Breast Cancer Research最新文献

Objectives: Triple negative breast cancer (TNBC) is an aggressive subtype with limitations in therapy. Although cyclin dependent kinase inhibitors (CDKi) have been proven in breast cancer, challenges remain in TNBC. Successful inhibition of CDK4/6 relies on intact Rb tumor suppressor (encoded by tumor suppressor gene RB1). However, in addition to gene mutation or deletion, RB1, as an imprinted gene, also has a mechanism of inactivation due to loss of imprinting (LOI). This study aimed to ascertain the imprinting status of RB1 in TNBC.

Methods: We applied bioinformatic analyses to evaluate methylation differences on the RB1 imprinting control region CpG85 among subtypes of breast cancer. Deregulation of RB1 expression by LOI in TNBC cell lines was further tested by RT-qPCR with stimulation by 5-aza-2-deoxycytidine (DAC) treatment. In addition, RB1 CpG85 methylation levels of circulating cell-free DNA (cfDNA) in plasma was assessed by pyrosequencing in 15 enrolled TNBC patients and 6 non-cancer donors. Survival analysis based on TCGA and GEO databases were performed to explored the potential clinical significance.

Results: Bioinformatic analysis showed hypomethylation at CpG85 of RB1 in TNBC, which was further confirmed in cell lines. LOI of RB1 affected its transcription. Analysis of cfDNA showed CpG85 was differentially methylated in TNBC patients, with 6/15 patients displaying hypomethylation at cg18481241 and 1/15 at cg03085377 within CpG85. Patients with hypomethylation of these sites correlated with worse overall survival.

Conclusions: RB1 exhibits potential LOI in TNBCs, laying the groundwork for more precise subtyping and treatment of TNBC patients.

Objectives: To validate cone-beam breast computed tomography (CBBCT) for evaluating NAT response using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and to explore correlations between multidimensional CBBCT features and pathological complete response (pCR).

Methods: We prospectively analyzed 73 patients who underwent pre- and post-NAT CBBCT, of whom 41 also received paired magnetic resonance imaging (MRI). Inter-modality and imaging-pathology concordance were assessed using Cohen's κ statistics. Determinants of CBBCT accuracy were identified through univariate and logistic regression analyses. Receiver operating characteristic (ROC) analysis with DeLong's test was used to determine the optimal quantitative parameter for discriminating pCR from non-pCR. Associations between pCR and changes in calcification, vascularity, and background parenchymal enhancement (BPE) were evaluated using Pearson's χ² and Fisher's exact tests.

Results: CBBCT showed excellent agreement with MRI (κ = 0.809) and good pathological concordance (κ = 0.618; MRI κ = 0.700). The area under the curve (AUC) for distinguishing responders from non-responders was 0.950 for CBBCT and 0.905 for MRI. For pCR assessment, the AUC values were 0.643 and 0.786, respectively. Targeted therapy (odds ratio [OR] = 0.059, p = 0.013) and linear/segmental calcifications (OR = 0.127, p = 0.042) were independent factors affecting CBBCT accuracy. The enhanced degree change (ΔE) on CBBCT demonstrated strong predictive performance for pCR (AUC = 0.941) with high computational efficiency. Significant associations with pCR were observed for reductions in calcification extent (p = 0.021), adjacent vascular sign (AVS) grade (p = 0.004), and BPE levels (p = 0.001).

Conclusion: CBBCT demonstrates high accuracy in assessing NAT response, with excellent agreement to MRI. ΔE is recommended as an optimal quantitative parameter for predicting pCR, supported by dynamic changes in calcification extent, AVS, and BPE grade as valuable markers, positioning CBBCT as a comprehensive tool for breast cancer management.

Clinical relevance statement: CBBCT enables a comprehensive and efficient tool for monitoring NAT response, showing excellent concordance with MRI, and its multidimensional features are also valuable for predicting pCR.

Background: Neighborhood socioeconomic deprivation is a recognized contributor to disparities in breast cancer outcomes, yet the biological mechanisms linking neighborhood context to tumor behavior remain poorly defined. The conserved transcriptional response to adversity (CTRA), characterized by upregulation of pro-inflammatory genes and downregulation of type I interferon and antibody-related genes, may represent a stress-related immune dysregulation pathway relevant to cancer aggressiveness and survival.

Methods: We examined associations among the Area Deprivation Index (ADI), CTRA gene expression profiles, tumor characteristics, and survival outcomes across two cohorts. Cohort 1 included 467 breast cancer patients treated at M.D. Anderson Cancer Center, with RNA-seq data from peripheral leukocytes used to evaluate associations of ADI with CTRA and tumor characteristics at baseline. Cohort 2 comprised 1082 TCGA breast cancer patients with RNA-seq data from tumor tissue analyzed to assess the prognostic relevance of CTRA. CTRA scores were calculated using established gene signatures. Multivariable regression and Cox proportional hazards models were applied.

