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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]

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis. TNBCs with high homologous recombination deficiency (HRD) scores benefit from DNA-damaging agents, including platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, whereas those with low HRD scores still lack therapeutic options. Therefore, we sought to exploit metabolic alterations to induce HRD and sensitize DNA-damaging agents in TNBCs with low HRD scores. We systematically analyzed TNBC metabolomics and identified a metabolite, guanosine diphosphate (GDP)–mannose (GDP-M), that impeded homologous recombination repair (HRR). Mechanistically, the low expression of the upstream enzyme GDP-mannose-pyrophosphorylase-A (GMPPA) led to the endogenous up-regulation of GDP-M in TNBC. The accumulation of GDP-M in tumor cells further reduced the interaction between breast cancer susceptibility gene 2 (BRCA2) and ubiquitin-specific peptidase 21 (USP21), which promoted the ubiquitin-mediated degradation of BRCA2 to inhibit HRR. Therapeutically, we illustrated that the supplementation of GDP-M sensitized DNA-damaging agents to impair tumor growth in both in vitro (cancer cell line and patient-derived organoid) and in vivo (xenograft in immunodeficient mouse) models. Moreover, the combination of GDP-M with DNA-damaging agents activated STING-dependent antitumor immunity in immunocompetent syngeneic mouse models. Therefore, GDP-M supplementation combined with PARP inhibition augmented the efficacy of anti–PD-1 antibodies. Together, these findings suggest that GDP-M is a crucial HRD-related metabolite and propose a promising therapeutic strategy for TNBCs with low HRD scores using the combination of GDP-M, PARP inhibitors, and anti–PD-1 immunotherapy. Editor's summary: Triple-negative breast cancer (TNBC) has worse prognosis than other breast cancer subtypes, and metabolites have been suggested as a potential target for therapy. Here, Ding et al. evaluated metabolites associated with homologous recombination deficiency in TNBC and identified that guanosine diphosphate–mannose (GDP-M) could suppress DNA repair and could be combined with other DNA repair–targeted therapy. They evaluated the combination of GDP-M with PARP inhibition and anti–PD-1 therapy to enhance antitumor immunity and survival of mouse models. This demonstrates the promising effects of GDP-M supplementation for TNBC therapy that requires further study. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

Background Tumor-infiltrating lymphocytes (TILs) and programmed cell death 1 ligand 1 (PD-L1) remain imperfect in predicting clinical outcomes of triple-negative breast cancer because outcomes do not always correlate with the expression of these biomarkers. Genomic and transcriptomic alterations that may contribute to the expression of these biomarkers remain incompletely uncovered. Methods We evaluated PD-L1 immunohistochemistry scores (SP142 and 28-8 assays) and TILs in our triple-negative breast cancer multiomics dataset and 2 immunotherapy clinical trial cohorts. Then, we analyzed genomic and transcriptomic alterations correlated with TILs, PD-L1 expression, and patient outcomes. Results Despite TILs serving as a decent predictor for triple-negative breast cancer clinical outcomes, exceptions remained. Our study revealed that several genomic alterations were correlated with unexpected events. In particular, PD-L1 expression may cause a paradoxical relationship between TILs and prognosis in certain patients. Consequently, we classified triple-negative breast cancers into 4 groups based on PD-L1 and TIL levels. The TIL-negative PD-L1–positive and TIL-positive PD-L1–negative groups were not typical "hot" tumors; both were associated with worse prognoses and lower immunotherapy efficacy than TIL-positive PD-L1–positive tumors. Copy number variation of PD-L1 and oncogenic signaling activation were correlated with PD-L1 expression in the TIL-negative PD-L1–positive group, whereas GSK3B-induced degradation may cause undetectable PD-L1 expression in the TIL-positive PD-L1–negative group. These factors have the potential to affect the predictive function of both PD-L1 and TILs. Conclusions Several genomic and transcriptomic alterations may cause paradoxical effects among TILs, PD-L1 expression, and prognosis in triple-negative breast cancer. Investigating and targeting these factors will advance precision immunotherapy for patients with this disease. [ABSTRACT FROM AUTHOR]

