Purpose
Brain-derived neurotrophic factor (BDNF) and the BDNF Val66Met polymorphism (rs6265) have been implicated in neurodegenerative conditions. This study aimed to investigate the associations of ...plasma BDNF and rs6265 with cancer-related cognitive impairment (CRCI) at the end of chemotherapy, and with persistent and delayed CRCI up to 24 months post chemotherapy, among survivors of early-stage breast cancer.
Methods
A multicenter, longitudinal study involving 174 breast cancer patients was conducted. CRCI was assessed using the FACT-Cog (V3) questionnaire and the CANTAB software. Plasma BDNF levels were quantified using an enzyme-linked immunosorbent assay at serial time points and genotyping was achieved using Sanger sequencing. The associations of BDNF and rs6265 with CRCI were analyzed using logistic regressions.
Results
A smaller magnitude of reduction in plasma BDNF between baseline and the end of chemotherapy was correlated with protection from overall subjective CRCI (OR 0.88; 95% CI 0.79–0.99). Furthermore, patients with higher plasma BDNF levels at the end of chemotherapy had lower odds of developing persistent overall subjective CRCI (OR 0.74; 95% CI 0.57–0.97) and persistent CRCI in the functional interference domain (OR 0.62; 95% CI 0.39–0.98). BDNF Met allele carriers were protected against subjective CRCI at the end of chemotherapy in the multitasking and memory domains, and against persistent subjective CRCI in the mental acuity and multitasking domains.
Conclusion
BDNF plasma level or rs6265 genotype information may facilitate the identification of patients at higher risk of long-term CRCI during survivorship and enable the implementation of early intervention strategies that increase BDNF levels.
Analysis of circulating cell-free DNA (cfDNA) has opened new opportunities for characterizing tumour mutational landscapes with many applications in genomic-driven oncology. We developed a customized ...targeted cfDNA sequencing approach for breast cancer (BC) using unique molecular identifiers (UMIs) for error correction. Our assay, spanning a 284.5 kb target region, is combined with a novel freely-licensed bioinformatics pipeline that provides detection of low-frequency variants, and reliable identification of copy number variations (CNVs) directly from plasma DNA. We first evaluated our pipeline on reference samples. Then in a cohort of 35 BC patients our approach detected actionable driver and clonal variants at low variant frequency levels in cfDNA that were concordant (77%) with sequencing of primary and/or metastatic solid tumour sites. We also detected ERRB2 gene CNVs used for HER2 subtype classification with 80% precision compared to immunohistochemistry. Further, we evaluated fragmentation profiles of cfDNA in BC and observed distinct differences compared to data from healthy individuals. Our results show that the developed assay addresses the majority of tumour associated aberrations directly from plasma DNA, and thus may be used to elucidate genomic alterations in liquid biopsy studies.
Abstract Background There has been a recent increase in the availability and use of oral anticancer agents (OAAs). Drug–drug interactions (DDIs) involving OAAs pose a major concern in oncology ...practice due to these drugs' narrow therapeutic indices and potential for compromised efficacy and fatal adverse events. Objective To assess the prevalence of the coprescription of potentially interacting drug combinations involving OAAs in Singapore. Methods A retrospective review of physicians' electronic prescription records between the years 2007 and 2009 was performed in the largest cancer center in Singapore. An overall prevalence rate of potential DDIs and a prevalence rate for each individual DDI pair were calculated. Logistic regression was used to identify risk factors for potential DDIs. Results Fifty-eight clinically significant DDIs were selected for evaluation from Drug Interaction Facts and Micromedex DrugDex. A total of 39,772 OAA prescriptions prescribed to 8837 patients were reviewed. Potential DDI coprescription was found in 5.4% of the patients on OAAs and in 4.7% of the OAA prescriptions. The drug pair prescribed to the largest number of patients was prednisolone and aspirin. About half (53.3%) of the observed DDIs were found on the same prescription. On multivariate analysis, older patients, males, and those taking prednisolone had a higher risk for potential DDIs. Conclusion Although limited by the data available, the analysis of prescription records found that ∼5% of patients taking OAAs in Singapore were exposed to ≥1 potentially interacting drug combination.
