Analysis of pharmacogenomic factors for chemotherapy-induced nausea and vomiting in patients with breast cancer receiving doxorubicin and cyclophosphamide chemotherapy.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) can lead to a significant deterioration in the quality of life of cancer patients receiving chemotherapy. This study aimed to determine whether ABCB1 2677G > T/A was associated with complete response (CR; defined as no vomiting and no rescue medication) in acute phase (CR0-24), as well as to explore the genetic factors affecting delayed phase (CR24-120) CINV in cancer patients treated with a standard triple antiemetic regimen that included aprepitant. METHODS: This prospective single-center study included a total of 166 chemotherapy-naïve patients with breast cancer who received a standard dose of doxorubicin and cyclophosphamide combination chemotherapy; granisetron, dexamethasone, and aprepitant were administered prior to chemotherapy. CR0-24 was compared between minor allele homozygous (TT, AA, and TA) and major allele homozygous plus heterozygous (GG, GA, and GT) groups of ABCB1 2677G > T/A. In addition, 14 genetic polymorphisms were genotyped and their associations with CRs were investigated. RESULTS: The proportion of patients who achieved CR0-24, which was the primary endpoint of this study, was 59% in the minor allele homozygous and 61% in the major allele homozygous plus heterozygous groups of ABCB1 2677G > T/A. Although this difference was not statistically significant, multivariate logistic regression analysis adjusted for potential risk factors showed that TACR1 1323TT (OR, 2.57; P = 0.014) was a significant determinant of CR24-120. CONCLUSION: No significant association was found between ABCB1 2677G > T/A and CR0-24. However, it was observed that the polymorphism of TACR1, which encodes the neurokinin 1 receptor, might be a potential genetic risk factor for the development of delayed phase CINV.

Genetic risk factors for chemotherapy-induced nausea and vomiting in patients with cancer receiving cisplatin-based chemotherapy.

PURPOSE: Younger age and female sex have already been well-known risk factors for chemotherapy-induced nausea and vomiting (CINV), and 30-50% of cancer patients still suffer from CINV. Genetic polymorphisms are suggested to influence antiemetic treatment response. METHODS: This study included a subset of patients previously enrolled in a randomised controlled trial; 156 patients were evaluated. This study aimed to evaluate the role of pharmacogenomic polymorphisms relevant to antiemetic response in patients with cancer receiving cisplatin-based chemotherapy. The study's efficacy endpoint was the proportion of patients with complete response (CR). The study endpoint was evaluated separately in the acute (CR0-24) and delayed (CR24-120) phases. Thirteen polymorphisms were genotyped, and the association of these genotypes with the efficacy of prophylactic antiemetics was then investigated. Confounding variables for the CR were identified using stepwise multivariate logistic regression analysis. Age and sex were included as independent variables by the forced-entry method, and the stepwise method was used to select the pharmacogenomic factors for inclusion as independent variables. RESULTS: Multivariate logistic regression analysis revealed that the ERCC1 8092AA (odds ratio [OR] = 11.25; 95% confidence interval [CI] 1.74-72.71; p = 0.011) and female sex (OR = 3.63; 95% CI 1.14-11.58; p = 0.029) were significant predictors of CR0-24. No significant association of CR24-120 with pharmacogenomic polymorphisms was found via multivariate logistic regression analysis. CONCLUSIONS: ERCC1 polymorphism influenced the extent of CINV control in patients receiving cisplatin-based chemotherapy. TRIAL REGISTRATION: Clinical trial information: UMIN 000009335.

Chemotherapy-induced neutropenia as a prognostic factor in patients with metastatic pancreatic cancer treated with gemcitabine.

PURPOSE: Chemotherapy-induced neutropenia (CIN) is a common side effect of chemotherapy and an important dose-limiting factor. However, an association between CIN development and longer survival was recently reported in several solid cancers. In the present study, we aimed to assess whether CIN could be a prognostic factor and clarify other prognostic factors for patients with metastatic pancreatic cancer. METHODS: We retrospectively analyzed the medical records of 84 patients who received gemcitabine monotherapy as first-line chemotherapy for metastatic pancreatic cancer to assess whether CIN could be a prognostic factor. Potential prognostic factors of survival were examined by univariate and multivariate analyses using the log-rank test and Cox proportional hazard model, respectively. RESULTS: Median survival time was 170 days [95% confidence interval (CI), 147-193] in patients without CIN (grade 0), 301 days (95% CI, 152-450) in patients with grade 1-2 CIN, and 406 days (95% CI, 271-541) in patients with grade 3 CIN. The multivariate analysis revealed that a pretreatment C-reactive protein level of <0.50 mg/dL [hazard ratio (HR), 0.534; 95% CI, 0.323-0.758, P = 0.015] and grade 3 CIN (HR, 0.447; 95% CI, 0.228-0.875, P = 0.019) were independent favorable prognostic factors in patients with metastatic pancreatic cancer treated with gemcitabine. CONCLUSIONS: Neutropenia during chemotherapy was associated with increased survival of patients with metastatic pancreatic cancer. Monitoring of CIN could be used to predict treatment responsiveness.

Drug-related genetic polymorphisms affecting severe chemotherapy-induced neutropenia in breast cancer patients: A hospital-based observational study.