Despite recent treatment advances, the prognosis for patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) remains poor. The antibody–drug conjugate datopotamab deruxtecan (Dato-DXd) is composed of a humanized anti-TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload via a stable, cleavable linker. The phase III TROPION-Breast02 trial in patients previously untreated for locally recurrent inoperable or metastatic TNBC, who are not candidates for PD-1/PD-L1 inhibitors is evaluating efficacy and safety of Dato-DXd versus investigator's choice of chemotherapy (ICC). Approximately 600 patients will be randomized 1:1 to Dato-DXd 6 mg/kg iv. every 3 weeks or ICC (paclitaxel, nab-paclitaxel, carboplatin, capecitabine or eribulin mesylate). Dual primary end points are progression-free survival by blinded independent central review and overall survival. Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is hard to treat. Tumors lack receptors for estrogen and progesterone, which means that standard endocrine therapy is ineffective, and it does not express HER2, so HER2 therapies are also not appropriate. However, the majority of TNBC tumors do possess a cell surface protein called TROP2 which provides a way of directing treatment inside tumor cells that is more selective than traditional chemotherapy. Datopotamab deruxtecan (Dato-DXd) is a drug that consists of two parts: datopotamab (an antibody) and DXd (the cancer-cell killing toxic component), which are joined via a stable linker. Datopotamab binds to the TROP2 protein found on TNBC tumors and is taken into the cell. The linker is then broken and releases DXd, which kills the tumor cell. By binding to cancer cells before releasing the payload, treatment is directed to the tumor, minimizing side effects in the rest of the body. The TROPION-Breast02 study aims to discover whether Dato-DXd is more effective than standard-of-care chemotherapy, allowing patients with TNBC to live longer without their breast cancer getting worse. This study is also looking at how Dato-DXd may affect patients' overall functioning and quality of life. TROPION-Breast02 will recruit approximately 600 patients who: Have cancer that has spread from the original site (metastatic), or cancer that returned to the same site (locally recurrent) that cannot be surgically removed Have not received any prior treatment for this stage of cancer Cannot receive an alternative type of anticancer treatment called PD-(L)1 inhibitors Had any length of time between their last treatment with the aim of cure and return of their disease Eligible patients will be randomly assigned to a treatment group in equal numbers to either Dato-DXd or an appropriate chemotherapy (one of five available options, chosen by the treating doctor). Each patient will generally continue to receive their designated treatments if the tumor is controlled by the drug, there are no unacceptable side effects, or the patient chooses to stop treatment. Clinical Trial Registration:NCT05374512 (ClinicalTrials.gov) [ABSTRACT FROM AUTHOR]

Metastasis is the main death reason for triple‐negative breast cancer (TNBC). Thus, identifying the driver genes associated with metastasis of TNBC is urgently needed. CRISPR screens have dramatically enhanced genome editing and made it possible to identify genes associated with metastasis. In this study, we identified and explored the crucial role of ras homolog family member V (RhoV) in TNBC metastasis. Here, we performed customized in vivo CRISPR screens targeting metastasis‐related genes obtained from transcriptome analysis of TNBC. The regulatory role of RhoV in TNBC was validated using gain‐ or loss‐of‐function studies in vitro and in vivo. We further conducted immunoprecipitation and LC–MS/MS to explore the metastasis mechanism of RhoV. In vivo functional screens identified RhoV as a candidate regulator involved in tumor metastasis. RhoV was frequently upregulated in TNBC and correlated with poor survival. Knockdown of RhoV significantly suppressed cell invasion, migration, and metastasis both in vitro and in vivo. In addition, we provided evidence that p‐EGFR interacted with RhoV to activate the downstream signal pathway of RhoV, thereby promoting tumor metastasis. We further confirmed that this association was dependent on GRB2 through a specific proline‐rich motif in the N‐terminus of RhoV. This mechanism of RhoV is unique, as other Rho family proteins lack the proline‐rich motif in the N‐terminus. [ABSTRACT FROM AUTHOR]

