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Breast cancer hormone therapy may affect cognitive function

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Differentiating the impacts of distress and interventions

While the relationship between chemotherapy and neurocognitive changes is increasingly well described, cognitive changes associated with hormone therapy for breast cancer has proven to be somewhat complex. Chemotherapy can confound this. There are questions about different reports of outcomes for different drugs, for selective estrogen-receptor modulators and aromatase inhibitors, as well as how menopausal status, prior oophorectomy, and hormone therapy all affect cognitive changes in women.

Dr. Julia White

The important points of this study are that there are measurements at baseline, 1 month, and 18 months for a longitudinal picture. In addition, both comprehensive neuropsychological testing and patient-reported outcomes are available at each of those time points.

Previous studies have assessed these relationships, including a small study of memory impairment with anastrozole vs. tamoxifen in 31 patients treated for a minimum of 3 months. There was no difference between groups in depression, anxiety and fatigue, but researchers found that those on anastrozole had significantly poorer performance on learning and memory measures than those taking tamoxifen (Menopause 2007;14:995-8).

Another small substudy compared 94 patients enrolled in the ATAC (Arimidex, Tamoxifen Alone or in Combination) study to 35 noncancer controls. There were no differences in working memory, attention and visual memory, but those on endocrine therapy had poorer performance on tests of verbal memory and processing speed compared with controls.

The IBIS II (International Breast Cancer Intervention II) prevention study comparing anastrozole vs. placebo showed no overall difference in cognitive function with the addition of anastrozole. At 6 months, those on anastrozole had poorer memory, but this finding resolved by 24 months.

In a subset of 179 patients in the TEAM (Tamoxifen Exemestane Adjuvant Multinational) phase III adjuvant study, comparing exemestane with tamoxifen then exemestane, there was little change from baseline to 1 year in all domains of cognitive function with the addition of exemestane.

A substudy done from the BIG 1-98 (Breast International Group 1-98) trial indicated significant improvement in cognitive function from year 5 of therapy to year 6 after cessation of hormone therapies. Interestingly, perceived cognition did not change in the patients.

The current study looked at the relationship between perceived and measurable cognitive deficits in the same group of patients. Prior reports showed that patient-reported cognitive complaints post breast cancer treatment are common and are associated with persistent fatigue and depressive symptoms. It’s often difficult to sort out the etiology of those complaints.

In the current study, after controlling for depression and fatigue, decline on memory tests predicted perceived cognitive problems. Similarly, decline in verbal fluency predicted perceived verbal fluency problems.

This finding corroborates similar results from a prospective, longitudinal study of cognitive complaints and neuropsychological testing for verbal memory, psychomotor speed, and executive functioning in 189 patients who were beginning hormone therapy at the University of California, Los Angeles. (J. Natl. Cancer Inst. 2013;105:791-801).

Evaluations at baseline, 6 months, and 12 months showed that 23% had higher memory complaints and 19% had higher cognitive complaints after starting hormone therapy, slightly lower percentages than those seen in Dr. Rugo’s study.



SAN FRANCISCO – Patients with breast cancer who received hormone therapy were over seven times more likely to show cognitive decline as were untreated patients after controlling for other factors, based on a prospective study of 81 patients.

Further, objective results on neuropsychological testing tended to back up patients’ complaints of cognitive difficulties.

Hormone therapy may be a risk factor for cognitive deficits, and interventional studies should be designed to focus on this group of patients, Dr. Hope S. Rugo and her associates recommended in a poster presentation at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

The study collected neuropsychological test results and patient reports before treatment and at several points after starting hormone therapy (22 patients), chemotherapy (14), or chemotherapy followed by hormone therapy (33), and in a control group of 12 untreated patients.

Dr. Hope Rugo

Compared with baseline results, nearly 25% of patients had cognitive decline on neuropsychological testing after 5 months. (Among treated patients, this occurred 1 month after ending chemotherapy or 5 months after starting hormone therapy.) Nearly 35% had cognitive declines at 9 months of follow-up, and 30% had cognitive declines after 18 months.

"Decline in cognitive function is common in patients receiving adjuvant therapy for early-stage breast cancer," concluded Dr. Rugo, director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco. "Ongoing hormone therapy appears to be a risk factor for worse cognitive function."

Other factors that did not predict cognitive decline in the multivariate analysis included age, education level, average estradiol level over time, and estimated verbal IQ at baseline.

Separate univariate conditional logistic regression analyses found that hormone therapy predicted cognitive decline with an odds ratio of 5, but chemotherapy, radiation therapy, average fatigue over time, and average depression over time were not predictive of cognitive decline at any point.

The study enrolled women aged 35-80 years with early-stage breast cancer. Those who underwent adjuvant therapy received 3-4 months of chemotherapy alone, 5 years of hormone therapy alone, or both.

A separate analysis in the same study looked at how well subjective patient reports correlated with objective measures on neuropsychological tests. Dr. Lara Heflin and her associates found significant cross-section correlations between patient-reported cognitive problems and psychological distress and fatigue.

After researchers controlled for the influence of depression and fatigue, however, significant relationships remained between patients’ perceived cognitive functioning and measurable cognitive decline from baseline (pretreatment) to the first follow-up. Patients whose scores indicated memory decline were more likely to perceive memory problems, and patients whose scores on letter fluency declined were more likely to perceive problems with verbal fluency.

"Patients who self-report cognitive problems may indeed be experiencing cognitive decline, and their self-report should not simply be attributed to fatigue or to psychological factors such as anxiety and depression," concluded Dr. Heflin, a visiting professor of psychology at New Mexico Highlands University, Las Vegas.

Patients in the study had no prior chemotherapy or central nervous system radiation and no history of major psychiatric illness, serious head injury, neurologic disease, drug or alcohol abuse, or significant medical illness. The median age was 54 years, and 78% of patients were white. Patient characteristics were similar between groups.

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

The National Institutes of Health funded the study. Dr. Rugo reported having financial associations with Merck, Novartis, and Pfizer.

On Twitter @sherryboschert

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