. 
7. ^ University of Pittsburgh. "STAR Study of Tamoxifen and Raloxifen". http://www.nsabp.pitt.edu/STAR/Index.html. Retrieved July 3 2007. 
8. ^ Dr Susan Love (April 22 2006). "Study Finds New Use for Raloxifene: Reducing Breast Cancer in High-Risk Postmenopausal Women". http://www.dslrf.org/breastcancer/content.asp?L2=2&L3=6&SID=130&CID=391&PID=14&CATID=0. Retrieved March 19 2009. 
9. ^ Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS (2005). "Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer". Lancet 365 (9453): 60–2. doi:10.1016/S0140-6736(04)17666-6. PMID 15639680. 
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External links

• Tamoxifen on OpenWetWare, a life scientist wiki

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