Tamoxifen Cuts the Risk of Breast Cancer in Half

abstract & commentary

One of the interesting secondary outcomes of the careful clinical studies conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and other multicenter groups through the years has been the observation that women with breast cancer who took adjuvant therapy with tamoxifen not only had a significantly lower rate of disease recurrence but, in addition, had a significantly lower risk of developing cancer in the contralateral breast.1-4 Because women who have had breast cancer are at high risk of developing a second breast cancer, this secondary benefit from tamoxifen adjuvant therapy led to the notion that perhaps tamoxifen would be capable of influencing the risk of developing breast cancer in other high-risk groups. Tamoxifen has also been shown to have beneficial effects on the risk of cardiovascular disease, the development of osteoporosis, and possibly even the occurrence of dementia and Alzheimer’s disease. Balanced against these substantial potential benefits was a small risk of developing estrogen-related complications, such as thromboembolic disease and endometrial cancer, because of the weakly estrogenic effects of tamoxifen.

In light of these considerations, NSABP implemented a randomized clinical trial (NSABP-P1) to examine whether tamoxifen could significantly lower the risk of developing breast cancer in a group of women considered to be at increased risk. Eligibility criteria included the following: age 60 years or older; age 35-59 years with a calculated five-year risk of 1.66% (note that the Breast Cancer Risk Assessment Tool used to calculate the risk [based upon the model of Gail et al5] is now available as an interactive computer program through the National Cancer Institute’s Cancer Information Service at 1-800-4-CANCER or online at http://cancertrials.nci.nih.gov) or a history of lobular carcinoma in situ; a life expectancy of at least 10 years; a negative breast examination and mammagram within the past six months; and no history of thromboembolic disease or deep venous thrombosis. Women with an intact uterus had an endometrial tissue sampling before starting treatment. Primary outcome measures were the rate of development of breast cancer. Secondary outcome measures were the incidence of myocardial infarctions and the incidence of osteoporotic bone fractures.

From April 1992 through May 1997, 13,388 women (of 98,018 undergoing risk assessment) were randomly assigned to receive either tamoxifen 20 mg/d or oral, daily placebo for five years. The trial was a double-blind, placebo-controlled design; 6707 received placebo and 6681 received tamoxifen. Twenty-one percent of women stopped their assigned therapy prematurely—19.7% in the placebo group and 23.7% in the tamoxifen group. Complete follow-up was available on 92.4% of the participants.

In total, 368 invasive and noninvasive breast cancers developed among the 13,175 patients with follow-up, 244 on placebo, 123 on tamoxifen. Of these, 175 cases of those on placebo were invasive and 89 cases on tamoxifen were invasive (P < 0.00001 in favor of tamoxifen). The cumulative incidence through 69 months was 43.4 per 1000 women in the placebo group and 22 per 1000 women in the tamoxifen group. Thus, tamoxifen significantly reduced the risk of both invasive and noninvasive breast cancer. Significantly reduced risk was seen in women of all ages: younger than 49, 44% risk reduction (RR); 50-59, 51% RR, and older than 60, 55% RR. Risk was reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%). Significantly reduced risks were observed in all risk categories.

Tamoxifen-treated patients did not have a reduced risk of myocardial infarction, but this may be related to the length of follow-up. Bone fractures were significantly reduced in the tamoxifen arm. Endometrial cancer occurred with increased incidence on the tamoxifen arm: 36 cases (13/1000 women) vs. 16 cases (5.4/1000 women) on the placebo arm. All the cancers on the tamoxifen arm were FIGO stage I. More women who received tamoxifen developed deep vein thrombosis (35 vs 22) and pulmonary embolus (18 vs 6). The incidence of strokes and cataracts was not significantly different on the two arms. (Fisher B, et al. J Natl Cancer Inst 1998;90:1371-1388.)

Commentary

Well, it’s hard to imagine news much better than this. The use of tamoxifen reduces a woman’s risk of developing breast cancer by about 50%. A bonus from the treatment is a reduction in osteoporosis and the morbidity associated with fractures. At this particular time of follow-up, tamoxifen has not yet shown a beneficial effect on deaths from heart disease, but only a small fraction of patients have died so far. This study did not assess cognitive endpoints, but it is also possible that tamoxifen-treated patients will have less age-related cognitive impairment.

With these documented and not-yet-documented gains come some downside risks. The risks of thromboembolic disease and endometrial cancer are somewhat increased by taking tamoxifen. However, the balance of risk and benefit is overwhelmingly in favor of benefit. The subset of patients with genetic mutations that increase their risk has not yet been examined; however, blood samples are available to determine BRCA1 and BRCA2 phenotypes and such correlations will be made in future analyses. In addition, given the broad efficacy of tamoxifen in diverse risk groups, the question must be asked about how high the risk must be before the risk-benefit ratio is favorable. Modifications of the existing algorithms are currently being made to help with these decisions.

Furthermore, we may not yet have gotten all the benefit that is possible to obtain from tamoxifen use. The question remains open whether longer duration of tamoxifen treatment would exert greater benefits. In addition, it is not yet clear whether the newer selective estrogen receptor modulators (SERMs), such as raloxifene, will have different or greater effects than tamoxifen. Ongoing studies, including NSABP-P2, are addressing this question. The success of this study makes interpretation of other ongoing studies somewhat complicated. In my opinion, it is no longer appropriate to include a placebo arm in breast cancer prevention studies. The new SERMs need to be demonstrated to be superior to tamoxifen rather than placebo. Primary care physicians should develop a level of comfort using the risk assessment tool and applying it to individual patients. If an individual is found to be at increased risk of breast cancer, the first choice would be to enter the patient on a prospective randomized trial. If that is not possible, women should be informed of the risks and benefits of tamoxifen use and be permitted to obtain the benefits proven in this landmark study.

References

1. Scottish Clinical Trials Office, Edinburgh. Lancet 1987;2:171-175.

2. Fisher B, et al. N Engl J Med 1989;320:479-484.

3. CRC Adjuvant Breast Trial Working Party. Br J Cancer 1988;57:604-607.

4. Rutqvist LE, et al. J Natl Cancer Inst 1991;83: 1299-1306.

5. Gail MH, et al. J Natl Cancer Inst 1989;81:1879-1886.