Results: In Cohort 1, higher ADI was significantly associated with elevated CTRA and pro-inflammatory gene expression in leukocytes (ρ = 0.082, p = 0.01). These immune profiles correlated with ER-negative status, stage III disease, and poor tumor differentiation. In TCGA (Cohort 2), elevated tumor CTRA expression was independently associated with worse overall survival (HR = 1.36, 95% CI: 1.04, 1.78, p = 0.02).

Conclusions: These findings suggest that neighborhood socioeconomic disadvantage may influence systemic immune regulation through stress-related transcriptional responses, which in turn contribute to tumor aggressiveness and survival disparities in breast cancer.

Background: Breast cancer, strongly associated with female hormones, peaks around perimenopause in Asia, versus post-menopause in Western countries. This study aims to investigate longitudinal changes in reproductive hormones and mammographic density (MD) through the menopausal transition (MT), as MD serves as both a strong breast cancer risk factor and a proxy marker of cumulative hormone exposure.

Methods: This longitudinal study included 4,737 Korean women who were in the premenopausal stage at baseline. MD was measured using digital mammography and analyzed with LIBRA software. Mean of craniocaudal views from both breasts were used for density assessments. A subset of 255 women with samples collected at four visits was assayed for hormone measurements across menopausal stages. Linear mixed-effects models were used to analyze longitudinal changes in reproductive hormones, including follicle-stimulating hormone (FSH), estradiol (E2), and anti-Müllerian hormone (AMH), and MD to evaluate potential interaction by obesity status.

Results: For MD analyses, the mean age of participants was 41.0 (± 3.3) years, with a median follow-up of 7.0 years (IQR 4.1-9.1). For hormone analyses, the mean age was 45.9 (± 2.4) years, with a median follow-up of 6.1 years (IQR 5.8-6.9). As menopausal stage advanced, FSH increased, whereas AMH and E2 decreased. The association between E2 and menopausal stages differed by obesity (P for interaction = 0.016); in early transition, E2 increased in the non-obese group (14.53 [95% CI: -15.68, 44.75]) but decreased in the obese group (- 86.02 [95% CI: -151.05, - 21.00]). Similarly, MD changes across the MT varied by BMI category (P for interaction < 0.001); overall, mean MD decreased with advancing stages, but an increasing MD pattern was observed during early transition in the underweight group (1.69 [95% CI: -0.08, 3.46]).

Conclusions: In Korean women undergoing MT, transient increases in MD paralleled E2 elevations, particularly in non-obese women. These findings align with the peak breast cancer incidence in Korean women in their 40s, preceding menopause, and the importance of considering hormonal and MD dynamics, as well as BMI, in breast cancer risk assessment and screening strategies for Asian women.

Background: The risk of breast cancer has been associated with various lifestyle factors, yet the evidence regarding how lifestyle modifications affect this risk remains limited. This study examines the relationship between changes in the Healthy Lifestyle Index (HLI) and postmenopausal breast cancer risk in women participating in the European Prospective Investigation into Cancer (EPIC).

Methods: HLI scores (ranging from 0 to 16) were computed based on smoking habits, alcohol consumption, body mass index (BMI), and physical activity levels, using data from baseline and follow-up questionnaires, which were separated by a median interval of 10  (IQR: 5.2-12.0) years. Among the 125,746 women included in the analyses, 2,175 developed breast cancer over a median follow-up period of nearly 4  (IQR: 2.9-8.4) years starting from the date of the second lifestyle questionnaire. Cox proportional hazards models were employed to estimate hazard ratios (HRs) and confidence intervals (CIs) for the relationship between changes in HLI and postmenopausal breast cancer risk, analysed both overall and by estrogen receptor (ER) status. Individual components of the HLI were also analysed, with sensitivity analyses addressing potential reverse causation by delaying the start of follow-up by 1 to 3 years.

Results: Each unit increase in the HLI-reflecting a healthier lifestyle-was not associated with the overall risk of postmenopausal breast cancer. Among individual components, only a one-unit increase in the BMI score, corresponding to a shift towards a healthier BMI, was inversely associated with overall (HR = 0.936; 95% CI 0.880-0.996) and ER-positive (HR = 0.930; 95% CI 0.865-1.000) postmenopausal breast cancer risks.

Conclusions: Lifestyle changes, as measured by the HLI, during mid-adulthood were not significantly associated with the risk of postmenopausal breast cancer. More specifically, the results of this study suggested that a shift towards a healthier BMI may contribute to breast cancer prevention. Further research involving diverse and larger study populations and lifestyle assessments at earlier life stages could provide deeper insights.