Breast Cancer Research and Treatment最新文献

Aim: Cancer-related cognitive impairment (CRCI) is one of the severe side effects affecting the quality of life of breast cancer (BC) patients. However, the mechanisms underlying CRCI are still unclear. The study aimed to examine the multiple mediating roles of resilience, social support, cortisol, and neutrophil-lymphocyte ratio (NLR) in the relationship between perceived stress and cognitive function.

Design: The study was a descriptive, cross-sectional study.

Methods: The study investigated 450 BC patients with chemotherapy in China. Convenience sampling was conducted from February to August 2023. The study used the Perceived Stress Scale, the Connor-Davidson Resilience Scale, the Social Support Rating Scale, the Functional Assessment of Cancer Therapy-Cognitive Function, the Montreal Cognitive Assessment, salivary cortisol, and NLR. SPSS 25.0 and AMOS 26.0 conducted bivariate correlations and multiple mediation analysis.

Results: The correlations of magnitude variables ranged from no correlation to moderate level (r = - 0.002 to - 0.617). The multiple mediation path demonstrated that resilience and morning cortisol levels mediated the relationship between perceived stress and cognitive function, with a 95% confidence interval (CI) not including 0 for the direct, indirect, and total effects.

Conclusions: The study confirmed that when BC patients endure physical and psychological stress during diagnosis and treatment, individuals' resilience can buffer the stress on cognitive function. Morning salivary cortisol levels, as the product and indicator of the hypothalamic-pituitary-adrenal (HPA) axis function, may play a significant role in the effect of perceived stress on cognitive function while incapable of finding NLR as the marker of individuals' immune inflammatory response and social support play a role in this relationship. The study, based on a stress perspective, explored the regulatory mechanisms by which perceived stress affects cognitive function in patients undergoing chemotherapy for breast cancer, providing intervenable targets for subsequent improvement of patients' cognitive function.

Purpose: Tamoxifen undergoes metabolic activation by cytochrome P450 (CYP) enzymes to metabolites with more potent anti-estrogenic effects. Numerous studies demonstrate decreased tamoxifen efficacy associated with reduced CYP2D6 activity or lower Z-endoxifen concentrations. Women taking tamoxifen frequently experience vasomotor symptoms (VMS) that may require medical treatment. Many medications used for VMS or depression are CYP substrates that may reduce Z-endoxifen concentrations. While the drug-drug interactions (DDI) from potent CYP2D6 inhibitors (CYPi) on tamoxifen metabolism has been studied, the impact of less potent CYPi including drugs used to treat VMS remains largely unknown.

Methods: We performed a prospective trial to evaluate the impact of gabapentin or non-potent CYPi (venlafaxine citalopram) on plasma concentrations of tamoxifen and its metabolites (Z-endoxifen, N-desmethyl-tamoxifen (NDMT) and 4-hydroxy-tamoxifen (4HT).

Results: Patients enrolled were intermediate to extensive metabolizers by CYP2D6 genotyping. While tamoxifen and NDMT plasma concentrations were not significantly altered, the percent decrease in plasma Z-endoxifen concentration was statistically significant with the addition of venlafaxine (n = 22) or citalopram (n = 18) (median - 14.7 and - 14.4%, respectively) but not with gabapentin (n = 14) (median - 2.3%). A reduction in Z-endoxifen concentrations below the 5.9 ng/ml threshold associated with tamoxifen efficacy was observed in 12% of patients.

Conclusion: The addition of venlafaxine and citalopram but not gabapentin during tamoxifen treatment decreases plasma Z-endoxifen concentrations. SSRIs/SNRIs affecting tamoxifen biotransformation pathways, but with less potent CYPi potential, should be used cautiously in tamoxifen-treated patients and non-CYP inhibiting medications considered when possible.

Purpose: This study aimed to evaluate treatment patterns and clinical outcomes in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) initiating at least one chemotherapy for metastatic disease in real-world settings in Japan.

