Association of plasma leptin, pro-inflammatory adipokines and cancer-related fatigue in early-stage breast cancer patients: A prospective cohort study.

Cancer-related fatigue (CRF) is subjective and has wide inter-individual variability. Given that leptin is commonly associated with fatigue syndrome, its use as a potential biomarker for CRF is being investigated. The primary objective of this study was to evaluate the association between leptin and CRF in early-stage breast cancer patients receiving chemotherapy. In a prospective cohort study, patients completed assessments at baseline (T1), during chemotherapy (T2) and after chemotherapy (T3). Levels of plasma leptin and adipokines were measured using a Luminex bead-immunoassay and CRF was measured using the Multi-Dimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). Data were analysed longitudinally using a generalised estimating equation incorporating clinically relevant parameters and pro-inflammatory adipokines. The analysis included 136 patients (mean age ± SD = 51.5 ± 8.8 years; 69.1% receiving anthracycline-based chemotherapy). More patients experienced CRF at T3 (23.8%) than at T2 (13.8%) compared to baseline. An increase was observed in the median plasma leptin level at T2, followed by a decrease at T3 (T1: 4.07 ng/mL, T2: 4.95 ng/mL and T3: 3.96 ng/mL). In the multivariate model, the change in leptin levels over time was significantly associated with the total MFSI-SF score (ß = -0.15, P = 0.003) after adjusting for the tumour necrosis factor-α (TNF-α) level, anxiety, depression, insomnia, age, menopausal status and type of chemotherapy. This is the first study to report leptin as a biomarker that predicts the onset of CRF over time. Future studies are required to validate the findings.

Association of mitochondrial DNA content in peripheral blood with cancer-related fatigue and chemotherapy-related cognitive impairment in early-stage breast cancer patients: a prospective cohort study.

PURPOSE: Cancer-related fatigue (CRF) and chemotherapy-related cognitive impairment (CRCI) are reported to be associated with mitochondrial dysfunction. Hence, mitochondrial DNA (mtDNA) content, a biomarker of mitochondrial dysfunction, is hypothesized to correlate with the onset of CRF and CRCI. This study aims to evaluate the association between peripheral blood mtDNA content reduction and severity of CRF and CRCI in patients receiving chemotherapy. METHODS: This was a prospective cohort study. Early-stage breast cancer patients receiving anthracycline- or taxane-based chemotherapy were recruited. CRF was assessed using MFSI-SF, and CRCI was assessed using FACT-Cog and CANTAB at two timepoints: baseline (T1; prior to treatment) and 6 weeks after initiation of treatment (T2). mtDNA content was measured at both timepoints using real-time quantitative polymerase chain reaction. Multiple logistic regression was utilized to evaluate the association between mtDNA reduction and worsening of CRF and CRCI, adjusting for age, anxiety, insomnia, plasma cytokines concentrations, and other clinically important covariates. RESULTS: A total of 108 patients (age 52.0 ± 9.2 years; 82.4% Chinese; 64.8% receiving anthracycline-based chemotherapy) were recruited. Proportions of patients with worsening of CRF increased from the lower to the upper quartiles of mtDNA reduction (22.2, 33.3, 55.6, and 63.0% in quartiles 1, 2, 3, and 4, respectively, p = 0.001 for trend). Reduction of mtDNA content was significantly greater among those with worsening of CRF and CRCI compared to those without CRF [mean reduction (± SD): 36.5 (46.1) vs. 9.4 (34.5), p < 0.001]. After adjusting for covariates, every 1-unit reduction of the mtDNA content was associated with a 4% increased risk for worsening of CRF (95% CI, 1-6%; p = 0.009). CONCLUSIONS: This is the first study to show that the reduction of mtDNA content in peripheral blood is associated with the onset of CRF in patients receiving chemotherapy. Further validation studies are required to confirm the findings.

Distinct and heterogeneous trajectories of self-perceived cognitive impairment among Asian breast cancer survivors.

