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Radiomics offers a noninvasive avenue for predicting clinicopathological factors. However, thorough investigations into a robust breast cancer outcome-predicting model and its biological significance remain limited. This study develops a robust radiomic model for prognosis prediction, and further excavates its biological foundation and transferring prediction performance. We retrospectively collected preoperative dynamic contrast-enhanced MRI data from three distinct breast cancer patient cohorts. In FUSCC cohort (n = 466), Lasso was used to select features correlated with patient prognosis and multivariate Cox regression was utilized to integrate these features and build the radiomic risk model, while multiomic analysis was conducted to investigate the model's biological implications. DUKE cohort (n = 619) and I-SPY1 cohort (n = 128) were used to test the performance of the radiomic signature in outcome prediction. A thirteen-feature radiomic signature was identified in the FUSCC cohort training set and validated in the FUSCC cohort testing set, DUKE cohort and I-SPY1 cohort for predicting relapse-free survival (RFS) and overall survival (OS) (RFS: p = 0.013, p = 0.024 and p = 0.035; OS: p = 0.036, p = 0.005 and p = 0.027 in the three cohorts). Multiomic analysis uncovered metabolic dysregulation underlying the radiomic signature (ATP metabolic process: NES = 1.84, p-adjust = 0.02; cholesterol biosynthesis: NES = 1.79, p-adjust = 0.01). Regarding the therapeutic implications, the radiomic signature exhibited value when combining clinical factors for predicting the pathological complete response to neoadjuvant chemotherapy (DUKE cohort, AUC = 0.72; I-SPY1 cohort, AUC = 0.73). In conclusion, our study identified a breast cancer outcome-predicting radiomic signature in a multicenter radio-multiomic study, along with its correlations with multiomic features in prognostic risk assessment, laying the groundwork for future prospective clinical trials in personalized risk stratification and precision therapy. [ABSTRACT FROM AUTHOR]

Breast tumor‐initiating cells (BTICs) of triple‐negative breast cancer (TNBC) tissues actively repair DNA and are resistant to treatments including chemotherapy, radiotherapy, and targeted therapy. Herein, it is found that a previously reported secreted protein, sclerostin domain containing 1 (SOSTDC1), is abundantly expressed in BTICs of TNBC cells and positively correlated with a poor patient prognosis. SOSTDC1 knockdown impairs homologous recombination (HR) repair, BTIC maintenance, and sensitized bulk cells and BTICs to Olaparib. Mechanistically, following Olaparib treatment, SOSTDC1 translocates to the nucleus in an importin‐α dependent manner. Nuclear SOSTDC1 interacts with the N‐terminus of the nucleoprotein, chromatin helicase DNA‐binding factor (CHD1), to promote HR repair and BTIC maintenance. Furthermore, nuclear SOSTDC1 bound to β‐transducin repeat‐containing protein (β‐TrCP) binding motifs of CHD1 is found, thereby blocking the β‐TrCP‐CHD1 interaction and inhibiting β‐TrCP‐mediated CHD1 ubiquitination and degradation. Collectively, these findings identify a novel nuclear SOSTDC1 pathway in regulating HR repair and BTIC maintenance, providing insight into the TNBC therapeutic strategies. [ABSTRACT FROM AUTHOR]

Breast cancer is a highly heterogeneous disease with varied subtypes, prognoses and therapeutic responsiveness. Human leukocyte antigen class I (HLA-I) shapes the immunity and thereby influences the outcome of breast cancer. However, the implications of HLA-I variations in breast cancer remain poorly understood. In this study, we established a multiomics cohort of 1156 Chinese breast cancer patients for HLA-I investigation. We calculated four important HLA-I indicators in each individual, including HLA-I expression level, somatic HLA-I loss of heterozygosity (LOH), HLA-I evolutionary divergence (HED) and peptide-binding promiscuity (Pr). Then, we evaluated their distribution and prognostic significance in breast cancer subtypes. We found that the four breast cancer subtypes had distinct features of HLA-I indicators. Increased expression of HLA-I and LOH were enriched in triple-negative breast cancer (TNBC), while Pr was relatively higher in hot tumors within TNBCs. In particular, a higher Pr indicated a better prognosis in TNBCs by regulating the infiltration of immune cells and the expression of immune molecules. Using the matched genomic and transcriptomic data, we found that mismatch repair deficiency-related mutational signature and pathways were enriched in low- Pr TNBCs, suggesting that targeting mismatch repair deficiency for synthetic lethality might be promising therapy for these patients. In conclusion, we presented an overview of HLA-I indicators in breast cancer and provided hints for precision treatment for low- Pr TNBCs. [ABSTRACT FROM AUTHOR]