Methods: In this observational retrospective cohort study, data of 2697 patients with HR+/HER2- mBC from a Japanese medical claims database who initiated the first chemotherapy in metastatic setting between January 1, 2017, and March 31, 2022, were analyzed. The study assessed treatment patterns, time to next treatment or death (TTNTD), time to treatment discontinuation, medical costs, and adverse events of interest for those receiving first-, second-, and third-line chemotherapies for mBC.

Results: The most common regimens were S-1 (20.1%), eribulin (12.2%), and paclitaxel + bevacizumab (6.9%) for each line of therapy, respectively. The TTNTD decreased as treatment advanced, with medians of 8.2, 7.3, and 6.0 months for each line. Monthly medical costs were 277.1, 340.9, and 378.4 thousand yen for each line of therapy, respectively. Nausea/vomiting and neutropenia/leukopenia occurred in 62.6% and 20.5% of patients, respectively.

Conclusion: This study highlights current chemotherapy practices for HR+/HER2- mBC in Japan, where treatment patterns largely align with clinical guidelines but vary according to patient characteristics. Notably, the TTNTD shortens with successive treatments, and medical costs increase, intensifying the financial burden on patients. These findings indicate unmet needs for improved treatment options that enhance outcomes and reduce patient burden in advanced therapy lines.

Purpose: Breast cancer (BC) survivors experience higher rates of cardiometabolic conditions, partly due to treatment. While healthy eating decreases the risk of these conditions in the general population, its association in BC survivors is unclear.

Methods: We included 3415 participants from the Pathways Study, a prospective cohort of women diagnosed with invasive BC between 2005 and 2013 and followed through 2021. Concordance of food intakes from food frequency questionnaires was estimated for five healthy eating patterns at BC diagnosis: Dietary Approaches to Stop Hypertension (DASH), healthy Plant-based Dietary Index (hPDI), 2020 Healthy Eating Index (HEI), American Cancer Society nutrition guidelines (ACS), and the alternate Mediterranean Diet Index (aMED). Incident hypertension, diabetes, and dyslipidemia were identified through electronic health records. Cumulative incidence rates (CIRs) were estimated accounting for the competing risk of death. Covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Fine and Gray regression models, stratified by BC treatment status.

Results: Over an average 11.5 years (range = 0.3-16.3) of follow-up, 554 (16.2%) participants developed hypertension, 362 (10.6%) developed diabetes, and 652 (19.1%) developed dyslipidemia. CIRs for any cardiometabolic condition 15 years after BC diagnosis were 39.2% for women in the highest HEI quartile compared to 49.3% in the lowest. After adjustment, women in the highest HEI quartile had lower risks of any cardiometabolic condition (HR = 0.70, 95% CI 0.54-0.91, P_trend = 0.006), including hypertension (HR = 0.71, 95% CI 0.54-0.94, P_trend = 0.007), diabetes (HR = 0.57, 95% CI 0.41-0.79, P_trend < 0.001), and dyslipidemia (HR = 0.77, 95% CI 0.59-0.99, P_trend = 0.04). Similar associations were observed for DASH, hPDI, and ACS with diabetes incidence.

Conclusion: Healthier diets at BC diagnosis, particularly those aligned with the HEI, were associated with lower cardiometabolic risks.

Purpose: Glucocorticoid receptor (GR) activity may mediate chemoresistance in advanced triple-negative breast cancer (TNBC). Preclinical studies demonstrate that GR antagonism can augment the effect of taxanes in TNBC models. We hypothesized that pretreatment with mifepristone, a potent GR antagonist, would enhance nab-paclitaxel efficacy in advanced TNBC.

Methods: This trial was terminated early due to poor accrual. 29 of 64 planned patients were enrolled. Patients were randomized to receive nab-paclitaxel with or without mifepristone; oral mifepristone 300 mg was administered the day prior and day of each dose of nab-paclitaxel. The primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included response rate and correlation of response with GR expression.

