The oestrogen receptor antagonist tamoxifen is recognised as an extremely effective drug for oestrogen receptor positive breast cancer. It is given for both early and advanced breast cancer and as a prophylactic for women at high risk of the disease. When tamoxifen is prescribed either as a prophylactic or in an adjuvant setting after surgery, it is usually over a period of a number of years. Long courses of tamoxifen have been associated with an increased risk of stroke and other cerebrovascular conditions. Little is known, however, about the effect of tamoxifen on cerebrovascular risk in the long term, after treatment ends.

In the 1980s, the Swedish Breast Cancer Cooperative Group set up a large, randomised trial comparing two-year and five-year courses of adjuvant tamoxifen for the prevention of breast cancer recurrence in post-menopausal women [1]. A group of researchers based at Linköping University and Hospital, Linköping. Sweden, have now used longer follow-up data available from the patients in this trial, together with further data on hospitalisations, to investigate the effect of tamoxifen on cerebrovascular disease both during and up to eighteen years after treatment [2].

The trial recruited 4610 breast cancer patients, all of whom were post-menopausal women who were under 75 years old at the time of cancer surgery. A total of 4150 who were alive and recurrence-free two years after surgery contributed to the study of long-term outcomes. Subjects were given tamoxifen doses of either 20mg/day or 40mg/day, depending on the region of Sweden in which they were treated, and randomised to receive this for either two or five years. In the current study, patient records were analysed for morbidity and mortality from cerebrovascular disease for a period of 20 years from first treatment, or until a diagnosis of recurrent or contra-lateral breast cancer or death from any cause. Cox regression was used to estimate hazard ratios for both cerebrovascular morbidity and mortality.

Results of the analysis showed statistically significant differences in hazard ratios between the active treatment phase and the post-treatment phase. In the active treatment phase, there was, indeed, an increased risk of stroke and other cerebrovascular events in the group given tamoxifen for five years (HR = 1.70, 95% CI 1.05-2.75). However, the position was reversed in the post-treatment period, with the five-year group experiencing reduced risk (HR = 0.78, 95% CI 0.63–0.96). The risk of death from cerebrovascular causes showed a similar pattern, with risk in the five-year group increasing during but decreasing after treatment, and the statistical significance was greater (treatment period, HR 3.18, 95% CI 1.03–9.87: post-treatment period, HR 0.60, 95% CI 0.40–0.90). When disease was sub-divided into different types of strokes, transient ischaemic attack (TIA) and other cerebrovascular conditions, there were no significant differences in hazard ratio between the different conditions. Neither the age of the patients at surgery or the daily dose of tamoxifen given – 20mg/day or 40mg/day – made any significant difference to the hazard ratios.

Tamoxifen is known to have both positive and negative effects on the cerebrovascular system. The time-dependent effect of long-term tamoxifen treatment on this system discovered in this study, in which a significant but slight increase in risk during therapy is followed by a similar-sized decrease in risk after the drug is discontinued, is a likely result of the interaction between these effects. The researchers recommended further long-term studies to confirm their results, and suggested that it would be useful to compare long-term tamoxifen treatment with other drugs and combination therapies.

References

[1] Swedish Breast Cancer Cooperative Group (1996) Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer. J Natl Cancer Inst 88, 1543– 1549

[2] Rosell, J., Nordenskjöld, B., Bengtsson, N.O., Fornander, T., Hatschek, T., Lindman, H., Malmström, P.O., Wallgren, A., Stål, O. and Carstensen, J. (2011). Time dependent effects of adjuvant tamoxifen therapy on cerebrovascular disease: results from a randomised trial. Brit. J. Cancer 104, 899 – 902. DOI: 10.1038/bjc.2011.45