Introduction: We have previously reported that Toll-like receptor 3 (TLR3) acts as a suppressor gene for breast cancer initiation and progression. In this study, we evaluated the role of TLR3 in breast cancer using our original Fudan University Shanghai Cancer Center (FUSCC) datasets and breast cancer tissue microarrays. Methods: Using FUSCC multiomics datasets on triple- negative breast cancer (TNBC), we compared the mRNA expression of TLR3 in TNBC tissue and the adjacent normal tissue. A Kaplan–Meier plotter was performed to investigate the expression of TLR3 on prognosis in the FUSCC TNBC cohort. We performed immunohistochemical staining to analyze TLR3 protein expression in the TNBC tissue microarrays. Furthermore, bioinformatics analysis was performed using the Cancer Genome Atlas (TCGA) data to verify the results of our FUSCC study. The relationship between TLR3 and clinicopathological features was analyzed with logistic regression and the Wilcoxon signed-rank test. The association between clinical characteristics and overall survival in TCGA patients was assessed using the Kaplan–Meier method and Cox regression analysis. Gene set enrichment analysis (GSEA) was performed to identify signaling pathways that are differentially activated in breast cancer. Results: The mRNA expression of TLR3 was lower in TNBC tissue than in the adjacent normal tissue in the FUSCC datasets. The TLR3 had high expression in immunomodulatory (IM) and mesenchymal-like (MES) subtypes and low expression in luminal androgen receptor (LAR) and basal-like immune-suppressed (BLIS) subtypes. High expression of TLR3 in TNBC predicted better prognosis in the FUSCC TNBC cohort. Immunohistochemical staining of the tissue microarrays showed that TLR3 had lower expression in breast cancer tissues than in the adject normal tissues. Furthermore, the TLR3 expression was positively associated with B cell, CD4 + T cells, CD8 + T cells, neutrophils, macrophages, and myeloid dendritic cells. Bioinformatic analysis using high-throughput RNA-sequencing data from the TCGA demonstrated that the reduced expression of TLR3 in breast cancer was associated with advanced clinicopathological characteristics, survival time, and poor prognosis. Conclusions: TLR3 has low expression in TNBC tissue. High expression of TLR3 in triple-negative breast cancer predicts better prognosis. TLR3 expression may be a potential prognostic molecular marker of poor survival in breast cancer. [ABSTRACT FROM AUTHOR]

Molecular subtyping of triple-negative breast cancer (TNBC) is essential for understanding the mechanisms and discovering actionable targets of this highly heterogeneous type of breast cancer. We previously performed a large single-center and multiomics study consisting of genomics, transcriptomics, and clinical information from 465 patients with primary TNBC. To facilitate reusing this unique dataset, we provided a detailed description of the dataset with special attention to data quality in this study. The multiomics data were generally of high quality, but a few sequencing data had quality issues and should be noted in subsequent data reuse. Furthermore, we reconduct data analyses with updated pipelines and the updated version of the human reference genome from hg19 to hg38. The updated profiles were in good concordance with those previously published in terms of gene quantification, variant calling, and copy number alteration. Additionally, we developed a user-friendly web-based database for convenient access and interactive exploration of the dataset. Our work will facilitate reusing the dataset, maximize the values of data and further accelerate cancer research. Measurement(s) RNA expression profiling • whole-exome sequencing (WES) • somatic mutations • copy number alterations (CNAs) Technology Type(s) RNA sequencing • DNA sequencing • OncoScan CNV assay Factor Type(s) Intervention or procedure Sample Characteristic - Organism Homo sapiens Sample Characteristic - Location China [ABSTRACT FROM AUTHOR]

Copy number alterations (CNAs) are pivotal genetic events in triple-negative breast cancer (TNBC). Here, our integrated copy number and transcriptome analysis of 302 TNBC patients reveals that gene alpha-endosulfine (ENSA) exhibits recurrent amplification at the 1q21.3 region and is highly expressed in TNBC. ENSA promotes tumor growth and indicates poor patient survival in TNBC. Mechanistically, we identify ENSA as an essential regulator of cholesterol biosynthesis in TNBC that upregulates the expression of sterol regulatory element-binding transcription factor 2 (SREBP2), a pivotal transcription factor in cholesterol biosynthesis. We confirm that ENSA can increase the level of p-STAT3 (Tyr705) and activated STAT3 binds to the promoter of SREBP2 to promote its transcription. Furthermore, we reveal the efficacy of STAT3 inhibitor Stattic in TNBC with high ENSA expression. In conclusion, the amplification of ENSA at the 1q21.3 region promotes TNBC progression and indicates sensitivity to STAT3 inhibitors. Copy number alterations are pivotal genetic events in triple-negative breast cancer. Here the authors show the amplification of ENSA at the 1q21.3 region promotes the progression of TNBC via up-regulation of cholesterol biosynthesis. [ABSTRACT FROM AUTHOR]