Introduction
Circulating tumor cells (CTCs) and cell-free tumor DNA (ctDNA) are tumor components present in circulation. Due to the limited access to both CTC enrichment platforms and ctDNA ...sequencing in most laboratories, they are rarely analyzed together.
Methods
Concurrent isolation of ctDNA and single CTCs were isolated from lung cancer and breast cancer patients using the combination of size-based and CD45-negative selection method
via
DropCell platform. We performed targeted amplicon sequencing to evaluate the genomic heterogeneity of CTCs and ctDNA in lung cancer and breast cancer patients.
Results
Higher degrees of genomic heterogeneity were observed in CTCs as compared to ctDNA. Several shared alterations present in CTCs and ctDNA were undetected in the primary tumor, highlighting the intra-tumoral heterogeneity of tumor components that were shed into systemic circulation. Accordingly, CTCs and ctDNA displayed higher degree of concordance with the metastatic tumor than the primary tumor. The alterations detected in circulation correlated with worse survival outcome for both lung and breast cancer patients emphasizing the impact of the metastatic phenotype. Notably, evolving genetic signatures were detected in the CTCs and ctDNA samples during the course of treatment and disease progression.
Conclusions
A standardized sample processing and data analysis workflow for concurrent analysis of CTCs and ctDNA successfully dissected the heterogeneity of metastatic tumor in circulation as well as the progressive genomic changes that may potentially guide the selection of appropriate therapy against evolving tumor clonality.
We aimed to study the prevalence of CTCs in breast cancer (BC) patients undergoing neoadjuvant or palliative therapy with a label-free microfluidic platform (ClearCell FX), and its prognostic ...relevance in metastatic BC (mBC).
Peripheral blood samples were collected from 108 BC patients before starting a new line of treatment ("baseline"), majority of whom had mBC (76/108; 70.4%). CTCs were retrieved by dean flow fractionation that enriched for larger cells, and enumerated using immunofluorescence-based staining. Progression-free survival (PFS) in mBC patients was analysed using Kaplan-Meier method; cox proportional hazard models were used for univariable and multivariable analyses.
The detection rate of CTCs before starting a new line of treatment was 75.9% (n = 108; median: 8 CTCs/7.5 ml blood) at a cut off of ≥2 CTCs. PFS was inferior for mBC patients with baseline CTC count ≥5 CTCs/7.5 ml blood vs. those with < 5 CTCs/7.5 ml blood (median PFS: 4.3 vs. 7.0 months; p-value: 0.037). The prognostic relevance of CTCs was most significant in patients with HER2- mBC (median PFS: 4.1 vs. 8.3 months; p-value: 0.032), luminal (HR+HER2-) subtype (median PFS: 4.2 vs. 8.3 months; p-value: 0.048), and patients who had one or more prior treatments (median PFS: 4.2 vs. 7.0 months; p-value: 0.02). On multivariable analysis, baseline CTC level (hazard ratio (HR): 1.84, p-value: 0.02) and pre-treatment status (HR: 1.87, p-value: 0.05) were independent predictors of PFS.
This work demonstrates the prognostic significance of CTCs in mBC detected using a label-free size-based enrichment platform.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cancer-related cognitive impairment (CRCI) adversely affects cancer patients. We had previously demonstrated that the
BDNF
Val66Met genetic polymorphism is associated with lower odds of subjective ...CRCI in the multitasking and verbal ability domains among breast cancer patients receiving chemotherapy. To further assess our previous findings, we evaluated the association of
BDNF
Val66Met polymorphism with subjective and objective CRCI in a temporally separate cohort of patients and pooled findings from both the original (
n
= 145) and current (
n
= 193) cohorts in a meta-analysis. Subjective CRCI was assessed using FACT-Cog. Objective CRCI was evaluated using computerized neuropsychological tests. Genotyping was carried out using Sanger sequencing. The association of
BDNF
Val66Met genotypes and CRCI was examined with logistic regression. A fixed-effect meta-analysis was conducted using the inverse variance method. In the meta-analysis (
n
= 338), significantly lower odds of CRCI were associated with Met allele carriers based on the global FACT-Cog score (OR = 0.52, 95% CI 0.29–0.94). Furthermore, Met allele carriers were at lower odds of developing impairment in the domains of memory (OR = 0.34, 95% CI: 0.17–0.70), multitasking (OR = 0.33, 95% CI: 0.18–0.59), and verbal ability (OR = 0.46, 95% CI: 0.24–0.88). Consistent with the previous study, lower odds of subjective CRCI among patients with the
BDNF
Met allele was observed after adjusting for potential confounders in the multitasking (OR = 0.30, 95% CI: 0.14–0.67) domain. In conclusion, carriers of the
BDNF
Met allele were protected against global subjective CRCI, particularly in the domains of memory, multitasking, and verbal ability. Our findings further contribute to the understanding of CRCI pathophysiology.