Chemotherapy-induced neutropenia (CIN) is one of the major adverse events that necessitate chemotherapy dose reduction. This study aimed to evaluate the association between grade 4 neutropenia and genetic polymorphisms in breast cancer patients. In this genetic polymorphism association study, peripheral blood samples from 100 consecutive breast cancer outpatients, between August 2012 and September 2014, treated with doxorubicin and cyclophosphamide (AC) combination chemotherapy were genotyped for polymorphisms in adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1), cytochrome P450 (CYP) enzyme-coding genes (CYP2B6 and CYP3A5), glutathione S-transferase (GST), and excision repair cross-complementing 1 (ERCC1). Associations between grade 4 neutropenia and genotypes as well as risk factors were examined using multivariate logistic regression. From 100 patients, 32.0% had grade 4 neutropenia. Multivariate logistic regression analysis revealed that ERCC1 118C > T (odds ratio [OR], 3.43; 95% confidence interval [CI], 1.22-9.69; P = 0.020), CYP2B6*6 (OR, 4.51; 95% CI, 1.21-16.95; P = 0.025), body mass index (BMI) (OR, 6.94; 95% CI, 1.15-41.67; P = 0.035), and baseline white blood cell (WBC) count (OR, 2.99; 95% CI, 1.06-8.40; P = 0.038) were significant predictors of grade 4 neutropenia. ERCC1 and CYP2B6 gene polymorphisms were associated with the extent of grade 4 neutropenia in patients receiving AC chemotherapy. In addition to previously known risk factors, BMI and WBC counts, ERCC1 and CYP2B6 gene polymorphisms were also identified as independent strong predictors of grade 4 neutropenia.

Exposure to bright light modifies HRV responses to mental tasks during nocturnal sleep deprivation.

This study was intended to determine the effects of continuous bright light exposure on cardiovascular responses, particularly heart rate variability (HRV), at rest and during performance of mental tasks with acute nocturnal sleep deprivation. Eight healthy male subjects stayed awake from 21.00 to 04.30 hours under bright (BL, 2800 lux) or dim (DL, 120 lux) light conditions. During sleep deprivation, mental tasks (Stroop color-word conflict test: CWT) were performed for 15 min each hour. Blood pressure, electrocardiogram, respiratory rate, urinary melatonin concentrations and rectal temperature were measured. During sleep deprivation, BL exposure depressed melatonin secretion in comparison to DL conditions. During sleep deprivation, exposure to BL delayed the decline in heart rate (HR) for 4 h in resting periods. A significant increment of HR induced by each CWT was detected, especially at 03.00 h and later, under DL conditions only. In addition, at 04.00 h, an index of sympathetic activity and sympatho-vagal balance on HRV during CWT increased significantly under DL conditions. In contrast, an index of parasympathetic activity during CWT decreased significantly under DL conditions. However, the indexes of HRV during CWT did not change throughout sleep deprivation under BL conditions. Our results suggest that BL exposure not only delays the nocturnal decrease in HR at rest but also maintains HR and balance of cardiac autonomic modulation to mental tasks during nocturnal sleep deprivation.

Modification of internal temperature regulation for cutaneous vasodilation and sweating by bright light exposure at night.

Bright light (BL) exposure at night leads to suppressed secretion of melatonin and an attenuated fall in internal temperature at rest from the night to the early morning. However, it is unknown at the present whether typical diurnal variations in reflex responses to thermal challenges are similarly affected by BL exposure at night. We investigated the control of cutaneous vasodilator and sweating responses to hyperthermia in the early morning after artificial BL exposure at night, compare with dim light (DL) exposure. Six subjects stayed awake in a semi-supine position under DL (120 lx) or BL (2800 lx) conditions between 21.00 and 04.30 h. Urine samples were collected at 04.30 h. Beginning at 05.30 h, the lower legs were immersed for 50 min in 42 degrees C water. The subjects remained awake for 21 h until the end of hot water immersion. Urinary 6-sulphatoxymelatonin levels following BL were significantly lower than after DL. Oesophageal temperature (T es) before heating was significantly higher following BL [36.41+/-0.10 (DL) vs. 36.55+/-0.09 (BL) degrees C]. The T es thresholds for the onset of cutaneous vasodilation and sweating were significantly higher with BL than with DL conditions (approximately 0.15 degrees C, respectively). We found that the internal temperature threshold for thermoregulatory control of cutaneous vasodilation and sweating responses to passive heating in the early morning can be modified by the level of light exposure the prior night. Thus both basal internal temperature and the regulation of internal temperature are modified by BL exposure at night.

Effect of bright light on EEG activities and subjective sleepiness to mental task during nocturnal sleep deprivation.

The purpose of this study was to investigate the effect of the exposure to bright light on EEG activity and subjective sleepiness at rest and at the mental task during nocturnal sleep deprivation. Eight male subjects lay awake in semi-supine in a reclining seat from 21:00 to 04:30 under the bright (BL; >2500 lux) or the dim (DL; <150 lux) light conditions. During the sleep deprivation, the mental task (Stroop color-word conflict test: CWT) was performed each 15 min in one hour. EEG, subjective sleepiness, rectal and mean skin temperatures and urinary melatonin concentrations were measured. The subjective sleepiness increased with time of sleep deprivation during both rest and CWT under the DL condition. The exposure to bright light delayed for 2 hours the increase in subjective sleepiness at rest and suppressed the increase in that during CWT. The bright light exposure also delayed the increase in the theta and alpha wave activities in EEG at rest. In contrast, the effect of the bright light exposure on the theta and alpha wave activities disappeared by CWT. Additionally, under the BL condition, the entire theta activity during CWT throughout nocturnal sleep deprivation increased significantly from that in a rest condition. Our results suggest that the exposure to bright light throughout nocturnal sleep deprivation influences the subjective sleepiness during the mental task and the EEG activity, as well as the subjective sleepiness at rest. However, the effect of the bright light exposure on the EEG activity at the mental task diminishes throughout nocturnal sleep deprivation.