Results

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**Results**
Tamoxifen has multiple uses for breast cancer patients. These uses were discovered from the multiple trials that were conducted to test Nolvadex, a tamoxifen citrate, under FDA regulations.



Tamoxifen was initially recognized as a hormone therapy drug for early breast cancer patients. The Early Breast Cancer Trialists’ Collaborative Group conducted an overview of systemic adjuvant therapy for these patients and found that tamoxifen-treated women who were estrogen receptor positive and had positive nodes had a slightly higher survival rate than placebo-treated women in the control group.This discovery provided an alternative form of treatment for breast cancer patients and was soon to be identified as a chemoprevention drug. The trial initiated by the National Cancer Institute revolutionized the pharmaceutical industry by supporting the prevention quality of tamoxifen.
 * Breast Cancer Prevention Trial: Tamoxifen**

The Breast Cancer Prevention Trial (BCPT) was a double-blind randomized trial that analyzed the role of Nolvadex in the reduced incidence of invasive breast cancer in high risk women. The study also sought to evaluate the incidence of ischemic heart disease and observe the incidence of bone fractures. The Gail Model was used to calculate the predicted risk for breast cancer of the women participants. Risk factors include but are not limited to: age, number of 1st degree female relatives with breast cancer, previous breast biopsies, presence/absence of atypical hyperplasia, and age at menarche.



Based on the [|Gail Model], all trial participants must have a predicted risk of greater than or equal to 1.67% of contracting breast cancer within 5 years. The BCPT found that 44% of the women assigned to Nolvadex had a reduced incidence of invasive breast cancer, among all ages and women with or without lobular carcinoma in situ.[18] There was no significant difference of ischemic heart disease related events, breast cancer-related mortality or hip fractures between the two treatment groups. However, Nolvadex decreased the incidence of small estrogen receptor positive tumors and not estrogen receptor negative tumors. Based on these findings Nolvadex is proven to be an adjuvant drug and a chemoprevention drug for women at risk.

In 2005, the Breast Cancer Prevention Trial was revisited. Tamoxifen reduced the invasive cancer rate from 42.5 per 1000 women in the placebo group to 24.8 per 1000 women in the tamoxifen group. Reported side effects (stroke, cataracts, etc.) remained the same as in the initial study, seven years before.
 * BCPT Revisited: Long Term Studies of Tamoxifen**



However, pulmonary embolism risk lowered by 11%. The risks of endometrial cancer increased by 29%. However, NSABP reported that neither of these were statistically significant. One potential problem with the long term follow up of the original BCPT was the unblinding of the study before it reached completion. When the trial results were announced in 1998, the women were informed as to whether they had received tamoxifen or placebo and given the option to start or continue tamoxifen treatment for five years. Of the placebo group, 32% either went on a five year course of tamoxifen or was randomized in the Study of Tamoxifen and Raloxifene (STAR) trial. Other women in the placebo group chose to receive a prescription of tamoxifen or raloxifene through their physician, not through the clinical trial. It is unsure as to how many women in the placebo group choose the option of chemoprevention. While the study claims this is not a source of bias, it certainly lowers the placebo group sample size for follow-up.

A clinical phase 1 study conducted on pregnant rabbits found a lower incidence of embryo implantation and higher incidence of fetal death or utero growth and low learning behavior among those treated with Nolvadex. In fact, treating rabbits 0.125mg/kg during day 6-18 of pregnancy resulted in an abortion or a premature delivery. An additional study on rats found a decreased fertility after 0.04mg/kg for two weeks prior to mating through day 7 of pregnancy. All fetuses were found dead and there was a significant decrease in the number of implantations. Based on the detrimental effects of fetal death/ reduced fertility found in animals, no clinical trial of pregnant women was conducted. Therefore, tamoxifen must not be taken if women are pregnant or believe they may be pregnant.
 * Now that we know Nolvadex is safe for the general population of women, how does it affect pregnant women?**

Whether tamoxifen is safe to treat women who are breast feeding is questionable since more studies need to be done to determine if tamoxifen can be excreted in human milk. It is unknown if Nolvadex delays the appearance of cancer or actually decreases the number of tumors that will develop since long-term studies have not been completed. The FDA approved and recommended dose for breast cancer patients, whether at risk or fighting the disease, is 20mg for 5yrs.

There are other SERMs available for women who would like to prevent incidence of breast cancer. One in particular that has perspective chemoprevention patients considering alternatives to tamoxifen is raloxifene.
 * Are there other drug options available for those who want to prevent breast cancer?**

In a Multiple Outcomes Raloxifene Evaluation (MORE) study double blind clinical trial tested raloxifene and placebo effect in postmenopausal women with osteoporosis. They found that the risk of estrogen receptor postivie invasive breast cancer reduced by 72%, but there was an elevated risk of thromboembolic disease.
 * MORE**

Once this study was released, the NSABP (National Surgical Adjuvant Breast and Bowel Project) held a comparative study between Tamoxifen and Raloxifen (STAR) to determine the safety and efficacy of each drug on at-risk breast cancer patients. Similar to the BCPT trial, eligibility requirements must be upheld by clinical trial participants: 5 year predicted breast cancer risk of 1.66% or higher, postmenopausal women, have no history of stroke/ pulmonary embolism/ malignancies. There was no difference between the effect of tamoxifen and raloxfiene on the incidence of invasive breast cancer, both drugs effectively prevented occurrence of breast cancer in patients who were estrogen receptor positive
 * STAR**



However, incidence of uterine cancer was lower in the raloxifene group than tamoxifen group, but not significantly different. There was a significant difference between groups in the incidence of thromboembolic events, raloxifene group had 30% lower risk than tamoxifen, and cataracts, raloxifene group had 21% lower rate.



These findings are appropriate for postmenopausal at-risk breast caner patients, not premenopausal women since clinical trials did not include them. There are efforts to determine safety and efficacy of raloxifene on premenopausal women, but a preliminary one found elevated incidence of ovarian cysts. Until more clinical trials or research is done on premenopausal women raloxifene cannot be prescribed to them.