Genome-wide association studies (GWAS) have proven highly successful in identifying single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. The majority of these studies are ...on European populations, with limited SNP association data in other populations. We genotyped 51 GWAS-identified SNPs in two independent cohorts of Singaporean Chinese. Cohort 1 comprised 1294 BC cases and 885 controls and was used to determine odds ratios (ORs); Cohort 2 had 301 BC cases and 243 controls for deriving polygenic risk scores (PRS). After age-adjustment, 11 SNPs were found to be significantly associated with BC risk. Five SNPs were present in <1% of Cohort 1 and were excluded from further PRS analysis. To assess the cumulative effect of the remaining 46 SNPs on BC risk, we generated three PRS models: Model-1 included 46 SNPs; Model-2 included 11 statistically significant SNPs; and Model-3 included the SNPs in Model-2 but excluded SNPs that were in strong linkage disequilibrium with the others. Across Models-1, -2 and -3, women in the highest PRS quartile had the greatest ORs of 1.894 (95% CI = 1.157-3.100), 2.013 (95% CI = 1.227-3.302) and 1.751 (95% CI = 1.073-2.856) respectively, suggesting a direct correlation between PRS and BC risk. Given the potential of PRS in BC risk stratification, our findings suggest the need to tailor the selection of SNPs to be included in an ethnic-specific PRS model.
To assess the cost-effectiveness of sacituzumab govitecan for treating relapsed or refractory metastatic triple-negative breast cancer (TNBC) in Singapore.
A three-state partitioned survival model ...was developed to evaluate the cost-effectiveness of sacituzumab govitecan from a healthcare system perspective over 5 years. Clinical inputs were obtained from the ASCENT trial. Health state utilities were retrieved from the literature and direct costs were sourced from public healthcare institutions in Singapore. Sensitivity and scenario analyses were conducted to explore the impact of uncertainties and assumptions on cost-effectiveness results.
Compared with single-agent chemotherapy, sacituzumab govitecan was associated with a base-case incremental cost-effectiveness ratio (ICER) of S$328,000 (US$237,816) per quality-adjusted life year (QALY) gained. One-way sensitivity analyses showed that the ICER was most sensitive to the cost of sacituzumab govitecan and progression-free utility values. Regardless of variation in these parameters, the ICER remained high, and a substantial price reduction was required to reduce the ICER.
At its current price, sacituzumab govitecan does not represent a cost-effective treatment for relapsed or refractory metastatic TNBC in Singapore. Our findings will be useful to inform funding decisions alongside other factors including clinical effectiveness, safety, and budget impact considerations.
Background:
There is conflicting evidence on the effect of chemotherapy and psychosocial distress on perceived cognitive changes in cancer patients.
Objective:
To compare the severity of perceived ...cognitive disturbance in Asian breast cancer patients receiving chemotherapy and those not receiving chemotherapy, and identify clinical characteristics associated with perceived cognitive disturbances.
Methods:
A cross-sectional, observational study was conducted at the largest cancer center in Singapore. Breast cancer patients receiving chemotherapy and not receiving chemotherapy completed the Functional Assessment of Cancer Therapy–Cognitive Function (FACT-Cog), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30), and Beck Anxiety Inventory to assess their perceived cognitive functioning, health-related quality of life, and anxiety, respectively. Multiple regression was conducted to delineate the factors associated with perceived cognitive disturbances.
