Long-term Results with Tamoxifen in Prevention of Breast Cancer
Long-term Results with Tamoxifen in Prevention of Breast Cancer
Abstract & Commentary
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: The risk of estrogen receptor-positive breast cancers is reduced for at least 10 years after treatment with tamoxifen.
Source: Cuzick J, et al. Long-term results of tamoxifen prophylaxis for breast cancer-96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst. 2007;99:272-282.
The Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial began in 1986, enrolling 2,471 women with a positive first-degree family history of breast cancer.1 The treatment group received 20 mg tamoxifen daily for 8 years. Twenty years later (median follow-up of 13 years), there were 139 estrogen receptor-positive breast cancers for a 39% reduction (HR = 0.61; CI = 0.43-0.86). The lowered risk did not become statistically significant until after the 8-year treatment period. The International Breast Cancer Intervention Study (IBIS) was also a randomized, double-blinded trial, beginning in 1992 and enrolling 7,145 women, but the treatment period with tamoxifen 20 mg daily was 5 years.1 After a median follow-up of 8 years, there was a 34% reduction in estrogen receptor-positive cancers (RR = 0.66; CI = 0.50-0.87). The Royal Marsden trial found the reduction only after the treatment period. The IBIS trial found a greater reduction during the treatment period, but when the analysis was restricted to estrogen receptor-positive cancers, the two trials were similar, finding a greater effect after treatment.
Commentary
There have been four randomized placebo-controlled tamoxifen prevention trials. The American trial reported a significant 43% reduction in estrogen receptor-positive cancers.2 The International Breast Cancer Intervention (IBIS) Study found a 32% reduction when invasive and ductal carcinoma in situ were combined, also only in estrogen receptor-positive tumors.3 Follow-up of the Italian national trial demonstrated a reduction of estrogen receptor-positive cancers in the group of women considered to be at the highest risk of cancer. The Royal Marsden Trial in England demonstrated no reduction in breast cancer in the initial report.4 The differences among these trials has been attributed to variations in risk factors in the studied populations. The American trial enrolled women with risk assigned by the Gail model. The women in the International trial were at a lower risk than those in the Royal Marsden trial, and the women in the Italian trial were not assessed for risk.
These long-term follow-up reports indicate that tamoxifen prevention of estrogen receptor-positive breast cancer in high-risk women lasts for many years after the treatment period. However, the long-term follow-up of tamoxifen-treated women continues to indicate an increase in cataracts, venous thrombosis, and gynecologic side effects (vasomotor symptoms, hysterectomy, endometrial cancer, and vaginal discharge), predominantly during the period of treatment.
Interestingly, the Royal Marsden trial (the American trial is the only one not to allow limited hormone therapy) could not detect any effect of hormone therapy on the results. However, the IBIS trial found that in women who used concurrent hormone therapy during the trial, no tamoxifen effect could be demonstrated; a finding, although limited by small numbers, that would be consistent with tamoxifen's antiestrogenic mechanism of action. It should be emphasized that hormone therapy is ineffective for the treatment of hot flushes associated with tamoxifen treatment.5
There is one lingering concern. There has been a slight increase in estrogen receptor-negative cancers in the follow-up period after treatment in all of the prevention trials. It is uncertain if this is related to tamoxifen exposure; however, in the trials assessing tamoxifen treatment of breast cancers, survival and recurrence rates worsened with longer therapy, probably due to the emergence of tamoxifen-resistant tumors. There are several possible explanations for resistance (such as tamoxifen stimulation of growth factor, and whichever of these are operative, it is believed that a subpopulation resistant to tamoxifen is present from the beginning, and over time grows to be clinically apparent.6
In conclusion, tamoxifen exposure for 5 to 8 years is associated with about a 30% to 40% reduction in estrogen receptor-positive breast cancers for at least 15 years after the treatment ends. An estimate of the absolute impact puts this in better perspective. The absolute reduction in cumulative overall incidence of breast cancer after 5 years is estimated to about 1.1% and after 10 years, 1.7%. This small impact combined with the serious side effects have made tamoxifen treatment an unattractive option. Note that there has been no differences in mortality rates comparing treatment and placebo groups in the prevention trials. We await the results of the prevention trials with aromatase inhibitors, anticipating even greater efficacy and a lower rate, if not an absence, of serious side effects.
References
- Cuzick J, et al. Long-term results of tamoxifen prophylaxis for breast cancer—96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst. 2007;99:272-282.
- Fisher B, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 2005;97:1652-1662.
- Cuzick J, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet. 2003;361:296-300.
- Powles T, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet. 1998;352:98-101.
- Sestak I, et al. Influence of hormone replacement therapy on tamoxifen-induced vasomotor symptoms. J Clin Oncol. 2006;24:3991-3996.
- Horwitz KB. Hormone-resistant breast cancer or "feeding the hand that bites you." Prog Clin Biol Res. 1994;387:29-45.
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