IBIS-I Long Term Follow Up
IBIS-I was the largest European breast cancer prevention trial starting its recruitment in the early 90s. It was a double-blind, randomised placebo-controlled trial investigating whether tamoxifen can prevent breast cancer in women at high risk of developing the disease. 7,154 pre- and postmenopausal women, aged 35-70 years, with an increased risk of developing breast cancer participated in thestudy. Detailed baseline characteristics and entry criteria can be found in the first publication . The initial analysis post 50 months of follow-up , observed the incidence of breast cancer (invasive and in situ) was reduced by 32% in women receiving tamoxifen (69 tamoxifen versus 101 placebo, OR=0.68 (0.50-0.92), P=0.013). The significant reduction was only seen for oestrogen receptor (ER) positive breast cancers. Endometrial cancers and Thromboembolic events were significantly increased in women receiving tamoxifen compared to those on placebo. Overall, large numbers of less serious side effects were reported in both treatment arms, but the major differences were for vasomotor and gynaecological events, which increased by 14.1% in the tamoxifen group, and breast complaints, which decreased by 4.2% in the tamoxifen group.
After a median follow-up of 96 months, updated efficacy results were reported . A total of 142 breast cancers were diagnosed in the tamoxifen group compared to 195 in the placebo group (RR=0.73 (0.58-0.91), P=0.004). The prophylactic effect of tamoxifen was fairly constant over the entire follow-up period after 10 years of randomisation. Once more a reduction in breast cancer incidence was only seen for ER-positive breast cancer. For all breast cancers, the reduction of incidence in the tamoxifen group was 32% for years 0-5 (active treatment period) and 18% in subsequent years. In total, 120 deaths were recorded (65 tamoxifen vs. 55 placebo, P=0.36) and the difference between treatment groups was smaller than it was in the original report , when there were 25 deaths in the tamoxifen group and 11 in the placebo group (P=0.028). Again, large numbers of side effects were reported but these were much lower after completion of the active treatment period when compared with those reported during treatment. For example, deep-vein thrombosis and pulmonary embolism were statistically significantly higher in the tamoxifen arm than the placebo arm during active treatment (52 vs. 23 cases, RR=2.26 (1.36 to 3.87)) but not after tamoxifen was stopped (16 vs. 14 cases, RR=1.14 (0.52 to 2.53)). In the IBIS-I trial, slightly larger risk reductions were observed for premenopausal women, who also have a lower rate of endometrial cancer and thromboembolic events than postmenopausal women, suggesting that tamoxifen is a particularly attractive option for these women, especially if they have a diagnosis of lobular carcinoma in situ or atypical hyperplasia . For postmenopausal women, these results also indicate a better risk–benefit ratio than previously calculated for tamoxifen prophylaxis. In conclusion, to date, 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. All participants had completed their active treatment by February 2007.
In 2008, a substantial amendment was made to the main protocol to convert the study from clinical trial to epidemiological cohort status. Participants are now followed up annually via a questionnaire despatched from the IBIS-I Co-ordinating centre. The aim is to collect data that shall assist the IBIS-I team in evaluating the long term efficacy in the reduction in incidence of, and mortality from breast cancer, associated with five years daily ingestion of 20mg tamoxifen.
Furthermore, tamoxifen's role in prevention is limited because of its adverse side effect profile. Endometrial cancer and thrombotic events are of most concern, but non–life threatening side effects, such as vasomotor symptoms, also limit its use for prevention. In addition to the aforementioned, the cohort study therefore aims to evaluate the long term side effect profile associated with taking 20mg tamoxifen daily for a period of five years. Women shall be followed up for ten years post active treatment before any further analyses are conducted.
The study has valid NHS numbers for 3,689 women within the UK. This cohort is flagged with the NHS Information Centre. The latter report ICD 10 classifications for all cancers and deaths they are notified of, to the IBIS-I Co-ordinating Centre, at quarterly intervals. The possibility of also obtaining HES data for these individuals is currently under exploration.
- Cuzick, J., J. Forbes, R. Edwards, et al., First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet, 2002. 360(9336): p. 817-24.
- Cuzick, J., J.F. Forbes, I. Sestak, 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(4): p. 272-82.
- Fisher, B., J.P. Costantino, D.L. Wickerham, 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(18): p. 1371-88.