Tamoxifen for Prevention of Breast Cancer: Is It For You?
by Paul Hueseman, RPh, PharmD
brought to you by Bellevue Pharmacy, a ProjectAWARE
Tamoxifen, marketed as Nolvadex, is a nonsteroidal antiestrogen
that has been used for the treatment of breast cancer since the
early 1970s, successfully helping save the lives of millions of
women with breast cancer. Interestingly, Nolvadex was initially
developed as a possible contraceptive when it was discovered that
it prevented implantation in rats, which suggested antiestrogenic
Tamoxifen works by binding to the estrogen receptor in the breast
and other estrogen-sensitive tissues, thereby preventing the subsequent
binding of estrogen. A possible alternative mechanism of tamoxifens
antiestrogenic effect is through the increased production of sex-hormone
binding globulin, a protein that binds estrogen and blocks its action.
In addition to its antiestrogenic effects, tamoxifen may also inhibit
cell division in cancer cells1 and promote the production
of a certain type of tumor-fighting white blood cells called "natural
killer cells"2. Although tamoxifen acts as an estrogen
"blocker" on the tumor, tamoxifen has an estrogen-like
effect on the bone, liver, and endometrium3.
Uses of tamoxifen include:
- the treatment of metastatic breast cancer
(breast cancer that has spread to other areas of the body)
- adjuvant treatment of breast cancer (treatment
given after surgery and/or radiation to kill any remaining cancer
cells), ductal carcinoma in situ (DCIS) (cancer that originates
in the milk ducts and has not yet spread to the surrounding breast
tissue and lymph nodes)
- prevention of breast cancer in women who have a high-risk for
getting the disease4.
This article will primarily focus on the use of tamoxifen for the
prevention of breast cancer in high-risk women.
Women are naturally at a higher risk for getting breast cancer,
and should know their risk for developing the disease at some point
in their life. The Breast Cancer Gail Model Risk Assessment Tool
can help determine that risk. Developed by scientists at the National
Cancer Institute (NCI) and the National Surgical Adjuvant Breast
and Bowel Project (NSABP) Biostatistics Center, the Breast Cancer
Gail Model Risk Assessment Tool calculates your chances of developing
breast cancer over the next 5 years, and up until the age of 90,
based on answers to questions about several known breast cancer
risks. A prescreener quiz can assist women in providing information
to their doctor so that he or she can quickly find out a womans
risk for developing breast cancer using the Gail Model Risk Assessment
Tool. This quiz can be accessed at http://www.cancer.gov/bcrisktool/.
Women who are age 35 or older should take this quiz.
Tamoxifen is one of the options that a woman may choose if she
is at least 35 years of age and has a predicted risk of developing
breast cancer in the next 5 years greater than or equal to 1.67
percent, calculated using the Gail Model Risk Assessment Tool. Evidence
for using tamoxifen for breast cancer prevention comes from the
Breast Cancer Prevention Trial (P-1) initiated by the National Surgical
Adjuvant Breast and Bowel Project5. This study resulted
in a 49 percent reduced risk of invasive breast cancer for those
women who took tamoxifen over the course of the five-year study.
The decision to start on tamoxifen for the prevention of breast
cancer is one that should be made between a woman and her physician
after careful consideration of the risks and benefits of treatment.
The recommended dose of tamoxifen for prevention is 20 mg once daily
for five years.
In addition to the benefit of decreasing the risk of developing
breast cancer in women who are at high risk, tamoxifen has additional
benefits for the bones and cholesterol. Tamoxifen has been demonstrated
to preserve bone in postmenopausal women, which may result in a
lessened risk of bone fractures6. Furthermore, tamoxifen
is know to decrease levels of LDL cholesterol (the "bad"
cholesterol), and is associated with increases in HDL cholesterol
(the "good" cholesterol) and triglycerides, typical of
the estrogen-like effect on the liver3.
Risks & Side Effects:
There are a number of side effects and safety concerns with tamoxifen
treatment that need to be balanced with the potential benefits.
