Background:Occult breast cancer (OBC) presents with axillary lymph node (ALN) metastases without detectable primary tumor (PT) yet exhibits paradoxically favorable prognosis compared to non-occult breast cancer (non-OBC). We aimed to elucidate mechanisms underlying PT clearance by integrating multi-omics approaches to characterize the unique immune landscape. Methods:Survival outcomes were validated using the Surveillance, Epidemiology, and End Results (SEER) database (n=12,162) with propensity score matching (PSM). Molecular features were characterized via quantitative proteomics, while immune landscapes were assessed using bulk transcriptomics. Single-cell RNA sequencing (scRNA-seq) and CellChat analysis dissected cellular heterogeneity and intercellular communication within tumor microenvironment. Results:Survival analysis confirmed OBC patients have survival comparable to T1N+M0 but significantly better than T2-3N+M0 breast cancer (BC) patients. Proteomic profiling identified B cell-related pathway upregulation in OBC lymph nodes (LN). Transcriptomics revealed enriched B cell infiltration in T1 tumors correlating with improved survival. scRNA-seq further demonstrated that B cells in T1 tumors act as central hubs in intercellular communication. These cells orchestrate a robust anti-tumor response via multi-faceted secretory signals (e.g., tumor necrosis factor, TNF; B-cell activating factor, BAFF) and contact-dependent interactions (e.g., CD40; major histocompatibility complex, MHC), effectively recruiting and activating immune effectors. Conclusion:Our findings suggest that B cell-mediated immune surveillance may be a key mechanism contributing to the clearance of PT in OBC. These exploratory results underscore the potential of B cells as prognostic biomarkers and therapeutic targets in BC, pending functional validation in larger cohorts.

BACKGROUND:Occult breast cancer (OBC) is defined as axillary lymph node metastasis without any evidence of a primary tumor in the breast. Because of the limited number of clinical cases, the clinicopathological features and treatment recommendations of OBC are still controversial. In addition, its natural history is poorly understood and its proteomic signature remains unknown. MATERIALS AND METHODS:We compared the clinicopathological features and prognosis of OBC patients and Non-OBC patients from the Surveillance, Epidemiology, and End Results (SEER) database and analyzed the effects of local treatment on the survival outcomes of OBC patients. Additionally, we performed a quantitative proteomic analysis for tissue samples of metastatic lymph nodes from OBC patients (OBC-LN), and paired tissue samples of metastatic lymph nodes (Non-OBC-LN) and primary tumors (Non-OBC-PT) from Non-OBC patients. We identified differentially expressed proteins in different comparable groups using Student's t test. Functional enrichment and protein-protein interaction network analyses were used to interpret the functions and interactions of the differentially expressed proteins in the comparison of OBC-LN vs Non-OBC-LN. Immunohistochemistry was used for the validation of the hub proteins. RESULTS:Analysis of data from the SEER database demonstrated that OBC patients had a better prognosis than Non-OBC patients did and that either mastectomy or radiation therapy improved the outcomes of OBC patients. A total of 7208 comparable proteins were successfully quantified. Compared with those of the Non-OBC-LN samples, the OBC-LN protein profiles exhibited an active extracellular matrix and a thoroughly upregulated epithelial-mesenchymal transition phenotype. COL1A1, COL1A2, COL3A1, MMP2 and LUM were overexpressed in the OBC-LN samples and were identified as hub proteins. Immunohistochemical staining demonstrated that the five hub proteins were overexpressed in OBC-LN samples. CONCLUSION:Our results provide insights for the clinical management of OBC and the proteomic signature of OBC offers molecular basis for further biological research.