Background: Age at the time of breast cancer diagnosis not only predicts clinical outcome but also indicates distinct molecular characteristics that provide the rationale for appropriate treatment strategies. However, to the authors' knowledge, little is known regarding the molecular profile and biological basis of triple-negative breast cancers (TNBCs) occurring in young and elderly patients.Methods: Using the study institution's largest, single-center, multiomics TNBC data set, the authors analyzed the clinical and genomic features of young (aged ≤39 years) and elderly (aged ≥65 years) patients with TNBC.Results: In the current study, a total of 50 patients, 354 patients, and 69 patients, respectively, were grouped as young, intermediate, and elderly patients with TNBC. Young patients with TNBC had worse short-term survival, upregulation of DNA repair, cell cycle and RNA metabolism gene sets, frequent pathogenic germline variants, and predominant homologous recombination deficiency-related mutational signatures. Several copy number alterations also were found to be enriched in young patients with TNBC. Nearly one-half of the TNBC cases in elderly patients were of the luminal androgen receptor subtype. TNBC in elderly patients was identified as being associated with severe fibrosis; a lower Ki-67 index; and somatic mutations in PIK3CA, KMT2D, ERBB2, ERBB3, and their corresponding pathways. Elderly patients with TNBC also were more likely to harbor targetable mutations.Conclusions: The findings of the current study indicated that young patients with TNBC had an enhanced cell cycle, which may have helped to explain their inferior short-term survival, whereas the homologous recombination deficiency and enriched pathogenic germline variants observed among young patients with TNBC suggested the need for genetic counseling and testing, as well as the potential use of DNA damage agents and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors. Molecular characteristics of elderly patients with TNBC, although suggesting less response to chemotherapy, provided a rationale for the routine detection of actionable somatic mutations. [ABSTRACT FROM AUTHOR]

(B) Patients in the PCb group and the CEF-T group were ordered by a representative pathway concerning hypoxia and glycolysis. Upregulation of glycolysis and hypoxia-related pathways was associated with inferior prognosis of patients treated by adjuvant anthracycline/taxane regimen. Abbreviations BCS breast conservative surgery BLIS basal-like and immune-suppressed CEF-T fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel FUSCC Fudan University Shanghai Cancer Center HRD homologous recombination deficiency IM immunomodulatory IQR interquartile range LAR luminal androgen receptor MES mesenchymal-like PCb paclitaxel and carboplatin Triple-negative breast cancer (TNBC) is associated with genome-wide instability caused by mutations in homologous recombination repair mechanism,1 and the application of DNA-damaging compounds has been explored for TNBC.2 Recently, we performed the PATTERN trial (NCT01216111) to compare six cycles of paclitaxel plus carboplatin (PCb) with a standard-dose regimen of three cycles of cyclophosphamide/epirubicin/fluorouracil followed by three cycles of docetaxel (CEF-T) in the adjuvant setting of early-stage TNBC, and the result indicated a superior efficacy of the carboplatin-containing regimen and good tolerance to both treatments.3 In this study, we conducted multi-omic profiling on 132 patients in the PATTERN cohort to investigate potential biomarkers for a more precise choice of adjuvant chemotherapy regimen for TNBC. [Extracted from the article]

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]