Results: The addition of mifepristone to nab-paclitaxel did not improve PFS (3.0 m vs 3.0 m, p = 0.687) or overall response rate (23% vs 31.5%) compared to nab-paclitaxel alone. There was a trend towards improved overall survival in the combination group, primarily driven by one long-term responder. Increased rates of grade 3 neutropenia (46% vs 7%) and febrile neutropenia were observed in the combination arm, while other toxicities were similar in both groups. Increased GR expression was not correlated with clinical response in the combination arm.

Conclusions: While there were responders to the combination, the study was underpowered to meet the primary endpoint. Higher rates of neutropenia were observed in the combination, but overall it was well tolerated. Preclinical data in TNBC and clinical data in other malignancies support further investigation of GR modulators. Future studies should incorporate biomarkers to select patients who benefit from GR inhibition.

Purpose: This study aimed to identify preferences of patients with high-risk hormone receptor positive/human epidermal growth factor receptor 2 negative (HR + /HER2-) early breast cancer (EBC) related to adjuvant endocrine therapy (ET) using the Adaptive Choice-Based Conjoint (ACBC) method.

Methods: A stepwise multimodal study was conducted in Germany between October 2021 and March 2022 consisting of desk research, qualitative interviews, and quantitative online surveys. Included patients had a high risk of recurrence at the time of their HR + /HER2- EBC diagnosis, completed primary therapy (surgery ± radiation + (neo)adjuvant chemotherapy), and were prescribed or undertaking adjuvant ET. In the desk research phase, online resources, patient material, and existing studies were reviewed. In the qualitative phase, interviews were conducted with 6 gynaecologists, 6 oncologists, 20 patients, and 5 caretakers. In the quantitative phase, 85 patients completed the ACBC analysis survey.

Results: Included patients were aged 49.4 years (mean) among which 69.4% were still working. In the ACBC absolute rating, diarrhoea, arthralgia, and nausea were least relevant attributes to patients. Relative assessment of ET attributes against each other revealed that achieving the ET goal, namely the reduction of risk of tumour recurrence, had the highest relevance, while avoiding side effects and maintaining quality of life were less relevant. Overall, 35% have considered taking a break or discontinuing adjuvant ET due to side effects.

Conclusion: Reduction of tumour recurrence was the attribute of highest relative importance for patients with high-risk HR + /HER2- EBC followed by side effect avoidance and quality-of-life maintenance, reflecting their importance in treatment decisions.

We read with great interest the recent article, "Comparison of survival between unilateral and bilateral breast cancers using propensity score matching: a retrospective single-center analysis" by Ozler et al. This study addresses an important gap in the literature by comparing disease-free survival (DFS) and overall survival (OS) between unilateral and bilateral breast cancer, and the use of propensity score matching (PSM) strengthens the validity of the findings. However, we would like to share several reflections that we believe can enhance the interpretation and future application of this research.

Purpose: Women residing in disadvantaged neighborhoods experience disparities in breast cancer (BC) survival which persist when accounting for individual-level socioeconomic/treatment factors. The chronic stress of living in a disadvantaged neighborhood may compound the stress of a new cancer diagnosis, leading to neuroendocrine dysregulation. Cognitive Behavioral Stress Management (CBSM) has shown efficacy at reducing distress and modulating neuroendocrine functioning, but it is unknown whether it is efficacious in this population.

Methods: This is a secondary analysis of a randomized trial of 10-week group-based CBSM (versus a psycho-educational control) in women with nonmetastatic BC. The Area Deprivation Index (ADI) was calculated, and women were categorized as living in low (n = 175) versus high disadvantage (n = 50). Women completed a measure of cancer-related distress (Impact of Events Scale-Intrusions) and underwent blood draws to collect PM cortisol at baseline, 6 months, and 12 months. Hierarchical linear modeling tested whether condition predicted the slope of outcomes, and whether ADI moderated these relationships.