The most troublesome side effects of tamoxifen are worsening of
hot flushes, sweats, and vaginal discharge. Other side effects include
nausea, vomiting, irregular menses, increased liver enzyme levels,
increased calcium levels, and corneal changes resulting in cataracts
and cataract surgery. As most patients taking tamoxifen are older
women, it is unknown whether the visual changes resulting in cataracts
and cataract surgery are due to tamoxifen or aging. While the incidence
is very low, more serious concerns with tamoxifen treatment include
blood clots, liver damage, endometrial cancer, and uterine sarcoma4.
Recently, a "black box" warning was added to the labeling
of tamoxifen that includes a warning of uterine sarcoma in rare
instances of 0.17 women per 1000 a year who take tamoxifen. Worldwide,
since the initial marketing of tamoxifen, only 159 cases of uterine
sarcoma have been reported in women taking the drug7.
Women who have ever had blood clots should not take tamoxifen for
the purpose of prevention of breast cancer. In addition, women who
are pregnant, or plan to become pregnant should not take tamoxifen,
as it classified as pregnancy category D and may cause birth defects.
Due to a drug interaction that could result in bleeding, women who
are taking a blood thinner known as Coumadin or warfarin should
also avoid taking tamoxifen4.
Tamoxifen has been established as a treatment of breast cancer
that has benefits far outweighing the risks. In addition, tamoxifen
has demonstrated effectiveness in clinical trials to prevent DCIS
from developing into invasive breast cancer, and in reducing the
occurrence of breast cancer in women who are at high risk for developing
the disease. However, it is in these two clinical scenarios that
a woman, along with her healthcare provider, must carefully evaluate
the benefits and risks to determine whether tamoxifen is the right
For those who decide the risks outweigh the benefits of tamoxifen,
one alternative may be indole-3-carbinol (Cervaplexx). Indole-3-carbinol
converts the "stronger" estrogen (estradiol) to the "weaker"
estrogen (2-hydroxyestrone) and decreases the level of 16-Hydroxyestrone,
a breakdown of estrogen that is associated with breast and endometrial
cancer. While there have been no long-term clinical trials to test
the effectiveness of this, animal studies suggest that this product
may help in preventing breast cancer.8 A dose-ranging
study in women with increased risk of breast cancer has been performed
which suggested that a minimum dose of 300 mg per day is a promising
chemopreventive agent for breast cancer9.
- Calabresi P, Chabner BA. Chemotherapy of neoplastic diseases.
In, Goodman & Gilmans: The Pharmacological Basis of
Therapeutics, 9th ed. (Hardman JG, Limbird LE, eds.), McGraw-Hill,
New York, 1996, pp. 1225-1285.
- Brenner BG, Friedman G, Margolese RG. The relationship of clinical
status and therapeutic modality to natural killer cell activity
in human breast cancer. Cancer. 1985;56:1543-1548.
- Howell A, DeFriend DJ, Robertson JFR, et al. Pharmacokinetics,
pharmacological and anti-tumour effects of the specific anti-oestrogen
ICI 182780 in women with advanced breast cancer. British Journal
of Cancer. 1996:300-308.
- Package insert. Nolvadex (tamoxifen). AstraZeneca, rev 05/2002.
- Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for
prevention of breast cancer: Report of the national surgical adjuvant
breast and bowel project P-1 study. J Natl Cancer Inst 1998:90;1371-1388.
- Love RR, Mazess RB, Barden HS. Effects of tamoxifen on bone
mineral density in postmenopausal women with breast cancer. N
Engl J Med 1992;326:852-6.
- Gottlieb S. Tamoxifen may increase risk of uterine sarcoma.
- Osbourne MP. Chemoprevention of breast cancer. Surgical Clinics
of North America. 79(5):1207-21, Oct 1999.
- Wong GY, Bradlow L, Sepkovic D, et al. Dose-ranging study of
indole-3-carbinol for breast cancer prevention. Journal of Cellular
Biochemistry Supplement. 28-29:111-6, 1997.
For questions and further information, contact Bellevue