OBJECTIVES: Currently, there are no studies that have established the self-perceived cognitive trajectories experienced by breast cancer patients (BCPs) post-chemotherapy. Therefore, we characterized the long-term trajectory of self-perceived cognitive function among Asian early-stage BCPs using the minimal clinically important difference of a subjective measure of cognitive function. METHODS: Early-stage BCPs who received chemotherapy were recruited and assessed at 4 time points: Before chemotherapy initiation (T1), 6 weeks post-chemotherapy initiation (T2), 12 weeks post-chemotherapy initiation (T3), and 15-months post-chemotherapy initiation (T4). All assessments were performed approximately within 2 weeks post-chemotherapy. Subjective and objective cognitive function were assessed using Functional Assessment of Cancer Therapy-Cognitive (version 3) and Headminder™. RESULTS: A total of 166 BCPs were recruited, of whom 131 completed assessment at all time points. Using the minimal clinically important difference of Functional Assessment of Cancer Therapy-Cognitive, 5 distinct cognitive trajectories were established. Of the 131 patients, 70 (53.4%) did not report any clinically significant cognitive impairment. Twenty-one (16.0%) patients reported acute cognitive changes during chemotherapy (T2 and/or T3) but not at T4. Forty patients (30.5%) reported clinically significant cognitive impairment at T4, of whom 18 did not report any cognitive impairment at earlier time points. Fifteen (11.5%) patients reported persistent cognitive impairment throughout all time points, while 7 (5.3%) patients reported intermittent cognitive impairment at T2 and T4 but not at T3. CONCLUSION: This is the first study to establish the existence of heterogeneous cognitive trajectories based on clinically significant thresholds of self-perceived cognitive impairment. The findings have important implications on the window for screening and management of post-chemotherapy cognitive impairment.

Psychometric properties and measurement equivalence of the Multidimensional Fatigue Syndrome Inventory- Short Form (MFSI-SF) amongst breast cancer and lymphoma patients in Singapore.

BACKGROUND: Currently, several fatigue measurement instruments are available to evaluate and measure cancer-related fatigue. Amongst them, Multidimensional Fatigue Syndrome Inventory-Short Form (MFSI-SF) is a self-reported instrument and a multidimensional scale that aims to capture the global, somatic, affective, cognitive and behavioural symptoms of fatigue. This study examines the psychometric properties and measurement equivalence of the English and Chinese versions of MFSI-SF in breast cancer and lymphoma patients in Singapore. METHODS: Patients were recruited from National Cancer Centre Singapore. Validity, reliability and responsiveness of MFSI-SF were evaluated in this study. Convergent validity was evaluated by correlating total and subscales of MFSI-SF to known related constructs in EORTC QLQ-C30. Known group validity was assessed based on patients' cancer stage, pain, insomnia and depression symptoms. Reliability was evaluated by Cronbach's α. Responsiveness analyses were performed with patients who have undergone at least one cycle of chemotherapy. Multiple regression was used to compare the total and subscale scores of MSFI-SF between the two language versions. RESULTS: Data from 246 (160 English and 86 Chinese version) breast cancer and lymphoma patients were included in the study. Moderate to high correlations were observed between correlated MFSI-SF subscales and EORTC QLQ-C30 domains (|r| = 0.524 to 0.774) except for a poor correlation (r = 0.394) observed between MFSI-SF vigour subscale and EORTC QLQ-C30 role functioning subscale. Total MFSI-SF scores could differentiate between patients with higher depression, pain and insomnia status. Internal consistency of MFSI-SF was also high (α = 0.749 to 0.944). Moderate correlation was observed between change in total MFSI-SF score and change in fatigue symptom scale score and global QoL score on EORTC QLQ-C30 (|r| = 0.478 and 0.404 respectively). Poor correlations were observed between change in scores of hypothesised subscales (|r| = 0.202 to 0.361) except for a moderate correlation between change in MFSI-SF emotional fatigue score and change in EORTC QLQ-C30 emotional functioning domain score. Measurement equivalence was established for all subscales and total MFSI-SF score except for the emotional and vigour subscales. CONCLUSIONS: This study supports the use of MFSI-SF as a reasonably valid scale with good internal consistency for measuring fatigue levels in the Singapore cancer population.

Breast cancer screening behavior, attitude, barriers among middle-aged Chinese women in Macao, China.