The molecular heterogeneity and distinct features of HER2-low breast cancers, particularly in the Chinese population, are not well understood, limiting its precise management in the era of antibody‒drug conjugates. To address this issue, we established a cohort of 434 Chinese patients with HER2-low breast cancer (433 female and one male) and integrated genomic, transcriptomic, proteomic, and metabolomic profiling data. In this cohort, HER2-low tumors are more distinguished from HER2-0 tumors in the hormone receptor–negative subgroup. Within HER2-low tumors, significant interpatient heterogeneity also exists in the hormone receptor–negative subgroup: basal-like tumors resemble HER2-0 disease, and non-basal-like HER2-low tumors mimic HER2-positive disease. These non-basal-like HER2-low tumors are enriched in the HER2-enriched subtype and the luminal androgen receptor subtype and feature PIK3CA mutation, FGFR4/PTK6/ERBB4 overexpression and lipid metabolism activation. Among hormone receptor–positive tumors, HER2-low tumors show less loss/deletion in 17q peaks than HER2-0 tumors. In this work, we reveal the heterogeneity of HER2-low breast cancers and emphasize the need for more precise stratification regarding hormone receptor status and molecular subtype. HER2-low breast cancer has recently been defined as a potential subtype for sensitivity to novel antibody-drug conjugates. Here, the authors analyse a multiomics cohort of 434 HER2-low patients and find an altered molecular status compared to other subtypes and the interpatient heterogeneity within this subtype. [ABSTRACT FROM AUTHOR]

Background: The germline variant spectrum of triple-negative breast cancer (TNBC) is different from that of other subtypes and has demonstrated ethnic differences. However, the germline variants of TNBC among Chinese patients and its clinical significance remain unclear.Methods: Using our multi-omics TNBC cohort (n = 325), we determined the spectrum of germline variants in TNBC and aimed to illustrate their biological and clinical implications.Results: Overall, 16.0% (52 of 325) of TNBC patients harbored at least 1 pathogenic or likely pathogenic germline variant. These germline variants were associated with early onset of TNBC, the occurrence of contralateral breast cancer, the basal-like immune-suppressed mRNA subtype, and the homologous recombination deficiency (HRD) mutation subtype. Somatic allele-specific imbalance was observed in 54.1% of these germline variants, which was correlated with early onset of breast cancer and elevated HRD. The genes BRCA1 (7.4%), RAD51D (2.8%), and BRCA2 (2.2%) were those most frequently mutated. The RAD51D germline variants, especially K91fs, were enriched in Chinese patients with TNBC compared with Caucasian and African American patients. The Chinese-specific RAD51D germline variants were functionally associated with the instability of the RAD51D protein, HRD, and sensitivity to PARP inhibitors.Conclusions: Chinese TNBC patients have a distinct spectrum of germline variants, with a remarkable impact on the clinical and molecular characteristics of the tumor. Integrative germline-somatic analysis may help identify TNBC patients who are most likely to be affected by their germline variants and in performing clinical interventions more precisely. The RAD51D variants enriched in our cohort may serve as therapeutic targets and guide precision treatment of TNBC. [ABSTRACT FROM AUTHOR]

Objectives: To identify clinicopathologic and ultrasound (US) variables that were associated with a heavy nodal tumor burden, which was defined as 3 or more lymph nodes involved with metastasis to the axilla after invasive breast carcinoma. Methods: With ethical approval, 621 patients with a pathologic diagnosis of invasive breast carcinoma were retrospectively analyzed for clinical, pathologic, and US data. Pathologic findings were ascertained by the final paraffin pathologic analysis. Ultrasound characteristics were evaluated on the basis of the American College of Radiology's Breast Imaging Reporting and Data System (BI‐RADS). Univariate and multivariate logistic regression analyses were used to assess the clinicopathologic and US variables that were associated with a heavy nodal tumor burden at the axilla. Results: There were 107 cases (17.2%) of invasive breast carcinoma with a heavy tumor burden at the axilla. The independent clinicopathologic variables for a heavy tumor burden at the axilla included a tumor size of 2 to 5 cm (odds ratio [OR], 1.86; P = .036), the presence of lymphovascular invasion (OR, 23.52; P < .001), the presence of papillary invasion (OR, 2.93; P = .043), and a non–triple‐negative subtype (OR, 2.34; P = .04). The independent US features of breast tumors that were associated with a heavy tumor burden at the axilla included BI‐RADS category 5 (OR, 5.50; P = .024) and a posterior acoustic shadow (OR, 1.94; P = .024). Conclusions: A large tumor size, lymphovascular invasion, papillary invasion, and a non–triple‐negative subtype on the pathologic analysis as well as BI‐RADS category 5 and a posterior acoustic shadow on a US assessment were associated with a heavy nodal tumor burden at the axilla. These US characteristics of the primary breast carcinoma might provide additional information to axillary US for the prediction of axillary nodal tumor loads. [ABSTRACT FROM AUTHOR]

