NPJ Breast Cancer最新文献

Cancer research emphasises early detection, yet quantitative methods for normal tissue analysis remain limited. Digitised haematoxylin and eosin (H&E)-stained slides enable computational histopathology, but artificial intelligence (AI)-based analysis of normal breast tissue (NBT) in whole slide images (WSIs) remains scarce. We curated 70 WSIs of NBTs from multiple sources and cohorts with pathologist-guided manual annotations of epithelium, stroma, and adipocytes (https://github.com/cancerbioinformatics/OASIS). We developed robust convolutional neural network (CNN)-based, patch-level classification models, named NBT-Classifiers, to tessellate and classify NBTs at different scales. Across three external cohorts, NBT-Classifiers trained on 128 × 128 µm and 256 × 256 µm patches achieved AUCs of 0.98-1.00. The model learned independent normal features different from those of precancerous and cancerous epithelium, which were further visualised using two explainable AI techniques. When integrated into an end-to-end preprocessing pipeline, NBT-Classifiers facilitate efficient downstream analysis within peri-lobular regions. NBT-Classifiers provide robust compartment-specific analytical tools and enhance our understanding of NBT appearances, which serve as valuable reference points for identifying premalignant changes and guiding early breast cancer prevention strategies.

HER2-low breast cancer (IHC 1+ or 2+ without HER2 gene amplification) is a distinct and understudied subtype. In a cohort of 14,593 early-stage breast cancer patients treated at MD Anderson from 2006 to 2019, 60.4% were HER2-low. Multivariable analysis showed HER2-low status was independently associated with race, histologic subtype, higher nuclear grade and stage, and estrogen receptor (ER) positivity. Among 2464 patients receiving neoadjuvant chemotherapy, HER2-low status was not linked to pathologic complete response (pCR), overall survival (OS), or disease-free survival (DFS) compared to HER2-0 tumors. Factors predicting pCR included nuclear grade III, stage I, invasive ductal carcinoma, lower ER/PR expression, and absence of lymphovascular invasion (LVI). Patients with TNBC had significantly higher pCR rates (31.9%) than those with luminal type (2.2%, p < 0.0001). Longer OS and DFS were associated with non-White race, lower stage and grade, negative LVI, and higher ER/PR levels. These findings confirm HER2-low status is common but not independently prognostic for response or survival.

Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma, frequently characterized by estrogen receptor alpha (ERα) negativity and limited treatment options. Our previous research showed that the second ER subtype, ERβ, is associated with reduced metastasis in IBC patients and xenografts. We linked its anti-metastatic function to the inhibition of actin-based cell migration and Rho GTPase signaling. In this study, we employed a genomics approach to fully delineate the signaling underlying the anti-metastatic activity of ERβ. By cross-examining responsive mRNAs and miRNAs against chromatin binding sites in IBC cells with agonist-activated transfected and endogenous ERβ, we identified key regulatory binding motifs, direct targets, and associated biological functions. Our findings implicate pathways in development, metabolism and tumor microenvironment in the anti-metastatic action of ERβ. Clinical dataset analysis associates downstream factors with patient outcomes, indicating new molecules with therapeutic potential and highlighting the relevance of tumor repressive ERβ signaling in breast cancer.

Tumoral BRCA1 promoter methylation occurs frequently in triple-negative breast cancer (TNBC) and contributes to homologous recombination deficiency (HRD). While constitutional BRCA1 methylation has been described, its relationship with tumoral methylation, genomic instability, and prognosis remains unclear. Paired tumor and blood samples from 136 TNBC patients (SCANDARE, NCT03017573) were analyzed for BRCA1 methylation, genomic alterations, HRD and outcomes. Constitutional BRCA1 methylation was detected in 20.6% of patients and tumoral methylation in 31.6%, including 11.5% with somatic-only methylation. In cases with constitutional BRCA1 methylation, tumoral methylation levels increased markedly, with 89% of high-methylation tumors (≥50%) associated with a Loss of Heterozygoty. Tumors with BRCA1 promoter methylation consistently exhibited high HRD (Homologous Recombination Deficiency) scores, comparable to those with pathogenic HRR (Homologous Recombination Repair) gene pathogenic variants (p < 0.001). Conversely, HRD was rare in tumors lacking both BRCA1 methylation and HRR gene alterations. Prognostically, constitutional BRCA1 methylation tended to associate with improved survival, while somatic-only methylation showed a trend toward poorer outcomes (p = 0.06). Constitutional BRCA1 methylation is associated with a high level of tumoral BRCA1 promoter methylation and HRD in TNBC. These findings support integrating constitutional and tumoral BRCA1 methylation into HRD assessment to improve patient stratification and precision treatment in TNBC.

This study aimed to investigate the clinicopathological characteristics, response to chemotherapy, and clinical outcomes according to estrogen receptor (ER) expression levels in breast cancer (BC) patients treated with neoadjuvant chemotherapy (NAC). ER expression levels were categorized as ER-negative (expression in <1% of tumor cells), ER-low positive (1-10%), ER-intermediate positive (11-50%), and ER- high positive (>50%). Of the 1,365 cases, 647 (47.4%) were classified as ER-negative, 49 (3.6%) as ER- low positive, 48 (3.5%) as ER-intermediate positive, and 621 (45.5%) as ER-high positive BCs in pre-NAC biopsies. ER-intermediate positive tumors as well as ER-low positive tumors showed no differences in clinicopathological characteristics compared to ER-negative tumors with the exception of progesterone receptor positivity. While ER-low positive and ER-negative tumors showed similar chemo-responsiveness, ER-intermediate positive tumors were less responsive to NAC compared to ER-negative tumors. In patients with residual disease, pre- and post-NAC ER expression levels were found to be independent prognostic factors, but with no significant differences among ER-negative, ER-low positive, and ER-intermediate positive tumors. Our study indicates that ER-low positive BCs are similar to ER-negative BCs and that ER-intermediate positive BCs exhibit characteristics heterogeneous between ER-negative and ER-high positive BCs in terms of clinicopathological characteristics, chemo-responsiveness, and clinical outcomes.