Background: Breast cancer is the third leading cause of death from cancer among females in Macao, but little is known about local practice of breast cancer screening. The study aims to evaluate breast cancer screening behaviors and to identify the predictors of insufficient knowledge and attitudes towards breast cancer and its screening among female residents. Methods: This was a cross-sectional study conducted from April to June 2016 in Macao. Quota sampling of women completed the modified Chinese Breast Cancer Screening Beliefs questionnaire (CBCSB) to assess their breast cancer-related perceptions, screening attitudes and behaviors. Univariate and multivariate logistic regressions were performed to identify the predictors of poor-screening practices, attitudes, knowledge and perceived barriers to mammography. Result: A total of 417 women (mean age±SD: 50.5±5.7) completed surveys, with 160 (38.4%), 196 (47.0%) and 103 (24.7%) women received breast self-examination, clinical breast examination and mammography as recommended, respectively. Nulliparity (OR=2.56, 95% CI = 1.14-5.73) and low education (OR = 1.72, 95% CI = 1.04-2.84) were significantly associated with negative attitude towards health check-ups. Women did not know anyone with breast cancer (OR = 2.30, 95% CI = 1.50-3.55) were more likely to have insufficient knowledge about breast cancer. Low education (OR = 1.95, 95% CI = 1.25-3.04) and not knowing anyone with breast cancer (OR = 2.02, 95% CI = 1.31-3.13) were identified as predictors for perceived barriers to mammography. Conclusion: Recommendations for breast cancer screening are poorly followed by the residents in Macao, and a culturally tailored educational program is urgently needed to raise the public's awareness of the disease and the screening practices.

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.

A culturally adapted survivorship programme for Asian early stage breast cancer patients in Singapore: A randomized, controlled trial.

BACKGROUND: As cancer mortality rates improve in Singapore, there is an increasing need to improve the transition to posttreatment survivorship care. This study aimed to evaluate the effectiveness of a psychoeducation group (PEG) intervention program compared with usual care to reduce distress for physical symptom and psychological aspects in Asian breast cancer survivors who have completed adjuvant chemotherapy. METHODS: This was a randomized, controlled trial comprising 72 Asian early stage breast cancer survivors who were randomized into the PEG (n = 34) or the control (n = 38) arm. The participants in the PEG arm underwent a weekly multidisciplinary PEG program delivered in a group format over 3 weeks coupled with cultural adaptation. Both arms were assessed at baseline and 2 months after intervention using the Rotterdam Symptom Checklist, Beck Anxiety Inventory, and EORTC QLQ-C30. A satisfaction questionnaire was also conducted among those survivors who have participated in the PEG program. Effective sizes were calculated using Cohen d. RESULTS: The mean age ± SD of all participants was 53.0 ± 8.9 years, with the majority being Chinese (84.7%) and Malay (6.9%), and clinical characteristics were well balanced in both arms. Compared to the control arm, the PEG arm showed a significantly greater reduction in physical symptom distress (d = 0.76, P = .01) and fatigue (d = 0.49, P = .04). The 82.4% of the participants in the intervention group responded to the satisfaction questionnaire, and the majority (92.9%) agreed that the overall duration of the PEG intervention program was appropriate. CONCLUSIONS: A culturally adapted PEG program was effective in reducing physical symptom distress in Asian breast cancer survivors. (ClinicalTrials.gov: NCT02600299).

Psychometric properties and measurement equivalence of the English and Chinese versions of the Beck Anxiety Inventory in patients with breast cancer.

BACKGROUND: There is a lack of psychometric data for both the English and Chinese versions of Beck Anxiety Inventory (BAI) to support its usage among breast cancer patients. This study examined the psychometric properties and measurement equivalence of the English and Chinese versions of BAI among breast cancer patients in Singapore. METHODS: Patients were recruited from two major cancer centers in Singapore. The criterion and construct validity of BAI was assessed by its correlation strength with (1) the emotional functioning subdomain of EORTC QLQ-C30 and (2) constructs related to anxiety, namely fatigue, dyspnea, and quality of life. The known-group validity was assessed according to the patients' breast cancer stage, religious beliefs, and emotional functioning levels. The internal consistency of the BAI domains was evaluated using Cronbach's alpha coefficient. Regression analysis was performed to compare the BAI total and domain scores between the two language versions. RESULTS: Data from 244 patients (144 English-speaking and 100 Chinese-speaking) were analyzed. For both language versions, the BAI total scores correlated moderately with the EORTC QLQ-C30 emotional functioning subdomain (r = -0.655 and -0.601). Correlations with fatigue, quality of life, and dyspnea were moderate (|r| = 0.456-0.606). Patients with poorer emotional functioning reported higher anxiety levels, establishing known-group validity. All BAI domains demonstrated satisfactory internal consistencies (α = 0.74-0.87), except for the panic domain (α = 0.57-0.61). Possible measurement equivalence between the language versions was established. CONCLUSION: Both English and Chinese versions of BAI are valid, reliable, and possibly equivalent for future use.

Minimal Clinically Important Difference of the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) for Fatigue Worsening in Asian Breast Cancer Patients.