Abstract Objectives Patients with T1N0M0 breast cancers are considered to have an excellent prognosis, even in triple-negative breast cancer (TNBC), which is often associated with diminished recurrence-free survival (RFS) and overall survival. Chemotherapy remains the only adjuvant treatment for TNBC, but evidence that adjuvant chemotherapy is beneficial for stage T1N0M0 TNBC patients is limited. In this study, we aimed to evaluate the effect of adjuvant chemotherapy and the benefit of taxanes in T1N0M0 TNBC patients. Material and methods A cohort of 354 consecutive patients with newly diagnosed T1N0M0 TNBC between January 2008 and December 2015 were included from the Fudan University Shanghai Cancer Center. Univariate and multivariate survival analyses were performed to compare patients treated with adjuvant chemotherapy with/without taxane addition. Results Median follow-up was 45 months. Chemotherapy was used in 92.4% of patients. The 5-year estimated RFS rates of patients with and without adjuvant chemotherapy were 94.5% and 83.6%, respectively. In multivariate analysis, adjuvant chemotherapy and a lack of lymphovascular invasion were associated with a significant benefit for RFS. A significant RFS benefit from adjuvant chemotherapy was observed in T1c (hazard ratio, HR = 0.24, 95% CI [0.08–0.76], P = 0.014) but not in T1b (HR = 0.32, 95% CI [0.03–3.18], P = 0.330) subgroups. Addition of taxane to an anthracycline-based regimen was not significantly associated with improved RFS in T1N0M0 TNBC patients. Conclusion Adjuvant chemotherapy improves recurrence-free survival in T1c TNBC patients but not in T1b. Anthracycline-based taxane-free regimens might be sufficient to achieve RFS benefits in T1N0M0 TNBC patients. Highlights • Adjuvant chemotherapy improves recurrence-free survival in T1c TNBC but not in T1b. • It might be considered to omit adjuvant chemotherapy in T1bN0M0 TNBC patients. • No significant RFS benefit is achieved from adding taxane in T1N0M0 TNBC patients. [ABSTRACT FROM AUTHOR]

DSCAM‐AS1 is one of the few intensively studied lncRNAs with high specific expression in luminal breast cancer. It is directly regulated by estrogen receptor α (ERα) and plays vital roles in tumor proliferation, invasion, and tamoxifen resistance. However, the detailed function of DSCAM‐AS1 in tumor progression and its clinical significance remain unclear. We reveal that DSCAM‐AS1 regulates cell proliferation and colony formation by inducing the G1/S transition. RNA‐seq analysis demonstrated that DSCAM‐AS1 participates in crucial biological processes, including DNA replication, the G1/S phase transition, sister chromatid cohesion, chromosome segregation, protein localization to the chromosome and DNA recombination. Most importantly, in the retrospectively registered clinical analysis, high expression of DSCAM‐AS1 is a poor prognostic factor in patients with luminal breast cancer treated with endocrine therapy. In conclusion, DSCAM‐AS1 is a promising clinical therapeutic target that may prolong survival of luminal breast cancer patients treated with endocrine therapy. We reveal that DSCAM‐AS1 regulates cell proliferation and colony formation by inducing the G1/S transition. RNA‐seq analysis demonstrated that DSCAM‐AS1 participates in crucial biological processes, including DNA replication, the G1/S phase transition, sister chromatid cohesion, chromosome segregation, protein localization to the chromosome and DNA recombination. Most importantly, in the retrospectively registered clinical analysis, high expression of DSCAM‐AS1 is a poor prognostic factor in patients with luminal breast cancer treated with endocrine therapy. [ABSTRACT FROM AUTHOR]

