Breast Cancer Research最新文献

Background: Metastatic disease is the main cause of breast cancer (BC)-related deaths, but prediction of metastases remains challenging especially in the large and diverse group with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative tumors. Molecular tumor features beyond currently used markers could provide important information for stratifying metastatic risk. To allow for the discovery of new subtypes and molecular tumor features associated with metastatic spread, i.e., both lymph node and distant metastases, we here leverage advances in proteomic profiling of tumors.

Methods: We developed a protocol for proteome and phosphoproteome analysis using label-free data independent acquisition (DIA) liquid chromatography tandem mass spectrometry (LC-MS/MS) and integrated the generated data with parallel transcriptome data for the profiling of 182 ER-positive, HER2-negative primary BC tumors from the SCAN-B cohort.

Results: A total of 13,571 protein groups, 7107 phosphopeptides and 13,085 expressed genes were quantified in at least 70% of the samples. The data showed clear differences between invasive lobular carcinoma and no special type cancers, including the hallmark loss of E-cadherin expression and differences in catenin levels. We identified potential new subtypes with differential immune infiltration patterns and survival through unsupervised consensus clustering. Additionally, by adopting an integrative, multiomic data analysis workflow, we identified several potential protein markers of both lymph node and distant metastases. For lymph node metastasis, the level of phosphorylated ES8L2 serine at position 570 (multivariable p value = 0.05, HR = 0.61, 95% CI 0.38-0.99) was associated with improved recurrence-free survival, and showed decreased abundance in lymph node positive cases. For distant metastases, on the other hand, proteins belonging to the heat shock protein 90 family were associated with worse distant recurrence-free survival (multivariable p value = 0.0058, HR = 2.10, 95% CI 1.24-3.55), with significantly higher abundance levels in patients with a distant recurrence event. These correlations with survival could also be validated in multiple external cohorts.

Conclusions: In summary, we present the most comprehensive matched multiomic dataset from ER-positive/HER2-negative BC tumors, not only serving as an invaluable resource for further advancing precision medicine but also allowing the discovery of potential biomarkers and providing unique insights into metastatic processes.

Trial registration: Sweden Cancerome Analysis Network-Breast: Genomic Profiling of Breast Cancer (SCAN-B), beginning 2010-08, NCT02306096.

Background: Midkine is a heparin-binding growth factor that is overexpressed in most human malignancies, including breast cancer. While elevated midkine levels have been associated with tumor progression and aging, its role as a predictive biomarker for breast cancer risk in healthy individuals remains unclear. We previously showed that higher midkine expression in estrogen receptor-positive (ER +) breast cancer in younger (< 55) women is associated with shorter disease-free survival. We investigated whether serum midkine levels in premenopausal women are associated with subsequent risk of ER + breast cancer.

Methods: We conducted a prospective, nested case-control study within the New York University Women's Health Study (NYUWHS). Serum midkine levels were measured in baseline blood samples from 249 premenopausal women who developed ER + breast cancer more than 10 years after blood collection and 249 matched controls. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) across quartiles and continuous midkine levels, adjusting for key breast cancer risk factors.

Results: Higher circulating midkine levels were associated with a marginally statistically significant lower risk of ER + breast cancer. Compared to the lowest quartile, women in the highest quartile had an OR of 0.55 (95% CI: 0.30-0.99; P for trend = 0.10). A doubling in midkine was associated with a 34% reduction in risk (OR = 0.66; 95% CI: 0.42-1.02). The inverse association was generally consistent across subgroups.

Conclusion: These findings suggest that higher baseline serum midkine levels in premenopausal women are associated with a reduced long-term risk of ER + breast cancer. This challenges prior assumptions about midkine's uniformly pro-tumorigenic role and suggests it may be a context-dependent biomarker in breast cancer development.

Background: Secondary lymphedema is characterized by limb swelling following lymphatic disruption. This results in decreased lymph flow through the collecting ducts and dermal backflow in the subdermal lymphatics. The role of dermal lymphatics in the development of lymphedema is poorly understood. The purpose of this study is to evaluate the effect of dermal lymphatic preservation in the development of lymphedema in a murine tail experimental model.

Methods: A standard murine lymphedema tail model was used as the study control. A 3 mm circumferential excision was performed 20 mm from the base of the tail. Both collecting lymphatics adjacent to the veins were transected (Full Dermal Disruption (FDD), control, n = 6). The experimental group was a modification of the standard model consisting of two hemi circumferential skin excision and collecting lymphatics transection with 3 mm interval (Partial Dermal Disruption (PDD), experimental, n = 8) maintaining continuity of capillary lymphatics. Tail volume measurements, lymphatic clearance with near Infrared Indocyanine Green (ICG) laser lymphangiography, and histology were assessed.

Results: The PDD group had lower tail volumes compared to FDD till day 28 (p < 0.001). ICG lymphangiography demonstrated better lymphatic clearance in the PDD when compared to FDD (p < 0.001). Reduced dermal thickness (p = 0.004) and collagen deposition (p = 0.008) were observed in PDD. Podoplanin-positive lymphatic vessel density was higher in PDD at the unadjusted level (p = 0.014) but did not meet Bonferroni-corrected significance (α = 0.010).

Conclusion: This study demonstrates dermal lymphatics can preserve lymphatic function despite injury to transporting lymphatic channels. Dermal lymphatics may have the potential for lymphedema prevention at the lymphatic injury site.

Background: Inflammatory breast cancer (IBC) is a rare but aggressive subtype of breast cancer characterized by rapid progression and poor prognosis. Despite its distinct clinical presentation and molecular features, the immune landscape of IBC and its potential role in driving the aggressive phenotype remain poorly understood. This study aimed to characterize the spatial immune landscape of IBC, compare it with that of subtype-matched non-inflammatory breast cancer (nIBC), and evaluate the prognostic implications of immune cell composition and localization.

Methods: We analyzed pre-treatment tumor samples from 161 IBC and 115 subtype-matched nIBC patients using immunohistochemistry (IHC) for CD8, FOXP3, CD79α, CD163, and PD-L1. Digital image analysis quantified the immune cell density and relative marker area in the tumor area (TA) and invasive margin (IM). Associations with clinicopathological features, pathological response to neoadjuvant chemotherapy (NACT), and survival were assessed using multivariate logistic regression and Cox proportional hazards models. Transcriptomic validation was performed using Affymetrix gene expression data and consensus TME deconvolution.

Results: IBC showed higher infiltration of CD163 + tumor-associated macrophages (TAMs) compared to nIBC. Gene expression data confirmed IHC findings, and pathway analysis linked high TAM density with inflammatory and proliferative pathways. The spatial distribution of immune cells was prognostically relevant, with high CD8 + T-cell infiltration (OR: 0.41, 95% CI: 0.22-0.76, P = 0.004) and low CD79α + B-cell infiltration (OR: 3.19, 95% CI: 1.68-6.03, P < 0.001) correlating with improved overall survival in IBC. Furthermore, the ratio of CD8+ T-cells to FOXP3+ regulatory T-cells within the TA was a significant prognostic indicator (OR: 0.34, 95% CI: 0.14-0.83, P = 0.018), whereas the absolute densities of either CD8+ or FOXP3 + T-cells alone were not associated with outcome.

Conclusions: These results highlight the immunosuppressive nature of the IBC microenvironment and the role of TAMs in promoting an aggressive IBC phenotype. Spatial context and the balance between the immune cells, rather than the overall abundance, was critical in determining outcome. Our findings underscore the importance of considering immune cell localization in prognostic assessment and support further investigation of TAM-targeted therapies in IBC.