Introduction

=Introduction= <- Back to the Home Page To Case Study ->

Tamoxifen is a competitive inhibitor of the estrogen receptor. It is part of a class of drugs called selective estrogen-receptor modulators (SERM ). These drugs can act as an inhibitor or analogue of estrogen depending on the type of tissue it is in. In breast cancer, it is anti-estrogenic. It's two metabolites, N-desmethyltamoxifen and trans-4-hydroxytamoxifen, are what causes it's drug activity. The trans conformation and dimethylation are crucial for tamoxifen activity and account for the metabolites' affinity to the estrogen receptor. Tamoxifen was first used in the prevention of breast cancer recurrence, but in 1998 was approved by the FDA to be used for breast cancer chemoprevention after the Breast Cancer Prevention Trial started in 1992. Tamoxifen is taken orally daily at a dose of 20 mg per day for five years.
 * What is Tamoxifen?**



General side effects of Nolvadex include endometrial cancer, deep vein thrombosis, pulmonary embolism, stroke, and cataract formation. The mechanism of endometrial cancer is unknown, but it has an estrogen-like effect. However among metastatic breast cancer patients [|hypercalcemia], increased bone/tumor pain, distaste for food, depression, vaginal dryness, and peripheral edema have been reported within weeks of treatment. Pregnant women are discouraged from taking Nolvadex since treatment may cause fetal death or birth defects. Some common side effects premenopausal women experience are menopause-like symptoms: hot flashes, vaginal discharge, and irregular menses.
 * What are the side effects?**


 * Summary of the side effects:**
 * 1) Major symptoms include :
 * Blood clots
 * Endometrial cancer
 * Uterine sarcomas
 * Strokes
 * Cataracts
 * 1) Minor symptoms include :
 * Menopausal symptoms
 * hot flashes
 * vaginal discharge
 * Fatigue
 * Nausea
 * Vomitting

For 30 years, tamoxifen has been used in the treatment of breast cancer. Tamoxifen is used as an [|adjuvant drug] in postmenopausal women and a preventative drug in cancer treatment for estrogen receptor positive breast cancers in pre- and post-menopausal women. Nolvadex, tamoxifen brand drug, reduces contralateral breast cancer in patients receiving adjuvant therapy as well as reduce the incidence of breast cancer in women with high risk. It is also a hormone therapy for men with breast cancer. More obscure uses include treatment of bipolar disorder infertility.
 * What are Tamoxifen's Uses?**

Simply, breast cancer is an accumulation of malignant tumors in the breast. In women the breast is made up of lobules, ducts, and stroma. Lobules are the milk-producing glands, ducts are the tubes that carry the milk from the lobules to the nipple, and the stroma consists of the fatty and connective tissue.Most breast cancers start in epithelial cells lining the ducts; these are called ductal cancers. Cancers in the cells that line the lobules are called lobule cancers. Breast cancers can spread through the body due to the breast's proximity to the [|lymphatic system].
 * What is breast cancer?**

Breast cancers can be invasive, non-invasive, or a mixture of both. Non-invasive cancers are called carcinomas in situ. These can occur in the ducts or lobules. Invasive cancers can start in the ducts or lobules, but eventually [|metastasize] throughout the body. There are several, but less common, variations of breast cancer (an extensive list can be found [|here]).

Breast cancer is caused by DNA mutations in the breast cells. These mutations can be acquired, such as HER 2 amplification, or inherited, which is the case with the BRCA 1/2 mutations. Cancer occurs when the DNA mutations turn on an oncogene, the gas pedal for the cell cycle, or turn off a tumor suppressor gene, the brakes of the cell cycle.
 * What are the causes and types of breast cancer?**

There are four basic types of breast cancer: luminal A and B, HER 2 type, and basal. Luminal breast cancers are estrogen receptor(ER)-positive. These cancers grow slowly and are considered low grade. The only difference between luminal A and B cancers is that luminal B cancers grow slightly faster and have a worse prognosis. HER 2 type cancers are a result of amplification of the gene coding for HER 2. These are high grade, fast growing and generally have a worse prognosis. However, HER 2 cancers are easily treated with targeted chemoterapeutics such as herceptin. Basal type cancers are triple negative cancers, meaning they lack estrogen and progesterone receptors and have normal HER 2 gene expression. These are high grade and have a very low prognosis.