Background: The response to neoadjuvant chemotherapy has been proven to predict long-term clinical benefits for patients. Our research is to construct a nomogram to predict pathological complete response of human epidermal growth factor receptor 2 negative breast cancer patients.Methods: We enrolled 815 patients who received neoadjuvant chemotherapy from 2003 to 2015 and divided them into a training set and a validation set. Univariate logistic regression was performed to screen for predictors and construct the nomogram; multivariate logistic regression was performed to identify independent predictors.Results: After performing the univariate logistic regression analysis in the training set, tumor size, hormone receptor status, regimens of neoadjuvant chemotherapy and cycles of neoadjuvant chemotherapy were the final predictors for the construction of the nomogram. The multivariate logistic regression analysis demonstrated that T4 status, hormone receptor status and receiving regimen of paclitaxel and carboplatin were independent predictors of pathological complete response. The area under the receiver operating characteristic curve of the training set and the validation set was 0.779 and 0.701, respectively.Conclusions: We constructed and validated a nomogram to predict pathological complete response in human epidermal growth factor receptor 2 negative breast cancer patients. We also identified tumor size, hormone receptor status and paclitaxel and carboplatin regimen as independent predictors of pathological complete response. [ABSTRACT FROM AUTHOR]

Background: The clinical significance of progesterone receptor (PgR) expression in estrogen receptor-negative (ER-) breast cancer is controversial. Herein, we systemically investigate the clinicopathologic features, molecular essence, and endocrine responsiveness of ER-/PgR+/HER2- phenotype.Methods: Four study cohorts were included. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n = 67,932) and Fudan University Shanghai Cancer Center (n = 2,338), respectively, for clinicopathologic and survival analysis. The third and fourth cohorts were from two independent publicly available microarray datasets including 837 operable cases and 483 cases undergoing neoadjuvant chemotherapy, respectively, for clinicopathologic and gene-expression analysis. Characterized genes defining subgroups within the ER-/PgR+/HER2- phenotype were determined and further validated.Results: Clinicopathologic features and survival outcomes of the ER-/PgR+ phenotype fell in between the ER+/PgR+ and ER-/PgR- phenotypes, but were more similar to ER-/PgR-. Among the ER-/PgR+ phenotype, 30% (95% confidence interval [CI] 17-42%, pooled by a fixed-effects method) were luminal-like and 59% (95% CI 45-72%, pooled by a fixed-effects method) were basal-like. We further refined the characterized genes for subtypes within the ER-/PgR+ phenotype and developed an immunohistochemistry-based method that could determine the molecular essence of ER-/PgR+ using three markers, TFF1, CK5, and EGFR. Either PAM50-defined or immunohistochemistry-defined basal-like ER-/PgR+ cases have a lower endocrine therapy sensitivity score compared with luminal-like ER-/PgR+ cases (P <0.0001 by Mann-Whitney test for each study set and P <0.0001 for pooled standardized mean difference in meta-analysis). Immunohistochemistry-defined basal-like ER-/PgR+ cases might not benefit from adjuvant endocrine therapy (log-rank P = 0.61 for sufficient versus insufficient endocrine therapy).Conclusions: The majority of ER-/PgR+/HER2- phenotype breast cancers are basal-like and associated with a lower endocrine therapy sensitivity score. Additional studies are needed to validate these findings. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) therapy is generating remarkable responses in individuals with cancer, but only a small portion of individuals with breast cancer respond well. Here we report that tumor-derived Jagged1 is a key regulator of the tumor immune microenvironment. Jagged1 promotes tumorigenesis in multiple spontaneous mammary tumor models. Through Jagged1-induced Notch activation, tumor cells increase expression and secretion of multiple cytokines to help recruit macrophages into the tumor microenvironment. Educated macrophages crosstalk with tumor-infiltrating T cells to inhibit T cell proliferation and tumoricidal activity. In individuals with triple-negative breast cancer, a high expression level of Jagged1 correlates with increased macrophage infiltration and decreased T cell activity. Co-administration of an ICI PD-1 antibody with a Notch inhibitor significantly inhibits tumor growth in breast cancer models. Our findings establish a distinct signaling cascade by which Jagged1 promotes adaptive immune evasion of tumor cells and provide several possible therapeutic targets. [Display omitted] • Tumor-derived Jagged1 promotes breast cancer progression • Notch activation in tumor cells leads to cytokine production and macrophage recruitment • Tumor education macrophages suppress CD8+ T cell proliferation and tumoricidal activity • Co-administration of PD-1 antibody and Notch inhibitor restrains tumor growth in vivo Meng et al. report that tumor-derived Jagged1 helps recruit macrophages and blocks tumor-killing T cell functions to promote tumor immune evasion during breast cancer progression. Co-administration of an immune checkpoint inhibitor and Jagged1-Notch pathway inhibitor restrains tumor growth in vivo. [ABSTRACT FROM AUTHOR]

