Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: the impact of APOE and smoking

Abstract

Purpose: This study examined the association of post-treatment changes in cognitive performance, apolipoprotein E (APOE), and smoking in breast cancer patients treated with adjuvant therapy.

Participants and methods: Breast cancer patients treated with chemotherapy (N = 55, age = 51.9 ± 7.1, education = 15.7 ± 2.6) were evaluated with a battery of neuropsychological tests prior to chemotherapy and at 1, 6, and 18 months post-chemotherapy. Matched groups of breast cancer patients not exposed to chemotherapy (N = 68, age = 56.8 ± 8.3, education = 14.8 ± 2.2) and healthy controls (N = 43, age = 53.0 ± 10.1, education = 15.2 ± 2.6) were evaluated at similar intervals. APOE epsilon 4 carrier status (APOE4+) and smoking history were also evaluated.

Results: The detrimental effect of APOE4+ genotype on post-treatment cognitive functioning was moderated by smoking history, that is, patients without a smoking history had significantly lower performance on measures of processing speed and working memory compared with those with a smoking history and healthy controls. Exploratory analyses revealed that APOE4+ patients without a smoking history who were exposed to chemotherapy showed a decline in performance in processing speed, compared with patients with a smoking history. A similar but less pronounced pattern was seen in the no chemotherapy group (primarily endocrine treatment). For working memory, the APOE4+ by smoking interaction was observed in the no chemotherapy group only.

Conclusions: The association between APOE status, breast cancer treatment, and cognitive functioning was moderated by smoking history suggesting that both chemotherapy and endocrine therapy interact with APOE status and smoking to influence cognition. A putative mechanism is that smoking corrects a deficit in nicotinic receptor functioning and dopamine levels in APOE4+ individuals.

Keywords: APOE; breast cancer; chemotherapy; cognition; smoking.

Figure 1

Average domain scores for Processing Speed over assessment time points, stratified into four groups by smoking history and cancer. Two lines are plotted for each sub panel, one for the ApoE4-positive status and the other for the ApoE4-negative status. The error bars are standard errors of the averages.

Figure 2

Impact of APOE and Smoking Status on Processing Speed for Patients vs. Controls (A) and by Treatment (B). Bar plots of the observed average post-treatment processing speed outcomes for cancer patients and non-cancer controls (subplot (A)). The error bars represent the model-predicted 95% confidence intervals. Sample sizes of the subgroups are listed at the bottom of the graphs in parentheses. The interaction between APOE4 status and smoking history is represented with color, in the order as shown, with APOE4 present and a history of smoking represented by dark blue bars, APOE4 present but never smoked (light blue), APOE4 absent and a history of smoking (dark yellow), and APOE4 absent and never smoked (light yellow). Specific statistical contrasts were applied to test, in subplot (A): APOE4 and smoking history within patients (contrast (a)); APOE4 by smoking history interaction within non-cancer controls ((b)); and whether the pattern of the APOE4 by smoking history interaction is significantly different among the patients compared to non-cancer controls ((c)). In subplot (B), the two patient groups were further stratified by cancer treatment.

Figure 3

Estimates of the Detrimental Effects in APOE4+ patients who had Never Smoked Versus Controls Across Neurocognitive Domains. The x-axis represents the magnitude of the standardized change scores, with a negative value indicating that APOE4 positive, never smokers were worse off than ever smokers, and this discrepancy is greater in patients than in controls. The horizontal error bars represent the 95% confidence intervals of the estimates. Statistically significant detrimental effects were found in processing speed and working memory, shown by the error bars excluding the null difference. The estimated effect in distractibility fell in the negative range, although the error bars did not exclude the null.

Figure 4

Impact of APOE and Smoking Status for Working Memory. Bar plot of the observed average post-treatment working memory outcomes. The error bars represent the model-predicted 95% confidence intervals. Specific statistical contrasts were applied to test the APOE4 and smoking history interaction within (a) patients treated with chemotherapy; (b) patients not treated with chemotherapy; and (c) controls.