Results: CBSM was associated with greater reductions in cancer-specific distress and cortisol, though these effects were not found to be moderated by ADI. Exploratory simple slope analyses showed that CBSM was associated with decreased cancer-related distress across ADI categories, while CBSM resulted in decreased cortisol among low ADI women only.

Conclusion: CBSM reduced cancer-related distress across neighborhoods, but this was only accompanied by cortisol changes among those in advantaged neighborhoods. Neighborhood disadvantage may represent a particularly salient stressor that is distinct from cancer-specific distress. Future interventions targeting this population should consider modifications to increase relevance and accessibility.

Background: The heterogeneity of breast cancer (BC) necessitates the identification of novel subtypes and prognostic models to enhance patient stratification and treatment strategies. This study aims to identify novel BC subtypes based on PANoptosis-related genes (PRGs) and construct a robust prognostic model to guide individualized treatment strategies.

Methods: The transcriptome data along with clinical data of BC patients were sourced from the TCGA and GEO databases. Consensus clustering was performed on 12 PRGs to ascertain potential BC subtypes, and variances in survival, infiltration of immune cells, and functional pathways among them were examined. A prognostic model was generated through 101 combinations of machine learning algorithms and validated across multiple cohorts. The response of patients towards immunotherapy were analyzed using multiple frameworks.

Results: Consensus clustering of 12 PRGs identified two distinct BC subtypes, with subtype B exhibiting significantly lower overall survival (OS) rates compared to subtype A. Immune cell infiltration analysis revealed higher immune activity in subtype A. Functional pathway analysis revealed that subtype A exhibited a significant enrichment in immune-related pathways, while subtype B was associated with cell cycle and metabolic processes. An integrated machine learning framework integrating CoxBoost and Random Survival Forest (RSF) algorithms was developed, demonstrating high predictive performance across multiple cohorts. A nomogram combining age and risk score was constructed, showing excellent predictive performance. Immune landscape analysis revealed that the high-risk group exhibited a suppressive tumor immune microenvironment (TIME). Immunotherapy response prediction suggested that low-risk patients were more likely to benefit from PD-1 and CTLA-4 inhibitors.

Conclusions: Our study provides a comprehensive framework for BC subtype classification and prognostic prediction, offering valuable insights for personalized treatment strategies.

Introduction: Triple-negative breast cancer (TNBC), is a highly aggressive tumor. Formosanin C (FC) is a diosgenin with immunomodulatory and antitumor properties, the precise mechanism through which it is against TNBC remains uncertain.

Objective: Clarifying the mechanism of FC against TNBC.

Materials and methods: The impact of FC on two TNBC cell lines for 24 h was investigated through various techniques including the CCK8 assay, flow cytometry, transwell assay, scratch tests, immunoblot assay, and immunofluorescence. To elucidate the mechanism behind the anti-TNBC effect of FC, MDA-MB-231 cells were subjected to STAT3 overexpression. Moreover, the in vivo efficacy of FC was examined using a xenograft nude mice (BALB/C). Mice were divided into the control group (equal amount of PBS), the napabucasin group (5 mg/kg) and the FC groups (1 mg/kg, 2 mg/kg). The study duration was 30 days.

Results: FC exhibited inhibitory effects against MDA-MB-231 and Hs578T cells. FC can decrease the migratory capacity of TNBC cells by inhibiting epithelial-mesenchymal transition (EMT). Meanwhile, we demonstrated that the inhibition of phosphorylation of STAT3 (Y705) is the crucial mechanism of FC against TNBC. Moreover, FC also hindered the polarization of macrophage M2.

Discussion and conclusion: This study is the first to show that FC restrains the EMT of TNBC cells by obstructing the STAT3 pathway and hinders the M2 polarization of macrophages and immune evasion. Therefore, FC holds the possibility of being utilized as a therapeutic remedy for TNBC.