Evaluation of plasma brain-derived neurotrophic factor levels and self-perceived cognitive impairment post-chemotherapy: a longitudinal study.

BACKGROUND: Preliminary evidence suggests that changes in plasma brain-derived neurotrophic factor (BDNF) levels may contribute to the occurrence of chemotherapy-associated cognitive impairment (CACI), and a previous study suggested that carriers of the BDNF Met homozygous genotype are protected from CACI. METHODS: This multicenter, prospective cohort study involved chemotherapy-receiving early-stage breast cancer (ESBC) patients. Self-perceived cognitive function was longitudinally assessed using the validated FACT-Cog (ver. 3) across three time points: Prior to chemotherapy (T1), during chemotherapy (T2), and at the end of chemotherapy (T3). Plasma BDNF levels were quantified using enzyme-linked immunosorbent assay. Genotyping was performed using Sanger Sequencing. RESULTS: A total of 51 chemotherapy-receiving ESBC patients (mean age: 52.6 ± 9.5 years) were recruited, and 11 patients (21.6%) reported subjective cognitive impairment post-chemotherapy. Overall, there was a reduction in median plasma BDNF levels over time (T1: 5423.0 pg/ml; T2: 5313.6 pg/ml; T3: 4050.3 pg/ml; p < 0.01). After adjusting for confounding factors, longitudinal analysis revealed that BDNF levels were associated with self-reported concentration deficit (p = 0.032). Carriers of Val/Val (p = 0.011) and Val/Met (p = 0.003) BDNF genotypes demonstrated a significant reduction in plasma BDNF levels over time; however, plasma BDNF levels were similar across all time points among Met homozygous carriers (p = 0.107). CONCLUSION: There was a statistically significant change in BDNF levels post-chemotherapy in ESBC patients, and plasma BDNF levels were associated with self-perceived concentration deficit in patients receiving chemotherapy.

Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients.

AIM: To investigate the impact of genetic polymorphisms in CYP2D6, CYP3A5, CYP2C9 and CYP2C19 on the pharmacokinetics of tamoxifen and its metabolites in Asian breast cancer patients. METHODS: A total of 165 Asian breast cancer patients receiving 20 mg tamoxifen daily and 228 healthy Asian subjects (Chinese, Malay and Indian; n= 76 each) were recruited. The steady-state plasma concentrations of tamoxifen and its metabolites were quantified using high-performance liquid chromatography. The CYP2D6 polymorphisms were genotyped using the INFINITI™ CYP450 2D6I assay, while the polymorphisms in CYP3A5, CYP2C9 and CYP2C19 were determined via direct sequencing. RESULTS: The polymorphisms, CYP2D6*5 and *10, were significantly associated with lower endoxifen and higher N-desmethyltamoxifen (NDM) concentrations. Patients who were *1/*1 carriers exhibited 2.4- to 2.6-fold higher endoxifen concentrations and 1.9- to 2.1-fold lower NDM concentrations than either *10/*10 or *5/*10 carriers (P < 0.001). Similarly, the endoxifen concentrations were found to be 1.8- to 2.6-times higher in *1/*5 or *1/*10 carriers compared with *10/*10 and *5/*10 carriers (P≤ 0.001). Similar relationships were observed between the CYP2D6 polymorphisms and metabolic ratios of tamoxifen and its metabolites. No significant associations were observed with regards to the polymorphisms in CYP3A5, CYP2C9 and CYP2C19. CONCLUSIONS: The present study in Asian breast cancer patients showed that CYP2D6*5/*10 and *10/*10 genotypes are associated with significantly lower concentrations of the active metabolite of tamoxifen, endoxifen. Identifying such patients before the start of treatment may be useful in optimizing therapy with tamoxifen. The role of CYP3A5, CYP2C9 and CYP2C19 seem to be minor.

Elucidating therapeutic molecular targets in premenopausal Asian women with recurrent breast cancers.

Breast cancer is an increasing problem in Asia, with a higher proportion of premenopausal patients who are at higher risk of recurrence. Targeted sequencing was performed on DNA extracted from primary tumor specimens of 63 premenopausal Asian patients who relapsed after initial diagnosis of non-metastatic breast cancer. The most prevalent alterations included: TP53 (65%); PIK3CA (32%); GATA3 (29%); ERBB2 (27%); MYC (25%); KMT2C (21%); MCL1 (17%); PRKDC, TPR, BRIP1 (14%); MDM4, PCDH15, PRKAR1A, CDKN1B (13%); CCND1, KMT2D, STK11, and MLH1 (11%). Sixty of the 63 patients (95%) had at least one genetic alteration in a signaling pathway related to cell cycle or p53 signaling. The presence of MCL1 amplification, HIF-1-alpha transcription factor network pathway alterations, and direct p53 effectors pathway alterations were independent predictors of inferior overall survival from initial diagnosis. Comparison with non-Asian premenopausal tumors in The Cancer Genome Atlas (TCGA) revealed a higher prevalence of TP53 mutations among HER2-positive cancers, and more frequent TP53, TET2, and CDK12 mutations among hormone receptor-positive HER2-negative cancers in our cohort. Given the limited number of non-Asian premenopausal breast cancers that had relapsed in TCGA, we compared the frequency of mutations in our cohort with 43 premenopausal specimens from both TCGA and International Cancer Genome Consortium that had relapsed. There was a trend toward higher prevalence of TP53 mutations in our cohort. Certain genomic aberrations may be enriched in tumors of poor-prognosis premenopausal Asian breast cancers. The development of novel therapies targeting these aberrations merit further research.