PurposeThis study aimed to investigate the factors associated with pathologic node-negativity (ypN0) in patients who received neoadjuvant chemotherapy (NAC) to develop and validate an accurate prediction nomogram.MethodsThe CSBrS-012 study (2010–2020) included female patients with primary breast cancer treated with NAC followed by breast and axillary surgery in 20 hospitals across China. In the present study, 7,711 eligible patients were included, comprising 6,428 patients in the primary cohort from 15 hospitals and 1,283 patients in the external validation cohort from five hospitals. The hospitals were randomly assigned. The primary cohort was randomized at a 3:1 ratio and divided into a training set and an internal validation set. Univariate and multivariate logistic regression analyses were performed on the training set, after which a nomogram was constructed and validated both internally and externally.ResultsIn total, 3,560 patients (46.2%) achieved ypN0, and 1,558 patients (20.3%) achieved pathologic complete response in the breast (bpCR). A nomogram was constructed based on the clinical nodal stage before NAC (cN), ER, PR, HER2, Ki67, NAC treatment cycle, and bpCR, which were independently associated with ypN0. The area under the receiver operating characteristic curve (AUC) for the training set was 0.80. The internal and external validation demonstrated good discrimination, with AUCs of 0.79 and 0.76, respectively.ConclusionWe present a real-world study based on nationwide large-sample data that can be used to effectively screen for ypN0 to provide better advice for the management of residual axillary disease in breast cancer patients undergoing NAC.

Hyperparathyroidism (HPT) manifests as a complex condition with a substantial disease burden. While advances have been made in surgical interventions and non-surgical pharmacotherapy for the management of hyperparathyroidism, radical options to halt underlying disease progression remain lacking. Identifying putative genetic drivers and exploring novel drug targets that can impede HPT progression remain critical unmet needs. A Mendelian randomization (MR) analysis was performed to uncover putative therapeutic targets implicated in hyperparathyroidism pathology. Cis-expression quantitative trait loci (cis-eQTL) data serving as genetic instrumental variables were obtained from the eQTLGen Consortium and Genotype-Tissue Expression (GTEx) portal. Hyperparathyroidism summary statistics for single nucleotide polymorphism (SNP) associations were sourced from the FinnGen study (5590 cases; 361,988 controls). Colocalization analysis was performed to determine the probability of shared causal variants underlying SNP-hyperparathyroidism and SNP-eQTL links. Five drug targets (CMKLR1, FSTL1, IGSF11, PIK3C3 and SLC40A1) showed significant causation with hyperparathyroidism in both eQTLGen and GTEx cohorts by MR analysis. Specifically, phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) and solute carrier family 40 member 1 (SLC40A1) showed strong evidence of colocalization with HPT. Multivariable MR and Phenome-Wide Association Study analyses indicated these two targets were not associated with other traits. Additionally, drug prediction analysis implies the potential of these two targets for future clinical applications. This study identifies PIK3C3 and SLC40A1 as potential genetically proxied druggable genes and promising therapeutic targets for hyperparathyroidism. Targeting PIK3C3 and SLC40A1 may offer effective novel pharmacotherapies for impeding hyperparathyroidism progression and reducing disease risk. These findings provide preliminary genetic insight into underlying drivers amenable to therapeutic manipulation, though further investigation is imperative to validate translational potential from preclinical models through clinical applications.

Abstract Background The use of systematic treatment for tubular carcinoma (TC) of the breast remained controversial. This study aimed to explore the efficacy of chemotherapy on TC to develop individualized treatment strategies. Methods Using the Surveillance, Epidemiology, and End Results (SEER) database, 6486 eligible cases with TC and 309,304 with invasive ductal carcinoma (IDC) were collected. Breast cancer‐specific survival (BCSS) was assessed through multivariable Cox analyses and Kaplan–Meier analyses. Differences between groups were balanced using propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). Results Compared with IDC patients, TC patients had a more favorable long‐term BCSS after PSM (hazard ratio = 0.62, p = 0.004) and IPTW (hazard ratio = 0.61, p < 0.001). Chemotherapy was an unfavorable predictor of BCSS for TC (hazard ratio = 3.20, p < 0.001). After stratifying by hormone receptor (HR) and lymph node (LN) status, chemotherapy was correlated with worse BCSS in the HR+/LN− subgroup (hazard ratio = 6.95, p = 0.001) but showed no impact on BCSS in the HR+/LN+ (hazard ratio = 0.75, p = 0.780) and HR−/LN− (hazard ratio = 7.87, p = 0.150) subgroups. Conclusions Tubular carcinoma is a low‐grade malignant tumor with favorable clinicopathological features and excellent long‐term survival. Adjuvant chemotherapy was not recommended for TC regardless of HR and LN status, while the therapy regimens should be carefully individualized.