Background: Molecular subtyping of triple‐negative breast cancers (TNBCs) via gene expression profiling is essential for understanding the molecular essence of this heterogeneous disease and for guiding individualized treatment. We aim to devise a clinically practical method based on immunohistochemistry (IHC) for the molecular subtyping of TNBCs. Materials and Methods: By analyzing the RNA sequencing data on TNBCs from Fudan University Shanghai Cancer Center (FUSCC) (n = 360) and The Cancer Genome Atlas data set (n = 158), we determined markers that can identify specific molecular subtypes. We performed immunohistochemical staining on tumor sections of 210 TNBCs from FUSCC, established an IHC‐based classifier, and applied it to another two cohorts (n = 183 and 214). Results: We selected androgen receptor (AR), CD8, FOXC1, and DCLK1 as immunohistochemical markers and classified TNBCs into five subtypes based on the staining results: (a) IHC‐based luminal androgen receptor (IHC‐LAR; AR‐positive [+]), (b) IHC‐based immunomodulatory (IHC‐IM; AR‐negative [−], CD8+), (c) IHC‐based basal‐like immune‐suppressed (IHC‐BLIS; AR−, CD8−, FOXC1+), (d) IHC‐based mesenchymal (IHC‐MES; AR−, CD8−, FOXC1−, DCLK1+), and (e) IHC‐based unclassifiable (AR−, CD8−, FOXC1−, DCLK1−). The κ statistic indicated substantial agreement between the IHC‐based classification and mRNA‐based classification. Multivariate survival analysis suggested that our IHC‐based classification was an independent prognostic factor for relapse‐free survival. Transcriptomic data and pathological observations implied potential treatment strategies for different subtypes. The IHC‐LAR subtype showed relative activation of HER2 pathway. The IHC‐IM subtype tended to exhibit an immune‐inflamed phenotype characterized by the infiltration of CD8+ T cells into tumor parenchyma. The IHC‐BLIS subtype showed high expression of a VEGF signature. The IHC‐MES subtype displayed activation of JAK/STAT3 signaling pathway. Conclusion: We developed an IHC‐based approach to classify TNBCs into molecular subtypes. This IHC‐based classification can provide additional information for prognostic evaluation. It allows for subgrouping of TNBC patients in clinical trials and evaluating the efficacy of targeted therapies within certain subtypes. Implications for Practice: An immunohistochemistry (IHC)‐based classification approach was developed for triple‐negative breast cancer (TNBC), which exhibited substantial agreement with the mRNA expression‐based classification. This IHC‐based classification (a) allows for subgrouping of TNBC patients in large clinical trials and evaluating the efficacy of targeted therapies within certain subtypes, (b) will contribute to the practical application of subtype‐specific treatment for patients with TNBC, and (c) can provide additional information beyond traditional prognostic factors in relapse prediction. This article describes an immunohistochemistry‐based approach to classification of triple‐negative breast cancers into molecular subtypes for purposes of the translation of TNBC molecular classification into clinical practice. [ABSTRACT FROM AUTHOR]

Lung metastasis is one of the leading causes of death for triple‐negative breast cancer (TNBC). We sought to characterize the genetic alterations underlying TNBC lung metastases by integrating whole‐genome sequencing and functional screening. Furthermore, we aimed to develop a metastasis‐related gene signature for TNBC patients to improve risk stratification. In this prospective observational study, we first conducted whole‐genome sequencing of paired primary tumor and lung metastasis from one TNBC patient to identify potential genetic driver alterations. An in vivo gain‐of‐function screening using an amplified open reading frame library was then employed to screen candidate genes promoting lung metastasis. Finally, we applied Cox proportional hazard regression modeling to develop a prognostic gene signature from 14 candidate genes in TNBC. Compared to the primary tumor, copy number amplifications of chromosomes 3q and 8q were identified in the lung metastasis. We discovered an enrichment of 14 genes from chromosomes 3q and 8q in mouse lung metastases model. We further developed and validated a four‐gene signature (ENY2, KCNK9, TNFRSF11B and KCNMB2) that predicts recurrence‐free survival and lung metastasis in TNBC. Our data also demonstrated that upregulated expression of ENY2 could promote invasion and lung metastasis of TNBC cells both in vitro and in vivo. In conclusion, our study reveals functional genes with copy number amplifications among chromosome 3q and 8q in lung metastasis of TNBC. And we develop a functional gene signature that can effectively stratify patients into low‐ and high‐risk subgroups of recurrence, helping frame personalized treatments for TNBC. What's new? Next‐generation whole‐genome sequencing has allowed the comprehensive characterization of genomic changes in the process of metastasis, but often the biological function or clinical relevance of these variants remains unclear. By using an approach combining whole‐genome sequencing and functional screening to seek genetic alterations underlying lung metastasis in triple‐negative breast cancer (TNBC), here the authors reveal several functional genes with copy number amplifications among chromosome 3q and 8q. Moreover, they present a functional four‐gene signature that can effectively stratify patients into low‐ and high‐risk subgroups of recurrence and could help frame personalized treatments for TNBC. [ABSTRACT FROM AUTHOR]