CONTEXT: The minimal clinically important difference (MCID) of the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), a questionnaire that measures cancer-related fatigue, has not been established in patients with cancer. OBJECTIVES: This study aims to determine the MCID of the MFSI-SF. METHODS: Breast cancer patients completed the MFSI-SF and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30) before chemotherapy and at least three weeks later. The EORTC-QLQ-C30 fatigue scale (EORTC-FA) was used as an anchor, and a receiver operating characteristic (ROC) curve was also used to identify the optimal MCID cut-off for fatigue deterioration. A distribution-based approach used one-third of the SD, half of the SD, and one SEM of the total MFSI-SF score to determine the MCID. RESULTS: A total of 201 patients were analyzed. Change scores of the MFSI-SF and EORTC-FA were moderately correlated (r = 0.47, P < 0.001). The EORTC-FA-anchored MCID was 8.69 points (95% CI: 4.03-13.34). The MCID attained from the ROC curve method was 4.50 points (sensitivity: 68.8%; specificity: 64.1%). For the distribution-based approach, the MCIDs corresponding to one-third of the SD, half of the SD, and one SEM were 5.39, 8.99, and 10.79 points, respectively. CONCLUSION: The MCID of the MFSI-SF identified by all approaches ranged from 4.50 to 10.79 points. The MCID can be used to interpret the clinical significance of fatigue deterioration in patients with breast cancer and to determine sample sizes for future clinical trials.

Impact of Adjuvant Anthracycline-Based and Taxane-Based Chemotherapy on Plasma VEGF Levels and Cognitive Function in Breast Cancer Patients: A Longitudinal Study.

BACKGROUND: Vascular endothelial growth factor (VEGF) has been shown to induce neurogenesis in the brain and yield neuroprotective effects. It is hypothesized that chemotherapy reduces circulating VEGF levels and leads to cognitive decline among patients. This multicenter longitudinal study aimed to evaluate the impact of chemotherapy on VEGF levels and the association between VEGF levels and cognitive function. PATIENTS AND METHODS: A total of 145 early-stage breast cancer patients were recruited and assessed before chemotherapy (T1), during chemotherapy (T2), and at the end of chemotherapy (T3). At each time point, plasma VEGF levels were assessed using a multiplex immunoassay. Cognitive function was assessed using both Functional Assessment of Cancer Therapy-Cognitive Function, Version 3 (FACT-Cog), and Headminder (a computerized, web-based neuropsychologic battery). RESULTS: Generally, we observed higher-than-baseline plasma VEGF levels after the start of chemotherapy (P < .001). Among patients receiving anthracycline-based chemotherapy, the median plasma VEGF levels were significantly higher at T2 (T2: 37.3 pg/mL vs. T1: 21.3 pg/mL; P < .001) and T3 (T3: 35.5 pg/mL vs. T1: 21.3 pg/mL; P < .001) than at baseline. Plasma VEGF levels were not associated with chemotherapy-associated cognitive impairment. CONCLUSION: Breast cancer patients experience an increasing trend in plasma VEGF levels during chemotherapy, and the regimen types may have a differential effect on circulating VEGF levels. Furthermore, changes in plasma VEGF levels during chemotherapy were not associated with cognitive impairment. VEGF may play a minor role in mediating the occurrence of chemotherapy-associated cognitive impairment.

Perceptions and Barriers of Survivorship Care in Asia: Perceptions From Asian Breast Cancer Survivors.

PURPOSE: With the long-term goal to optimize post-treatment cancer care in Asia, we conducted a qualitative study to gather in-depth descriptions from multiethnic Asian breast cancer survivors on their perceptions and experiences of cancer survivorship and their perceived barriers to post-treatment follow-up. METHODS: Twenty-four breast cancer survivors in Singapore participated in six structured focus group discussions. The focus group discussions were voice recorded, transcribed verbatim, and analyzed by thematic analysis. RESULTS: Breast cancer survivors were unfamiliar with and disliked the term "survivorship," because it implies that survivors had undergone hardship during their treatment. Cognitive impairment and peripheral neuropathy were physical symptoms that bothered survivors the most, and many indicated that they experienced emotional distress during survivorship, for which they turned to religion and peers as coping strategies. Survivors indicated lack of consultation time and fear of unplanned hospitalization as main barriers to optimal survivorship care. Furthermore, survivors indicated that they preferred receipt of survivorship care at the specialty cancer center. CONCLUSION: Budding survivorship programs in Asia must take survivor perspectives into consideration to ensure that survivorship care is fully optimized within the community.

