Originally published as JCO Early Release 10.1200/JCO.2009.24.3329 on September 21 2009

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Exploring the Impact of the Hormonal Milieu on Cognitive Functioning

Greater Los Angeles Veterans Affairs Healthcare System, David Geffen School of Medicine at UCLA, Los Angeles, CA

Patricia A. Ganz

Jonsson Comprehensive Cancer Center, UCLA Schools of Medicine and Public Health, Los Angeles, CA

An area receiving increasing empirical attention in the past several years is cognitive functioning among cancer survivors exposed to adjuvant systemic therapies. This increased focus can be attributed to the recognition that a sizeable minority of those patients undergoing adjuvant chemotherapy report and/or demonstrate some degree of cognitive compromise—colloquially called chemobrain or chemofog.¹ However, to date, there has been considerably less research on the possible cognitive effects of endocrine therapies for cancer treatment or risk reduction/prevention. Medications such as tamoxifen and raloxifene or the aromatase inhibitors—drugs that modify the hormonal milieu in those women with hormone receptor–positive tumors—may independently, or with chemotherapy, be associated with cognitive complaints. Given the importance of estrogen, the main target for these drugs, for normal brain function and its relationship to several neurological processes,^2,3 it makes sense to better understand the potential cognitive sequelae of these medications.

In this issue of the Journal of Clinical Oncology, Legault and colleagues⁴ report their findings comparing the impact of two selective estrogen receptor modulators (SERM)—tamoxifen and raloxifene—on the cognitive function of postmenopausal women at increased risk for breast cancer. The Cognitive Aging Study of Tamoxifen and Raloxifene (Co-STAR) study enrolled nearly 1,500 healthy women older than 65 years (excluding any with suspected dementia) who had been randomly assigned to one of two groups, either oral tamoxifen 20 mg/d or oral raloxifene 60 mg/d, as part of the STAR trial.⁵ The majority of women were enrolled in Co-STAR after having initiated their STAR trial medication, although a small number of women (n = 273) had cognitive functioning assessment before starting SERM therapy. In this article, they report results from those women observed for at least 3 years who completed a focused, brief, neurocognitive battery at three assessment points roughly 12 months apart. Although the investigators had hypothesized that raloxifene would confer cognitive benefits compared with tamoxifen, they found little difference in cognitive performance between the tamoxifen and raloxifene groups and suggested that these two SERMs have a similar impact on cognitive functioning in this particular cohort of older women deemed at elevated risk for breast cancer.

There are several important strengths of the Co-STAR study conducted by Legault and colleagues. For example, they undertook the challenging task of assessing cognitive function in a large scale, multisite, longitudinal study, paying close attention to the important issue of practice effects (ie, that repeated exposure to the same or similar tests often leads to higher performance after the initial assessment). They also attempted to measure meaningful domains of cognition that have been previously implicated in cognitive aging and also with chemobrain sufferers—learning and memory and executive functioning (ie, working memory and verbal fluency). A large sample size, a sound analytic strategy, and the investigators' careful attention to potential confounds such as depression and affective style all lend weight to their conclusion that those women who received tamoxifen did not differ in neuropsychological performance from those that received raloxifene. Scores on the majority of neuropsychological tasks either stayed stable or improved over time (as would be expected based on practice effects). The one task on which a clinically significant decline in performance was noted was on a verbal learning and memory task that had been significantly modified including what the authors describe as the introduction of a more difficult form.

However, the applicability of these findings beyond this population, for example to patients with breast cancer, is unclear. As the authors note, there may be group differences in lifetime and current estrogen exposure that may leave some groups primed to benefit from SERM administration (eg, those with osteoporosis) or, conversely, groups that are more likely to experience cognitive compromise. In terms of groups more vulnerable to cognitive compromise, this article does not address (and wasn't intended to) an issue of considerable importance to the Journal of Clinical Oncology readership, which is whether SERM exposure during adjuvant systemic chemotherapy might be more likely to cause cognitive changes in women with breast cancer. Certainly the limited data available in the breast cancer studies that have examined adjuvant tamoxifen therapy does not suggest a neuroprotective effect of SERM exposure.^6–11 Our group at University of California, Los Angeles has reported, in a cross-sectional study of long-term breast cancer survivors, that patients exposed to both tamoxifen and chemotherapy were more likely to experience cognitive compromise several years after treatment than were those who received no adjuvant therapy or who received chemotherapy alone⁶ and that this group is more likely to show altered neurophysiology, as assessed by brain positron emission tomography.⁷ A recent study of premenopausal breast cancer patients who did not receive any chemotherapy, but who had been taking tamoxifen for an average of 2.3 years before cognitive testing, reported evidence of cognitive compromise in those who received this SERM. Although this was a small, cross-sectional study, the study found several differences of greater than 0.5 standard deviations on memory tests between those taking tamoxifen and healthy controls and greater than 1 standard deviation on tests of information processing speed.¹¹