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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]

Copyright of Oncologist is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose To examine the clinicopathologic characteristics and survival outcomes of different histologic types of triple-negative breast cancer (TNBC). Methods We used the SEER database to identify patients with TNBC diagnosed between 2010 and 2014. Our analysis focused on the seven most prevalent histologic types. Differences were compared between invasive carcinoma of no special type (NST) and the other six types. Results Significant differences were observed in age at diagnosis, tumor grade, size, nodal status and treatment. As tumor size increased, the number of positive lymph nodes increased markedly in invasive lobular carcinoma (ILC) and mixed NST and lobular carcinoma (NST-ILC), while in metaplastic carcinoma the number only increased slightly. In multivariate survival analyses, compared with patients with invasive carcinoma NST, breast cancer-specific survival (BCSS) and overall survival (OS) were worse for those with NST-ILC (BCSS: hazard ratio [HR] 1.81, P < .001; OS: HR 1.56, P = .005) or metaplastic carcinoma (BCSS: HR 1.95, P < .001; OS: HR 1.73, P < .001). By contrast, patients with medullary (HR 0.40, P = .010) or apocrine carcinoma (HR 0.27, P = .008) showed better BCSS. Time-dependent receiver operating characteristic (ROC) analyses indicated that T category in ILC and N category in metaplastic carcinoma were of less prognostic value. Conclusions According to the histologic classification of TNBC, this heterogeneous disease can be divided into several entities with different clinicopathologic features and prognoses. In the era of molecular subtyping of breast cancer, the histologic classification of TNBC is still of considerable clinical significance. [ABSTRACT FROM AUTHOR]

Treatment of triple-negative breast cancer (TNBC) remains challenging. Deciphering the orchestration of metabolic pathways in regulating ferroptosis will provide new insights into TNBC therapeutic strategies. Here, we integrated the multiomics data of our large TNBC cohort (n = 465) to develop the ferroptosis atlas. We discovered that TNBCs had heterogeneous phenotypes in ferroptosis-related metabolites and metabolic pathways. The luminal androgen receptor (LAR) subtype of TNBC was characterized by the upregulation of oxidized phosphatidylethanolamines and glutathione metabolism (especially GPX4), which allowed the utilization of GPX4 inhibitors to induce ferroptosis. Furthermore, we verified that GPX4 inhibition not only induced tumor ferroptosis but also enhanced antitumor immunity. The combination of GPX4 inhibitors and anti-PD1 possessed greater therapeutic efficacy than monotherapy. Clinically, higher GPX4 expression correlated with lower cytolytic scores and worse prognosis in immunotherapy cohorts. Collectively, this study demonstrated the ferroptosis landscape of TNBC and revealed an innovative immunotherapy combination strategy for refractory LAR tumors. [Display omitted] • Integrated analysis systematically demonstrates the ferroptosis heterogeneity in TNBC • LAR subtype of TNBC is hypersensitive to ferroptosis inducers, especially GPX4 inhibitors • AR plays a dual role in regulating ferroptosis of LAR tumors • Combination of GPX4 inhibitors and immunotherapy is an option for LAR tumors Yang et al. systematically demonstrated the ferroptosis heterogeneity in triple-negative breast cancer (TNBC). They found that luminal androgen receptor (LAR) subtype of TNBC was hypersensitive to ferroptosis inducers and revealed that the combination of GPX4 inhibitors and immune checkpoint inhibitors was a novel treatment strategy for LAR TNBCs. [ABSTRACT FROM AUTHOR]