The following is a list of some risk factors for female breast cancers. This is not a complete list by any means, but includes the basic risk factors.
 * What are the risks for developing breast cancer?**
 * Gender
 * Age
 * Genetic Mutations
 * The most common being BRCA 1 and 2
 * Family History
 * Race and Ethnicity
 * Benign Breast Conditions
 * Fibrocystic disease is one example
 * Not Having Children by Age 30
 * Oral Contraceptive Use
 * Lifestyle Choices
 * Such as diet, vitamin intake, and physical activity

Because more is known about the risk factors and genetics of breast cancer, chemoprevention options are becoming readily available. These chemoprevention drugs are selective estrogen receptor modulators (SERMs), such as tamoxifen. For chemotherapy, tamoxifen is generally used for ER-positive cancers because its drug action involves the estrogen receptor. However, for chemoprevention, a variety of risk factors may be lowered by tamoxifen.
 * How can breast cancer be prevented?**

Two other drugs have been suggested as possible chemotherapeutics. Raloxifene is a SERM as well, but reportedly has less side effects than tamoxifen. The effectiveness of raloxifene was covered in the STAR trial. Aromatase inhibitors are currently used as hormone therapies to prevent breast cancer recurrence. It is possible these drugs can be used for chemoprevention in postmenopausal women, but none have been approved for that use.

Tamoxifen was approved by the FDA as a drug therapy for breast cancer patients and a chemoprevention drug for patients at risk for breast cancer. Its ability to treat patients at both stages is due to its capability to target estrogen receptors and is thus categorized as a selective estrogen receptor modulator ([|SERM]).SERM drugs compete with estrogen to bind to estrogen receptors. This trait is effective in chemoprevention since estrogen is a ligand that can promote the growth of breast cancer cells. Unlike the binding between estrogen and its cognate ligand, the binding between tamoxifen and the estrogen receptor does not result in a conformational change of the receptor which obstructs the activation of co-activators.
 * How and why is Tamoxifen being used for those at risk for breast cancer?**

Tamoxifen is provided to patients in a small pill. The pill must be digested to efficiently play out its role as a SERM. Though the discussion of this page and the general concept of chemoprevention are centered on the use of tamoxifen, tamoxifen is not the driving force in blocking estrogen, endoxifen is. An enzyme produced by the CYP2D6 gene converts tamoxifen into endoxifen, a phenolic metabolite that has a high binding affinity to estrogen receptors. Endoxifen is the chemical configuration that actually acts as the anti-estrogen. Therefore, the presence and proper function of the CYP2D6 gene is essential to treat patients at risk for breast cancer. As stated above, CYP2D6 interacts with tamoxifen to produce endoxifen but it also interacts with selective serotonin reuptake inhibitors (SSRI), antidepressants. The SSRIs were found to prevent hot flashes among patients treated with tamoxifen. This discovery is important for patients who are weary about experiencing menopause-like symptoms since the elevated concentration of endoxifen in a patient’s blood stream will elevate the symptoms. SSRIs are beneficial in counteracting the uncomfortable side effect of tamoxifen, but it can also block the activation of tamoxifen. Both drugs are metabolized by the same enzyme, a CYP2D6 product. A randomized clinical trial among women treated with tamoxifen found that SSRIs were twice as effective as placebos in reducing menopausal symptoms, but SSRI reduced endoxifen levels by 64% in women with the wildtype CYP2D6 enzyme.
 * How is tamoxifen metabolized?**

The following statements dictate what must be conducted for a drug to be a approved:
 * Comply with FDA's good laboratory practice rules (covers record-keeping, personnel training, animal handling, and equipment requirements) Extensive preclinical testing in the lab on animals, including nonclinical tests
 * nonclinical tests provide information about how the drug functions
 * More than one clinical study on human beings (exception are drugs that treat biological, chemical or radiological toxicity ie. anthrax)

For a drug to be tested on humans the following must be conducted:
 * Submit appropriate application for an investigational new drug or investigational new animal drug
 * Specify how sponsoring institution and researcher plan to determine safety of the investigational new drug in humans
 * Investigational new drugs intended to treat serious illnesses are allowed to make the drug available to patients who are not part of the clinical trial

The Early Breast Cancer Trialists' Collaborative Group found a study that focused on women who were estrogen receptor positive. These women were treated with Nolvadex in varying lengths of time: 1years, 2 years and 5 years. They found that women involved in the study had a reduced rate in breast cancer of 21%, 29% and 47% respectively. These results were independent of age and estrogen receptor status of the primary tumor. To confirm the length of time tamoxifen should be prescribed, the NSABP trial randomized treatment of Nolvadex (20mg/day) and placebo pills for 5 years and re-randomized treatment for an additional 5 years. They found that continuing hormone therapy beyond the 5 year period did not provide any additional benefit to the patient. Therefore, Nolvadex at this stage should not be taken longer than 5 years.
 * FDA Approved Dosage and Length**