Immune surveillance plays a pivotal role in controlling tumor emergence, dormancy and progression, including in breast cancer. Despite its potential clinical relevance, the mechanisms governing dormancy initiation, maintenance and escape, as well as the molecular mediators involved, remain poorly understood. Here, we identify the interferon-inducible chemokine CXCL10 and its receptor CXCR3 as key regulators of immunological dormancy in triple-negative breast cancer (TNBC). By transcriptomic profiling, we observed high expression of Cxcl10 in dormant cells in two different orthotopic, syngeneic models of breast cancer dormancy (D2.0R and 4T1-MR20). Genetic silencing of Cxcl10 in dormant cells or pharmacological blockade of CXCR3 in vivo led to early tumor onset and rapid growth in immunocompetent mice. In contrast, dormant cells effectively formed tumors in immune-deficient mice independently of Cxcl10 status, demonstrating that the CXCL10/CXCR3 axis-mediated dormancy requires a functional immune system. Further analysis confirmed that Cxcl10 silencing altered the local immune microenvironment, reducing CD4⁺ and CD8⁺ T cell infiltration while increasing the presence of granulocytic Myeloid Derived Suppressor Cells and Natural Killer cells. Moreover, Cxcl10 silencing significantly increased the burden of tumor cells disseminated to the lung. Leveraging these findings, we identified a CXCL10-mediated dormancy signature that predicts improved overall survival in TNBC patients. Our findings have identified a new mechanism modulating breast cancer dormancy with two important clinical implications: the CXCL10/CXCR3 axis as a potential therapeutic target for improving survival of patients with TNBC, and the CXCL10-dependent dormancy signature as a tool for identifying these patients.

Circulating tumor DNA (ctDNA) has potential as a prognostic factor for predicting relapse in high-risk breast cancer (BC). This study investigates the utility of ctDNA assessment using a tumor-informed assay, in patients with high-risk BC treated with neoadjuvant chemotherapy (NAC). Thirty newly diagnosed patients with various high-risk BC subtypes participated, providing serial blood samples at multiple time points, including baseline, during NAC, and during follow-up. ctDNA was detected at baseline in 29/29 patients for whom an assay panel could be designed, with detection sensitivity reaching 0.0083% (variant allele frequency). Among patients with detectable baseline ctDNA, 94% showed clearance during treatment, correlating with improved outcomes. Additionally, ctDNA detection post-surgery or during follow-up predicted disease recurrence. These findings suggest that serial ctDNA monitoring throughout NAC and follow-up can effectively identify residual disease in BC and correlate with clinical outcomes.

Inflammatory breast cancer (IBC) is an aggressive subtype with early metastatic spread. This study evaluated whether adding adjuvant radiation therapy (RT) to surgery and chemotherapy improves survival in metastatic IBC using the National Cancer Database (2010-2021). A total of 3219 patients were categorized into four groups: chemotherapy alone; chemotherapy plus surgery; chemotherapy plus RT; and trimodality therapy (chemotherapy and surgery followed by RT). Median follow-up was 23.6 months. Two-year overall survival was 51.8% (chemotherapy alone), 57.8% (chemotherapy + surgery), 36.5% (chemotherapy + RT), and 73% (trimodality therapy). Compared with chemotherapy + surgery, chemotherapy alone and chemotherapy + RT were associated with higher mortality, while adding adjuvant RT after chemotherapy + surgery (trimodality therapy) was not associated with improved survival. In subgroup analysis, adding PMRT to surgery and chemotherapy in those with positive surgical margins was associated with improved survival compared with surgery and chemotherapy alone, adjusting for age (aHR 0.57; 95% CI: 0.34-0.97). Further research is needed to understand the role of local therapy in metastatic IBC.

The sub-study of the INSEMA trial (randomization-2) compares completion axillary lymph node dissection (cALND) with sentinel lymph node biopsy (SLNB) alone in cN0 patients with T1/T2 invasive breast cancer and one to three sentinel node macrometastases undergoing upfront breast-conserving surgery. The key secondary objective is to assess whether the SLNB-alone arm is non-inferior to cALND in terms of invasive disease-free survival (iDFS). Finally, 485 patients were recruited, and 386 patients (cALND: N = 169, SLNB alone: N = 217) were included in the per-protocol set. The median follow-up is 74.2 months. The 5-year iDFS analysis in the per-protocol set demonstrates a non-significant difference between study arms, with a hazard ratio (HR) of 1.69 (95% CI: 0.98-2.94) for SLNB alone compared to cALND. The 5-year iDFS rates are 86.6% (81.0%-90.7%) in the SLNB-alone arm and 93.8% (88.7%-96.6%) in the cALND arm (P = 0.058). The 5-year overall survival rates are 94.9% (90.6%-97.2%) in the SLNB-alone arm and 96.2% (91.7%-98.3%) in the cALND arm (P = 0.663). Locoregional recurrences (LRR) were infrequent, with 5-year incidence rates of 1.1% versus 0.0% (P = 0.405) in the SLNB-alone arm compared to cALND. In summary, no significant differences were observed between SLNB alone versus cALND for iDFS, overall survival, and LRR. Trial registration number: NCT02466737.