Background The anti-tumor activity of nab -paclitaxel followed by epirubicin/cyclophosphamide (EC) as neoadjuvant chemotherapy (NAC) in Asian patients remain unclear, particularly in the aggressive subtype triple-negative breast cancer (TNBC). This study aimed to evaluate the efficacy and safety of this NAC regimen in TNBC. Methods In this Simon's two-stage, phase II study, treatment-naïve patients with unilateral primary invasive TNBC were enrolled. Eligible patients received nab -paclitaxel 125 mg/m2 weekly on day 1 for 12 weeks, followed by dose-dense EC (epirubicin 90 mg/m2; cyclophosphamide 600 mg/m2) on day 1 for four 2-week cycles. The primary endpoint was the total pathological complete response (tpCR, ypT0/is ypN0) rate. Results A total of 55 eligible patients were enrolled and treated. After NAC, tpCR and breast pathological complete response were respectively observed in 43.1% (95% CI, 29.3-57.8) and 49.0% (95% CI, 34.8-63.4) of 51 evaluable patients for pathological response evaluation. 44 had an objective response as their best response (80.0%; 95% CI, 67.0-89.6). No correlations between clinicopathological variables and pathological/clinical response were observed. Grade 3 or more adverse events (AEs) occurred in 63.6% of 55 patients. The most frequent AEs were alopecia. No treatment-related surgical delay or death occurred. Conclusion Nab -paclitaxel followed by dose-dense EC as NAC demonstrates promising anti-tumor activity and acceptable tolerability for patients with TNBC. (ClinicalTrials.gov Identifier: NCT03799679). [ABSTRACT FROM AUTHOR]

Purpose: Nucleolar spindle-associated protein (NuSAP1) is an important mitosis-related protein, and aberrant NuSAP1 expression is associated with abnormal spindles and mitosis. This study investigated the prognostic value of NuSAP1 in breast cancer. Methods: Two sets of tissue microarrays (TMAs) that included samples from 450 breast cancer patients were constructed, of which 250 patients were training set and the other 200 patients were validation set. Immunohistochemical staining was performed to determine the NuSAP1 levels. A Kaplan-Meier analysis was used to estimate the prognostic value of NuSAP1 in breast cancer. A stepwise Cox analysis was performed to construct a risk-prediction model for triple-negative breast cancer (TNBC). All statistical analysis was performed with SPSS software. Results: There were 108 (43.5%) and 88 (44.0%) patients expressed NuSAP1 in the training set and validation set respectively. High levels of NuSAP1 expression were related to poor disease-free survival (DFS) in both training (P = 0.028) and validation (P = 0.006) cohorts, particularly in TNBC. With combination of two cohorts, both NuSAP1 (HR = 4.136, 95% CI: 1.956–8.747, P < 0.001) and BRCA1 (HR = 0.383, 95% CI: 0.160–0.915, P = 0.031) were independent prognostic indicators of DFS in TNBC. A receiver operating characteristic (ROC) analysis revealed that the combination of NuSAP1 and BRCA1 significantly improved the prognostic power compared with the traditional model (0.778 versus 0.612, P < 0.001). Conclusions: Our study confirms the prognostic value of NuSAP1 in breast cancer. The combination of NuSAP1 and BRCA1 could improve the DFS prediction accuracy in TNBC. [ABSTRACT FROM AUTHOR]