Impact of TNF-α (rs1800629) and IL-6 (rs1800795) Polymorphisms on Cognitive Impairment in Asian Breast Cancer Patients.

OBJECTIVE: Expression of pro-inflammatory cytokines is influenced by single nucleotide polymorphisms (SNPs) in the promoter regions of the pro-inflammatory cytokine genes, and cytokines are associated with the occurrence of post-chemotherapy cognitive impairment. Hence, the aim of this study was to evaluate the associations between two common pro-inflammatory cytokine gene polymorphisms namely, IL6-174 (rs1800795 G>C) and TNF-308 (rs1800629 G>A), and chemotherapy-associated cognitive impairment (CACI) among Asian early-stage breast cancer patients. In addition, the differential effect of these SNPs on plasma IL-6 and TNF-α levels, and the associations of plasma IL-6 and TNF-α levels with CACI were also assessed. METHODS: Asian early-stage breast cancer patients (Stage I to III) receiving chemotherapy were prospectively recruited from two cancer centers in Singapore. Patients' cognitive function was longitudinally assessed using the validated FACT-Cog (ver. 3) and an objective computerized battery, Headminder™ at three-time points. Plasma IL-6 and TNF-α levels were analyzed using the multiplex immunoassay, and genotyping was performed using Sanger sequencing. Regression analyses and generalized estimating equation were utilized for statistical analysis. RESULTS: A total of 125 patients were included (mean age: 50.3; Chinese: 80.8%; post-menopausal: 48.0%; 68.0% received anthracycline-based chemotherapy). 36.8% patients experienced self-perceived cognitive impairment, detected in memory (32.8%) and attention (34.2%) domains. Patients with higher levels of anxiety (p<0.001) and insomnia (p = 0.003) also reported more self-perceived cognitive impairment. Higher plasma concentrations of IL-6 were associated with greater severity of self-perceived cognitive impairment (p = 0.001). Polymorphisms of cytokine genes were not associated with expression of plasma cytokines. CONCLUSION: Present findings further contribute to the growing evidence that supports the role of the pro-inflammatory cytokine IL-6 in the occurrence of cognitive impairment post-chemotherapy. However, genetic polymorphism of these cytokines did not play a major role to the cytokine fluctuations as well as cognitive impairment in this cohort. With an increasing evidence to support the cytokine hypothesis, future studies should investigate the role of anti-inflammatory agents in mitigating the cognitive impairment associated with chemotherapy.

Brain-derived neurotrophic factor genetic polymorphism (rs6265) is protective against chemotherapy-associated cognitive impairment in patients with early-stage breast cancer.

BACKGROUND: Brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal function and development, is implicated in several neurodegenerative conditions. Preliminary data suggest that a reduction of BDNF concentrations may lead to postchemotherapy cognitive impairment. We hypothesized that a single nucleotide polymorphism (rs6265) of the BDNF gene may predispose patients to cognitive impairment. This study aimed to evaluate the effect of BDNF gene polymorphism on chemotherapy-associated cognitive impairment. METHODS: Overall, 145 patients receiving chemotherapy for early-stage breast cancer (mean age: 50.8 ± 8.8 y; 82.1% Chinese) were recruited. Patients' cognitive functions were assessed longitudinally using the validated Functional Assessment of Cancer Therapy-Cognitive Function (v.3) and an objective computerized tool, Headminder. Genotyping was performed using Sanger sequencing. Logistic regression was used to evaluate the association between BDNF Val66Met polymorphism and cognition after adjusting for ethnicity and clinically important covariates. RESULTS: Of the 145 patients, 54 (37%) reported cognitive impairment postchemotherapy. The Met/Met genotype was associated with statistically significant lower odds of developing cognitive impairment (odds ratio [OR] = 0.26; 95% CI: 0.08-0.92; P = .036). The Met carriers were less likely to experience impairment in the domains of verbal fluency (OR = 0.34; 95% CI: 0.12-0.90; P = .031) and multitasking ability (OR = 0.37; 95% CI: 0.15-0.91; P = .030) compared with the Val/Val homozygote. No associations were observed between Headminder and the BDNF Val66Met polymorphism. CONCLUSIONS: This is the first study to provide evidence that carriers of the BDNF Met allele are protected against chemotherapy-associated cognitive impairment. Further studies are required to validate the findings.