Through the detection of COMT gene polymorphism in peripheral blood and the evaluation of MMSE, DST, VFT, EBPM and TBPM, the results declared that 1) The EBPM and TBPM deficits were presented in breast cancer following chemotherapy; 2) breast cancer patients with ki-67 > 14% revealed more poorly than patients with ki-67 < 14% on the task of MMSE,DST, VFT and EBPM after chemotherapy; 3) There were genotypic differences about COMT rs737865 between ki-67 < 14% and ki-67 > 14% groups, A/G genotype was associated with memory protective susceptibility, A/G genotype carriers exhibited more better on EBPM test relative to A/A genotype, and the COMT rs737865 polymorphism could be a potential genetic factor for chemo-brain in breast cancer patients with various index of ki-67.
The cognitive function of animals could be affected by single or combined chemotherapy, and the learning and memory functions related to hippocampus are impaired after chemotherapy. Doxorubicin, as a commonly used chemotherapeutic drug for breast cancer, patients treated with doxorubicin had poor scores on cognitive scales and visuospatial skills tests. Koppelmans et al. conducted cognitive tests for breast cancer patients and found that the rapid onset and delayed verbal memory, processing speed, executive function and psychomotor speed were significantly lower than those in the control group, even after the end of treatment. Janelsins et al. found that the cognitive impairment could partially recover after 6 months of chemotherapy in breast cancer, but it did not return to the level before chemotherapy, originating from a longitudinal study. The different degrees of EBPM damage was existed in breast cancer patients following chemotherapy, and hormone receptors were related to chemo-brain, specifically, ER-/PR- breast cancer had worse cognitive function. In this study, the finding indicated that patients with ki-67 > 14% breast cancer suffered worse chemotherapy-related EBPM deficits than those with ki < 14% breast cancer.
Ki-67, a large molecule antigen located in the nucleus, which was expressed in all cell cycles except G0 phase and had been identified as a highly efficient molecular marker for cell proliferation. The marker of ki67 was closely related to the degree of malignancy, which possessed important reference value for predicting the prognosis of tumor, and had become a routine item in the pathological examination of breast cancer.The higher levels of ki-67 are associated with pathological diagnosis for primary central system tumor, with nerve numb, cognitive deficit, and disturbance of consciousness and other neuropsychiatric symptoms. Minisini et al. found that the risk of developing brain metastases was higher in breast cancer patients with high ki-67, which are associated with a worse prognosis and cognitive decline. Moderate ki-67 level was found to be significantly related with positive concentration performance before adjuvant treatment for cognitive task. The study found that breast cancer patients with high level expression of ki67 were more sensitive to chemotherapy[38, 39]. Chemotherapy could lead to a series of cognitive dysfunction, which was consistent with the poor cognitive function of breast cancer patients with high index of ki-67 after chemotherapy in this study.
COMT gene polymorphism can affect dopamine concentration in the brain, and it has been found that Met carriers were more susceptible to decrease COMT enzyme activity relative to Val carriers. The three SNPs of COMT (rs 4680, rs737865 and rs165599) were the common sites in the study of psychiatric disorders[41, 42]. The cognitive functions such as memory, attention and executive control for Val carriers of COMT were significantly lower than those of Met carriers in schizophrenia patients. As well, Juarez-Cedillo et al. found that COMT polymorphisms were associated with dementia susceptibility and cognitive impairment when investigating the elderly in the community. COMT was widely distributed in the hippocampus, which could directly regulate the level of dopamine in the hippocampus to affect the hippocampal structure[45, 46]. The structure and function of hippocampus were closely related to working memory, episodic memory and spatial memory[47, 48]. McDermott et al.indicated that the expression of COMT was significantly decreased by high level estrogen, which adjusted the concentration of catecholamine in hippocampus, and enhanced the formation of fear memory. Our past research declared that COMT rs165599 was genetic factors influencing chemo-brain in triple negative breast cancer patients. Furthermore study, we found the influence of COMT rs737865 in EBPM deficits on chemo-brain in ER-/ER- or ER+/PR + breast cancer patients. What we found in this study, consistent with our previous research, was that the A/G genotype of COMT rs737865 patients projected better on TBPM task following chemotherapy, which was genetic factors for chemo-brain in breast cancer with various index of ki-67.
The advantage of this study is to integrate cognitive neuropsychology, genetics and oncology to explore the mechanism of chemotherapy brain, including memory scale tests, genetic dection, and chemotherapy regimen selection. However, the limitation and challenge of this study should also be stated. First, this study only had a before-and-after comparison, missing a healthy control group, the expression of COMT and cognitive test in healthy women could not be known. Second, this study pay attention to early cognitive impairments that occurred one month after chemotherapy. It is unknown whether results are suitable to follow up cognitive impairment research. Third, the sample size was insufficient, the quantity of breast cancer and healthy controls need to be supplemented in subsequent study. Four, the task scale of EBPM and TBPM were made by referring to Mcdougal's research methods, the task were subjective memory representation, the objective cognitive scales for tumor patients may be better.