Background Chemoresistance is problematic and its mechanisms are unclear in breast cancer. More predictive markers are urgently required. Methods GSE32646, GSE34138, and GSE20271 were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) between chemosensitive and chemoresistant tumors. LinkedOmics was used to analyze ADAM-like Decysin-1 (ADAMDEC1) expression among patients with different clinical characteristics and detect co-expression genes for functional analysis. Tumor Immune Estimation Resource (TIMER) and an integrated repository portal for tumor-immune system interactions (TISIDB) were used to investigate the association between the target gene and the immune response. Gene Set Cancer Analysis (GSCA) was utilized to explore the related pathways of ADAMDEC1 and evaluate the correlation between the expression of ADAMDEC1 and drug sensitivity. RNA22, miRWalk, and miRmap were used to predict the upstream micro ribonucleic acids (miRNAs) regulating ADAMDEC1 expression, while DIANA-LncBase v2 was applied to predict the upstream long non-coding ribonucleic acids (lncRNAs). Kaplan-Meier curve analysis was applied to determine the survival time. Results We identified that ADAMDEC1 was upregulated among chemosensitive triple-negative breast cancer (TNBC) tissues in GSE32646, GSE34138, and GSE20271. Higher expression of ADAMDEC1 indicated longer survival in breast cancer. Next, we found that ADAMDEC1 was significantly related to the immune response in breast cancer through functional enrichment analysis and further meta-data validation. Moreover, we recognized that hsa-miR-4534 was the potential upstream miRNA regulating ADAMDEC1 expression and Taurine Up-Regulated 1 (TUG1) was the most likely upstream lncRNA of ADAMDEC1 and hsa-miR-4534. Finally, the correlation between ADAMDEC1 and chemosensitivity was confirmed through drug database analysis. Conclusions Elevated ADAMDEC1 expression is associated with increased chemosensitivity and better prognosis in breast cancer patients.

Abstract Background The efficacy of breast reconstruction for patients with N2‐3M0 stage female breast cancer (FBC) remained unclear due to the lack of randomized clinical trials. This retrospective study aimed to explore the efficacy of breast reconstruction for patients with N2‐3M0 stage FBC. Methods Two thousand five hundred forty‐five subjects with FBC staged by N2‐3M0 from 2010 to 2016 were retrieved from the Surveillance, Epidemiology, and End Results database. Generalized boosted model (GBM) and propensity score matching (PSM) analyses and multivariable Cox analyses were employed to assess the clinical prognostic effect of postmastectomy reconstruction for patients with N2‐3M0 stage FBC in breast cancer‐specific survival (BCSS). Results Totally, 1784 candidates underwent mastectomy alone (mastectomy group), and 761 candidates underwent postmastectomy reconstruction (PMbR group), with 418 breast‐specific deaths after a median follow‐up time of 57 months (ranging from 7 to 227 months). BCSS in the mastectomy group showed no statistical difference from that in the PMbR group in the PSM cohort (HR = 0.93, 95% CI: 0.70–1.25, p = 0.400) and GBM cohort (HR = 0.75, 95% CI: 0.56–1.01, p = 0.057). In the multivariate analyses, there was no difference in the effect of PMbR and mastectomy on BCSS in the original cohort (HR = 0.85, 95% CI: 0.66–1.09, p = 0.197), PSM cohort (HR = 0.86, 95% CI: 0.64–1.15, p = 0.310), and GBM cohort (HR = 0.84, 95% CI: 0.61–1.17, p = 0.298). Triple‐negative breast cancer (TNBC) was a detrimental factor affecting BCSS for patients in the PMbR group. Conclusions Our study demonstrated that PMbR is an oncologically safe surgical treatment and can be widely recommended in clinics for females with non‐TNBC staged by T0‐3N2‐3M0.

