imported_womens-health

The Promise of New Medications to Reduce Breast Cancer Risk: Tamoxifen and Raloxifene


By: John P. Leonard, MD
Given the prevalence of breast cancer and the presence of defined risk factors (such as family history), many women wish to consider options that could help reduce their risk of developing the disease. Many factors affect the growth and proliferation of normal breast tissue and may play a role in the development of a tumor. Hormones such as estrogen and progesterone, which have many important effects in normal female physiology, also seem to be involved in the growth and spread of breast cancer cells.
Tamoxifen is a drug that has anti-estrogenic (as well as other) properties and that has been an extremely important oral agent in the treatment of breast cancer, especially in patients with tumor cells that express receptors for the estrogen and/or progesterone hormones. Tamoxifen has been primarily used and studied in the adjuvant treatment of breast cancer (following surgery and/or radiation, with or without chemotherapy) in order to help prevent a recurrence of the disease. It can also be effective in the treatment of advanced disease to help reduce the extent of tumor.

An important study demonstrating the effectiveness of Tamoxifen in early breast cancer was a meta-analysis (review of multiple studies) performed by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) published in 1992 and updated in 1998 (Lancet, Vol. 351:1451-1467). A significant finding in this study of women with early breast cancer was that those who were treated with tamoxifen for 5 years (to prevent disease recurrence) had a 47% reduction in the development of new cancers in the opposite (previously unaffected) breast.

This study as well as others led to further evaluation of tamoxifen. When evaluating the utility of a potential cancer therapeutic intervention, it's important to keep in mind several issues.
Reduced incidence of cancer does not necessarily mean prevention. An intervention may simply delay the onset of cancer formation, rather than keep it from forming altogether. If this is occurring, the benefit to the patient may be less dramatic, though not necessarily zero. If the patient has the same ultimate outcome several years down the line, the intervention is clearly as not as helpful as it would be if the tumor did not occur at all. Therefore, longer-term results are always more valuable for analysis, especially those that measure overall survival.
There are relative risks and benefits for any treatment. Tamoxifen has certain side effects that can be serious. Whether these potential side effects are acceptable to an individual patient depends on how much benefit she may receive. If a patient has a high risk of breast cancer and an intervention may substantially reduce that risk, then the side effects are more palatable than if a patient is at low risk for cancer and can expect little incremental benefit (which may be outweighed by the side effects). Furthermore, tamoxifen's possible beneficial effects on other organs such as the heart and bones (which estrogen is known to affect) also plays a role in the equation. A recent study in the Journal of Clinical Oncology (Vol. 16, No 6; June 1998: p 2018-2024) suggested that for breast cancer survivors on tamoxifen treatment, the balance between avoided deaths (from new breast cancer or cardiovascular disease) outweighed excess deaths (from uterine cancer and blood clots), yielding an overall survival benefit.
Breast cancers are a variable group of tumors that occur in a variable group of women of different ages and genetic make-ups. Thus, it is possible that different types of tumors may be more or less likely to be prevented by an intervention. If a patient's characteristics are not similar to those of women who participated in a trial, then she may not be able to expect the same potential benefits and risks. Furthermore, individual patients with other illnesses may derive more or less benefit, depending on their situation.

The largest study to date evaluating the effects of tamoxifen on prevention of breast cancer was initiated in 1992 by the National Surgical Adjuvant Breast and Bowel Project (NSABP); it was called the Breast Cancer Prevention Trial (BCPT or P-1). This trial led to the October 29th approval by the U.S. Food and Drug Administration of the use of tamoxifen to reduce the risk of breast cancer in healthy women at high risk for the disease. The trial enrolled 13,388 women, and its results were recently reported in the Journal of the National Cancer Institute (Vol. 90, No 18; Sept. 16,1998: p 1371-1388). These patients were considered at increased risk for breast cancer based on a number of parameters:
Age greater than 60
Age between 35-59, but determined to be at increased risk of breast cancer over the next 5 years through a calculation involving age, family history, childbirth history, past history of breast disease, and age at onset of menses
A previous biopsy that was diagnosed as lobular carcinoma in situ (an abnormal, pre-cancerous diagnosis).
Importantly, most of the women enrolled in the study were at significantly higher breast cancer risk; thus, the applicability of these findings to a lesser risk (though still greater than average) population is unclear. The enrolled women were randomly assigned to receive tamoxifen 20 mg per day orally for 5 years versus a placebo pill, and were followed up for a median time of 54.6 months.
It was found that tamoxifen reduced the risk of development of invasive breast cancer by 49%, with 22.0 diagnoses of breast cancer vs. 43.4 diagnoses per 1000 women in each group, respectively. Tamoxifen reduced the risk of estrogen receptor positive tumors by 69%, but had no effect on the development of estrogen receptor negative tumors. Also, the tumors observed in the tamoxifen group tended to be smaller and with less lymph node involvement.

Additionally, major bone fractures were reduced in the tamoxifen group, although no significant differences were noted in regard to risk of heart disease. Rates of endometrial cancer (cancer in the lining of the uterus) were increased in the tamoxifen group (2.53 fold); however, these endometrial cancers were seen primarily in patients who were 50 years or older and were all early-stage, and resulted in no deaths. The 50 years old or greater population did experience increased rates of stroke (1.59 fold), pulmonary embolism (3.01 fold), and deep vein thrombosis (blood clot) (1.6 fold). Cataract development was also slightly increased in the tamoxifen group.

Continue Article at:
http://womens_health.healthology.com...oxifen&spg=FLA