Results:
A total of 85 breast cancer patients receiving chemotherapy and 81 not receiving chemotherapy were recruited. Chemotherapy patients experienced more fatigue (QLQ-C30 fatigue scores: 33.3 vs 22.2 points; p = 0.005) and moderate-to-severe anxiety (21.9% vs 8.6%; p = 0.002) compared to non-chemotherapy patients. Non-chemotherapy patients reported better perceived cognitive functioning than those who received chemotherapy (FACT-Cog scores: 124 vs 110 points, respectively; p < 0.001). Chemotherapy and endocrine therapy were strongly associated with perceived cognitive disturbances (p < 0.001 and 0.021, respectively). The interacting effect between anxiety and fatigue was moderately associated with perceived cognitive disturbances (β = -0.29; p = 0.037).
Conclusions:
Chemotherapy and endocrine treatment were associated with significant cognitive disturbances among Asian breast cancer patients. Psychosocial factors could be used to identify cancer patients who are more susceptible to cognitive disturbances in the clinical setting.
Healthcare sustainability is a global challenge. Various value-driven healthcare strategies have been implemented by Singapore's national health technology assessment (HTA) agency, the Agency for ...Care Effectiveness (ACE). Considering the high and growing expenditure on biologics, strategies have been implemented to drive the use of biosimilars. As Singapore has reached the 5-year mark since the subsidy listing of the first monoclonal antibody biosimilar infliximab, this review aimed to evaluate the impact of these strategies on the changes in adoption rates, utilisation, spending and cost savings for biosimilars in the public healthcare sector.BACKGROUNDHealthcare sustainability is a global challenge. Various value-driven healthcare strategies have been implemented by Singapore's national health technology assessment (HTA) agency, the Agency for Care Effectiveness (ACE). Considering the high and growing expenditure on biologics, strategies have been implemented to drive the use of biosimilars. As Singapore has reached the 5-year mark since the subsidy listing of the first monoclonal antibody biosimilar infliximab, this review aimed to evaluate the impact of these strategies on the changes in adoption rates, utilisation, spending and cost savings for biosimilars in the public healthcare sector.A retrospective cross-sectional study was conducted using aggregated drug utilisation data from all public healthcare institutions. Five monoclonal antibodies with biosimilars, namely infliximab, adalimumab, trastuzumab, rituximab and bevacizumab, were included in this study. The outcomes evaluated were the monthly trends for utilisation volume, proportion attributed to biosimilar use, and drug spending up to December 2022. The simulated cost savings associated with biosimilar adoption were also reported.METHODSA retrospective cross-sectional study was conducted using aggregated drug utilisation data from all public healthcare institutions. Five monoclonal antibodies with biosimilars, namely infliximab, adalimumab, trastuzumab, rituximab and bevacizumab, were included in this study. The outcomes evaluated were the monthly trends for utilisation volume, proportion attributed to biosimilar use, and drug spending up to December 2022. The simulated cost savings associated with biosimilar adoption were also reported.After subsidy implementation, an upward trend in biosimilar use and proportion attributed to biosimilar adoption was observed, while spending reduced substantially. The adoption rate of most biosimilars reached more than 95% within 1 year of listing. Drugs with more than one approved biosimilar brand at the time of subsidy listing reported substantial price reductions of over 80%. Overall, spending for the five monoclonal antibodies have significantly reduced after biosimilar subsidy listing, with an estimated cumulative cost savings of $136 million over 5 years.RESULTSAfter subsidy implementation, an upward trend in biosimilar use and proportion attributed to biosimilar adoption was observed, while spending reduced substantially. The adoption rate of most biosimilars reached more than 95% within 1 year of listing. Drugs with more than one approved biosimilar brand at the time of subsidy listing reported substantial price reductions of over 80%. Overall, spending for the five monoclonal antibodies have significantly reduced after biosimilar subsidy listing, with an estimated cumulative cost savings of $136 million over 5 years.Value-driven healthcare strategies implemented in Singapore's public healthcare institutions have contributed to high adoption rates of biosimilars and have improved affordable access through lower treatment costs. This in turn has led to significant cost savings to the healthcare system.CONCLUSIONValue-driven healthcare strategies implemented in Singapore's public healthcare institutions have contributed to high adoption rates of biosimilars and have improved affordable access through lower treatment costs. This in turn has led to significant cost savings to the healthcare system.
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