In Co-STAR, we hypothesized that raloxifene would confer comparatively greater cognitive benefits, particularly in the domain of verbal memory. Contrary to our hypothesis, there were no significant differences in cognitive test performance between raloxifene and tamoxifen groups. The lack of a robust difference between the two treatments was evident in all 1,498 enrolled women and in an analysis restricted to 273 women with pretreatment baseline data. The only trend observed for cognitive measures was that raloxifene was associated with higher scores compared with tamoxifen (P = .04) on the List B interference trial, one of four verbal memory measures in the analysis involving all 1,498 women. Overall, these results demonstrated no significant differences in the effect of tamoxifen versus raloxifene on global or domain-specific cognitive function.
In contrast to this study, modest cognitive benefits were observed with raloxifene in the MORE trial, which examined cognitive function in 7,478 women with osteoporosis randomly assigned to receive raloxifene at 60 or 120 mg/d or placebo.6
Over a 3-year period, there were no overall differences in cognitive function between women randomly assigned to receive either dose of raloxifene versus placebo in a sample with a mean age of 66 years. There was a trend in the overall sample (P
= .05) for women randomly assigned to receive raloxifene to have a reduced risk of cognitive impairment on verbal memory. In addition, secondary analyses restricted to women age 70 years and older demonstrated a significant benefit of raloxifene on verbal memory and psychomotor speed in MORE. Given that Co-STAR participants were recruited to be age 65 years and older, we hypothesized that raloxifene would confer cognitive benefits compared with tamoxifen. Although the raloxifene group showed a trend to better performance than the tamoxifen group on the List B outcome of the CVLT, this finding was not confirmed in the subset of women with a pretreatment baseline. Therefore, our findings did not support this hypothesis. Although 59% of the Co-STAR sample was younger than age 69 years and thus would not be expected to enjoy the possible age-related benefit of raloxifene, we observed only one interaction between treatment and age (< 70 v
≥ 70 years) suggesting improved fluency with raloxifene in younger versus older women. Also importantly, in MORE, raloxifene was compared with placebo, whereas in Co-STAR raloxifene was compared with tamoxifen.
Several other differences between Co-STAR and MORE are worth considering. More than 4,000 women in the MORE trial completed pre- and post-treatment cognitive assessments, leading to greater power to detect an effect of raloxifene on cognitive function, especially if that effect was greatest from baseline to 1-year post-treatment. Second, unlike Co-STAR participants, all MORE participants had osteoporosis. A strong risk factor for osteoporosis is estrogen deficiency.27
Conversely, early menses and older age at first birth—two factors in the Gail model for determination of breast cancer risk—are associated with higher levels of estrogen. In preclinical studies, raloxifene in the absence of estradiol exerted partial agonist effects in the hippocampus, but in the presence of estrogen, it exerted mixed agonist/antagonist effects.28
The hippocampus is a critical structure in mediating verbal memory29
and the effects of estrogen compounds, including raloxifene, on memory.30–32
Thus, raloxifene may have different effects on tasks mediated by the hippocampus such as verbal memory in women with low estrogen compared with women with higher estrogen, such that greater cognitive benefits may be evident in women with low estrogen. Another difference between MORE and Co-STAR was that in Co-STAR, there was only a 60 mg/d dose of raloxifene, whereas in MORE, there were doses of 60 and 120 mg/d.
Earlier observational studies provided mixed evidence concerning the effects of tamoxifen on cognition. Previous clinical studies provided some suggestion that tamoxifen might produce impairments in cognitive function. For example, a study of women with breast cancer found that those receiving treatment with chemotherapy and tamoxifen performed worse than women receiving chemotherapy alone on tests of visual memory and visuospatial function.8
Conversely, in a cross-sectional study of early-stage breast cancer, anastrozole led to significant impairments in verbal and visual learning and memory compared with tamoxifen.33
In a cross-sectional study of elderly nursing home patients, women treated with tamoxifen showed a reduced risk of Alzheimer's disease, improved activities of daily living, and improved decision making.34
To our knowledge, Co-STAR is the first clinical trial to examine the effects of tamoxifen on cognitive function in healthy women, and no significant differences were observed between tamoxifen and raloxifene.
The study has two important limitations. First, there was no placebo arm for comparison with the tamoxifen and raloxifene treatment arms. If both tamoxifen and raloxifene had beneficial or adverse effects on memory in Co-STAR, then cognitive effects would not be evident. Therefore, we cannot rule out the possibility that either or both treatments would have positive or negative effects on cognition when compared with placebo. Second, only a minority (approximately 20%) of participants completed assessments at baseline and throughout the trial, resulting in low power to detect treatment effects occurring within the first year of treatment. Notably, Co-STAR has several strengths. The results address the important clinical issue of whether cognitive effects should be considered when choosing between two SERMs that show similar efficacy in preventing breast cancer.1
The test battery was the same as that used in the Women's Health Initiative Memory Study,25
which will allow for comparisons of tamoxifen and raloxifene with placebo and conjugated equine estrogen with and without medroxyprogesterone acetate.
In summary, the present findings indicate that tamoxifen and raloxifene are associated with similar patterns of cognitive function in healthy postmenopausal women at increased risk of breast cancer. These findings will help women and their health care providers make more informed decisions regarding the use of tamoxifen or raloxifene for the prevention of breast cancer, because the data do not support one SERM conferring a cognitive advantage over the other. These results, however, should be interpreted with caution because of the absence of a placebo group. Future comparisons between these findings and patterns of cognitive function in hormone therapy and placebo groups in WHISCA should provide further insights into the effects of tamoxifen and raloxifene on cognitive function in older women.