Background: Hyperparathyroidism (HPT) manifests as a complex condition with a substantial disease burden. While advances have been made in surgical interventions and non-surgical pharmacotherapy for the management of hyperparathyroidism, radical options to halt underlying disease progression remain lacking. Identifying putative genetic drivers and exploring novel drug targets that can impede HPT progression remain critical unmet needs.Methods: A Mendelian randomization (MR) analysis was performed to uncover putative therapeutic targets implicated in hyperparathyroidism pathology. Cis-expression quantitative trait loci (cis-eQTL) data serving as genetic instrumental variables were obtained from the eQTLGen Consortium and GTEx portal. Hyperparathyroidism summary statistics for single nucleotide polymorphism (SNP) associations were sourced from the FinnGen study (5,590 cases; 361,988 controls). Colocalization analysis was performed to determine the probability of shared causal variants underlying SNP-hyperparathyroidism and SNP-eQTL links.Results: Five drug targets (CMKLR1, FSTL1, IGSF11, PIK3C3 and SLC40A1) showed significant causation with hyperparathyroidism in both eQTLGen and GTEx cohorts by MR analysis. Specifically, phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) and solute carrier family 40 member 1 (SLC40A1) showed strong evidence of colocalization with HPT. Multivariable MR and PheWAS analyses indicated these two targets were not associated with other traits. Additionally, drug prediction analysis implies the potential of these two targets for future clinical applications.Conclusion: This study identifies PIK3C3 and SLC40A1 as potential genetically proxied druggable genes and promising therapeutic targets for hyperparathyroidism. Targeting PIK3C3 and SLC40A1 may offer effective novel pharmacotherapies for impeding hyperparathyroidism progression and reducing disease risk. These findings provide preliminary genetic insight into underlying drivers amenable to therapeutic manipulation, though further investigation is imperative to validate translational potential from preclinical models through clinical applications.Funding: This study was funded by The National Natural Science Foundation of China (NSFC; no. 26 82003183, to N. Hao; Key R & D program in Shaanxi Province of China (Program No. 2022SF-080).Declaration of Interest: All authors declare no conflict of interest.

Background:Due to the loss of prediction of overall survival (OS) for patients with invasive micropapillary carcinoma (IMPC) after breast-conserving surgery (BCS), this study aimed to construct a nomogram for predicting OS in IMPC patients after BCS. Methods:In total, 481 eligible cases staged 0-III IMPC from 2000 to 2016 were retrieved from the SEER database. A nomogram was built based on the variables selected by LASSO regression to predict the 3-year and 5-year probabilities of OS. Results:A total of 336 patients were randomly assigned to the training cohort and 145 cases in the validation cohort. The LASSO regression revealed that six variables (age at diagnosis, AJCC stage, marital status, ER status, PR status, and chemotherapy) were predictive variables of OS, and then a nomogram model and an easy-to-use online tool were constructed. The C-indices 0.771 in the training cohort and 0.715 in the validation cohort suggested the robustness of the model. The AUC values for 3-year and 5-year OS in the training cohort were 0.782, 0.790, and 0.674, and 0.682 in the validation cohort, respectively. Based on the cutoff values of 147.23 and 222.44 scores calculated by X-tile analysis, participants in the low-risk group (≤147.23 scores) had a more favorable OS in comparison with those in the medium (>147.23, but <222.44 scores)- and high-risk groups (≥222.44 scores). Conclusions:By risk stratification, this model is expected to provide a precise and personalized prediction of the cumulative risk and guide treatment decision-making in improving OS strategies for IMPC patients.