The remarkable advances in next-generation sequencing technology have enabled the wide usage of sequencing as a clinical tool. To promote the advance of precision oncology for breast cancer in China, here we report a large-scale prospective clinical sequencing program using the Fudan-BC panel, and comprehensively analyze the clinical and genomic characteristics of Chinese breast cancer. The mutational landscape of 1,134 breast cancers reveals that the most significant differences between Chinese and Western patients occurred in the hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer subtype. Mutations in p53 and Hippo signaling pathways are more prevalent, and 2 mutually exclusive and 9 co-occurring patterns exist among 9 oncogenic pathways in our cohort. Further preclinical investigation partially suggests that NF2 loss-of-function mutations can be sensitive to a Hippo-targeted strategy. We establish a public database (Fudan Portal) and a precision medicine knowledge base for data exchange and interpretation. Collectively, our study presents a leading approach to Chinese precision oncology treatment and reveals potentially actionable mutations in breast cancer. Chinese breast cancer patients have not been well represented in clinical sequencing studies. Here the authors analyse the mutational landscape of 1,134 Chinese breast cancer patients, finding actionable targets and a higher prevalence of p53 and Hippo pathway mutations compared to Western cohorts. [ABSTRACT FROM AUTHOR]

Breast tumor initiating cells (BTICs) with ALDH+CD24−CD44+ phenotype are the most tumorigenic and invasive cell population in breast cancer. However, the molecular mechanisms are still unclear. Here, it is found that a negative immune regulator interleukin‐1 receptor type 2 (IL1R2) is upregulated in breast cancer (BC) tissues and especially in BTICs. BC patients with high IL1R2 expression have a poorer overall survival and relapse‐free survival. High IL1R2 promotes BTIC self‐renewal and BC cell proliferation and invasion. Mechanistically, IL1R2 is activated by IL1β, as demonstrated by the fact that IL1β induces the release of IL1R2 intracellular domain (icd‐IL1R2) and icd‐IL1R2 then interacts with the deubiquitinase USP15 at the UBL2 domain and promotes its activity, which finally induces BMI1 deubiquitination at lysine 81 and stabilizes BMI1 protein. In addition, IL1R2 neutralizing antibody can suppress the protein expression of both IL1R2 and BMI1, and significantly abrogates the promoting effect of IL1R2 on BTIC self‐renewal and BC cell growth both in vitro and in vivo. The current results indicate that blocking IL1R2 with neutralizing antibody provides a therapeutic approach to inhibit BC progression by targeting BTICs. [ABSTRACT FROM AUTHOR]

Co-occurrence and mutual exclusivity of genomic alterations may reflect the existence of genetic interactions, potentially shaping distinct biological phenotypes and impacting therapeutic response in breast cancer. However, our understanding of them remains limited. Herein, we investigate a large-scale multi-omics cohort (n = 873) and a real-world clinical sequencing cohort (n = 4,405) including several clinical trials with detailed treatment outcomes and perform functional validation in patient-derived organoids, tumor fragments, and in vivo models. Through this comprehensive approach, we construct a network comprising co-alterations and mutually exclusive events and characterize their therapeutic potential and underlying biological basis. Notably, we identify associations between TP53 mut -AURKA amp and endocrine therapy resistance, germline BRCA1 mut -MYC amp and improved sensitivity to PARP inhibitors, and TP53 mut -MYB amp and immunotherapy resistance. Furthermore, we reveal that precision treatment strategies informed by co-alterations hold promise to improve patient outcomes. Our study highlights the significance of genetic interactions in guiding genome-informed treatment decisions beyond single driver alterations. [Display omitted] • We built a large multi-omics cohort and a real-world clinical sequencing cohort • A genetic interaction network involves co-occurring and mutually exclusive events • Co-alterations influence treatment outcomes across diverse clinical scenarios • Genome-informed treatment decisions should extend beyond single driver alterations Lin et al. leverage a large-scale multi-omics cohort and a real-world clinical sequencing cohort to explore genetic interactions and their impact on treatment outcomes across various clinical scenarios in breast cancer. These findings underscore the importance of making genome-informed precision treatment decisions that consider individual driver alterations and beyond. [ABSTRACT FROM AUTHOR]