Given the provocative (but inconclusive) studies listed above, it is important to note that the Legault et al study had no placebo control or comparison group with whom the SERM groups' results could be compared. In addition, their study focused only on women who were 65 years or older, in whom the effects of SERM therapy may be different than women in the early postmenopausal years.¹² While they used standardized measures to assess cognitive functioning, there were some important modifications to some measures that preclude direct comparison with normative data. It is therefore impossible to discern whether the performance of the Co-STAR participants was different from demographically similar postmenopausal women who did not take a SERM. It is entirely possible that both groups may have performed significantly worse than a matched comparison group would have performed on these tests. The authors note that their testing battery was modeled after the one used in Women's Health Initiative Study of Cognitive Aging (WHISCA); however, comparison data from the WHISCA sample are not reported here, although they could be quite informative regarding the expected performance of a comparison group.

The rationale for focusing the Co-STAR study on older women is not discussed in the Legault et al article, although it is likely that the investigators were interested in women at higher risk for cognitive decline, as well as a sample that could match those enrolled in WHISCA. This is unfortunate, as women most likely to take SERMS either for breast cancer or osteoporosis prevention are more likely to be somewhat younger, in the early postmenopausal years. Thus, taking into account cognitive changes that are part of the normal menopausal transition is important, and the impact of SERMS in this setting is not addressed by the Co-STAR study.

Cognitive complaints are common at the time of the menopause transition, and the information about the effects of SERMS at that time in a woman's life would be valuable to assess. Recent findings from Greendale and her colleagues¹² taken from the Study of Women Across the Nation suggest transient but significant learning and memory compromise associated with the transition from pre- to postmenopausal status. In the Study of Women Across the Nation study of cognitive function, nearly 2,400 women between the ages of 42 and 52 years were tracked for 4 years with a very brief battery of neurocognitive tests purported to assess working memory, verbal memory, and processing speed. The complex set of analyses emanating from this study suggested that the late perimenopausal period was associated with the absence of an expected practice effect on a test of processing speed—an effect that was clearly seen in both pre- and postmenopausal women. Similarly, all perimenopausal women (both early and late peri) failed to benefit from repeated exposure to a verbal memory test, while premenopausal and postmenopausal women each showed a relatively healthy improvement trajectory on this task. So, although the adverse impact of the transition might be time limited, it does appear to be a measurable phenomenon and to be related to the self-reported cognitive complaints of the women going through menopause. These findings have relevance for healthy high-risk women who have recently transitioned to menopause and may be considering SERM therapy, as we do not know the impact of such therapy on cognitive function. In addition, given the high rates of chemotherapy treatment–induced (and therefore more abrupt) menopausal transitions commonly seen among younger patients with breast cancer, future research should address the additive impact of SERM therapy on cognitive function in this subgroup of patients.

In summary, the good news is that in older women considering the use of either tamoxifen or raloxifene for the prevention of breast cancer, there is no evidence of serious cognitive changes that would preclude their use. The choice of which drug to use for high-risk women should be determined by other medical factors and quality-of-life issues.^6,13 However, further research should be conducted in early postmenopausal women to evaluate the cognitive effects of these drugs and to determine whether or not both SERMS have similar effects, preferably in comparison to an untreated control group.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Steven A. Castellon, Patricia A. Ganz

Manuscript writing: Steven A. Castellon, Patricia A. Ganz

Final approval of manuscript: Steven A. Castellon

NOTES

See accompanying article on page 5144

REFERENCES

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4. Legault C, Maki PM, Resnick SM, et al: Effects of tamoxifen and raloxifene on memory and other cognitive abilities: Cognition in the study of tamoxifen and raloxifene. J Clin Oncol 27:5144–5152, 2009.[Abstract/Free Full Text]

5. Vogel VG, Costantino JP, Wickerham DL, et al: Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295:2727–2741, 2006.[Abstract/Free Full Text]

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10. Shilling V, Jenkins V, Fallowfield L, et al: Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psychooncology 13:61–66, 2004.[CrossRef][Medline]

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13. Land SR, Wickerham DL, Costantino JP, et al: Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295:2742–2751, 2006.[Abstract/Free Full Text]

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