© The Author 2007. Published by Oxford University Press.
ARTICLES |
Long-Term Results of Tamoxifen Prophylaxis for Breast Cancer—96-Month Follow-up of the Randomized IBIS-I Trial
For the International Breast Cancer Intervention Study (IBIS) I Investigators
Affiliations of authors: Centre for Epidemiology, Mathematics, and Statistics, Cancer Research UK, Wolfson Institute of Preventive Medicine, London, UK (JC, IS); Department of Surgical Oncology, Newcastle Mater Hospital, University of Newcastle, and Australian New Zealand Breast Cancer Trials Group, Newcastle, Australia (JFF); Breast Care Centre, Frenchay Healthcare Trust, Bristol, UK (SC); Breast Unit, Clinical Oncology, Guy's Hospital, London, UK (HH); Department of Oncology and Palliative Medicine, Tampere University Hospital, Tampere, Finland (KH); Family History Clinic, University Hospital of South Manchester, Manchester, UK (AH)
Correspondence to: Jack Cuzick, PhD, Centre for Epidemiology, Mathematics, and Statistics, Cancer Research UK, Wolfson Institute of Preventive Medicine, Charterhouse Square, London EC1M 6BQ, UK (e-mail: jack.cuzick{at}cancer.org.uk).
Background: Initial results from the first International Breast Cancer Intervention Study (IBIS-I) found that tamoxifen reduced the risk of invasive estrogen receptor (ER)–positive tumors by 31% in women at increased risk for breast cancer, but most of the follow-up at this time was during the active treatment phase. We report an updated analysis of IBIS-I that focuses on the period after active treatment was completed, a time for which little evidence from other trials is available.
Methods: A total of 7145 women who were aged 35–70 years and at increased risk of breast cancer were randomly assigned to receive either tamoxifen (20 mg/day) or placebo for 5 years. The primary outcome measure was the incidence of breast cancer (including ductal carcinoma in situ), but side effects were also investigated. Relative risks were computed as the ratio of incidence rates. All statistical tests were two-sided.
Results: After a median follow-up of 96 months after randomization, 142 breast cancers were diagnosed in the 3579 women in the tamoxifen group and 195 in the 3575 women in the placebo group (4.97 versus 6.82 per 1000 woman-years, respectively; risk ratio [RR] = 0.73, 95% confidence interval [CI] = 0.58 to 0.91, P = .004). The prophylactic effect of tamoxifen was fairly constant for the entire follow-up period, and no diminution of benefit was observed for up to 10 years after randomization. However, side effects in the tamoxifen group were much lower after completion of the active treatment period than during active treatment. For example, deep-vein thrombosis and pulmonary embolism were statistically significantly higher in the tamoxifen arm than in the placebo arm during active treatment (52 versus 23 cases, RR = 2.26, 95% CI = 1.36 to 3.87) but not after tamoxifen was stopped (16 versus 14 cases, RR = 1.14, 95% CI = 0.52 to 2.53). The two arms did not differ in the risk of ER-negative invasive tumors (35 in each arm, RR = 1.00, 95% CI = 0.61 to 1.65) across the entire follow-up period, but the risk of ER-positive invasive breast cancer was 34% lower in the tamoxifen arm (87 versus 132 cases, RR = 0.66, 95% CI = 0.50 to 0.87).
Conclusions: The risk-reducing effect of tamoxifen appears to persist for at least 10 years, but most side effects of tamoxifen do not continue after the 5-year treatment period.
| CONTEXT AND CAVEATS Prior knowledge Tamoxifen reduces the risk of breast cancer in women at high risk of the disease during active treatment, but less is known about the period after active treatment. Tamoxifen also increases the risk of endometrial cancer, thromboembolic events, and other side effects. Study design Women in a randomized chemoprevention trial who had been assigned to take tamoxifen or placebo for 5 years were followed for a median of 8 years. Contribution Tamoxifen reduced the incidence of all breast cancers (invasive plus ductal carcinoma in situ) by 27% overall (from 6.82 to 4.97 events per 1000 woman-years), and the reduction was fairly constant over the entire follow-up period. Incidence rates of ER-positive invasive breast cancers in the tamoxifen group were 26% lower than those in the placebo group during active treatment and 44% lower during the subsequent years. Rates of deep-vein thrombosis, pulmonary embolism, and endometrial cancer were higher in the tamoxifen arm than the placebo arm during active treatment but not in the subsequent years. Implications The preventive effect of tamoxifen on breast cancer in high-risk women is undiminished for at least 5 years beyond active treatment but the risk of serious side effects drops, leading to an improved risk–benefit ratio. Limitations Information on side effects was obtained somewhat differently during active treatment and in subsequent years. Women in the trial were permitted to take hormone replacement therapy, which could have confounded the results. Even longer follow-up is needed to determine the full extent of the risk reduction associated with tamoxifen prophylaxis.
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Manuscript received November 9, 2006; revised December 27, 2006; accepted January 3, 2007.
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J Natl Cancer Inst 2007 99: 258-260.
J Natl Cancer Inst 2007 99: 257.
J Natl Cancer Inst 2007 99: 257.
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