Immunotherapy has achieved limited success in patients with triple-negative breast cancer (TNBC), an aggressive disease with a poor prognosis. Commensal microbiota have been proven to colonize the mammary gland, but whether and how they modulate the tumor microenvironment remains elusive. We performed a multiomics analysis of a cohort of patients with TNBC (n = 360) and found genera under Clostridiales , and the related metabolite trimethylamine N-oxide (TMAO) was more abundant in tumors with an activated immune microenvironment. Patients with higher plasma TMAO achieved better responses to immunotherapy. Mechanistically, TMAO induced pyroptosis in tumor cells by activating the endoplasmic reticulum stress kinase PERK and thus enhanced CD8+ T cell-mediated antitumor immunity in TNBC in vivo. Collectively, our findings offer new insights into microbiota-metabolite-immune crosstalk and indicate that microbial metabolites, such as TMAO or its precursor choline, may represent a novel therapeutic strategy to promote the efficacy of immunotherapy in TNBC. [Display omitted] • Microbial metabolite TMAO correlates with improved efficacy of immunotherapy in TNBC • TMAO inhibits tumor growth by activating CD8+ T cell-mediated antitumor immunity • TMAO activates antitumor immunity by inducing pyroptosis of tumor cells • The TMAO precursor choline enhances response to immunotherapy in TNBC Wang et al. report that the microbial metabolite trimethylamine N-oxide enhances CD8+ T cell-mediated antitumor immunity in triple-negative breast cancer (TNBC) by inducing pyroptosis in tumor cells, revealing insights into microbiota-metabolite-immune crosstalk. The findings indicate that microbial metabolites represent a potential therapeutic strategy to promote the efficacy of immunotherapy in TNBC. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) remains an unmet medical challenge. We investigated metabolic dysregulation in TNBCs by using our multi-omics database (n = 465, the largest to date). TNBC samples were classified into three heterogeneous metabolic-pathway-based subtypes (MPSs) with distinct metabolic features: MPS1, the lipogenic subtype with upregulated lipid metabolism; MPS2, the glycolytic subtype with upregulated carbohydrate and nucleotide metabolism; and MPS3, the mixed subtype with partial pathway dysregulation. These subtypes were validated by metabolomic profiling of 72 samples. These three subtypes had distinct prognoses, molecular subtype distributions, and genomic alterations. Moreover, MPS1 TNBCs were more sensitive to metabolic inhibitors targeting fatty acid synthesis, whereas MPS2 TNBCs showed higher sensitivity to inhibitors targeting glycolysis. Importantly, inhibition of lactate dehydrogenase could enhance tumor response to anti-PD-1 immunotherapy in MPS2 TNBCs. Collectively, our analysis demonstrated the metabolic heterogeneity of TNBCs and enabled the development of personalized therapies targeting unique tumor metabolic profiles. • The metabolic reprogramming and heterogeneity of TNBC is systematically characterized • TNBCs are classified into three subtypes on the basis of metabolic pathways • Three subtypes show distinct sensitivities to various metabolic inhibitors • Inhibition of LDH enhances tumor response to anti-PD-1 immunotherapy in MPS2 TNBCs Gong et al. reveal the metabolic heterogeneity of triple-negative breast cancer and identify three metabolic-pathway-based subtypes with distinct molecular features and sensitivities to various metabolic inhibitors. They find that inhibition of lactate dehydrogenase could enhance the anti-PD-1 immunotherapy response in a certain subtype of triple-negative breast cancer. [ABSTRACT FROM AUTHOR]

Background: Enhanced glycolysis in tumors, known as the Warburg effect, provides the metabolic basis of enhanced cancer cell proliferation and metastasis. The Warburg pathway enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is a newly identified key kinase that regulates transcriptional reprogramming and cell proliferation. Here we show the prognostic value of PFKFB4 expression in patients with operable breast cancer. Methods: PFKFB4 expression was evaluated by immunohistochemistry in surgical specimens retrospectively collected from 200 patients with histologically proven invasive ductal breast cancer. Kaplan–Meier survival analysis and Cox regression analysis were performed to assess the prognostic significance of PFKFB4 expression. Results: Kaplan–Meier survival analysis revealed that breast cancer patients with high PFKFB4 expression demonstrated unfavorable disease-free survival (p = 0.008) and overall survival (p = 0.002). PFKFB4 had an hazard ratio (HR) of 7.38 (95% CI 1.69–32.3; p = 0.008) in univariate Cox analysis and retained prognostic power (HR 7.44, 95% CI 1.67–33.2; p = 0.009) when adjusted by tumor size, lymph node status, grade, estrogen receptor status, human epidermal growth factor receptor 2 status and subtype, which indicated PFKFB4 was an independent prognostic factor in breast cancer. Conclusions: Together, our findings establish the prognostic value of metabolic enzyme PFKFB4 in patients with operable breast cancer. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and it lacks specific therapeutic targets and effective treatment protocols. By analyzing a proteomic TNBC dataset, we found significant upregulation of sideroflexin 1 (SFXN1) in tumor tissues. However, the precise function of SFXN1 in TNBC remains unclear. Immunoblotting was performed to determine SFXN1 expression levels. Label-free quantitative proteomics and liquid chromatography-tandem mass spectrometry were used to identify the downstream targets of SFXN1. Mechanistic studies of SFXN1 and cellular inhibitor of PP2A (CIP2A) were performed using immunoblotting, immunofluorescence staining, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Functional experiments were used to investigate the role of SFXN1 in TNBC cells. SFXN1 was significantly overexpressed in TNBC tumor tissues and was associated with unfavorable outcomes in patients with TNBC. Functional experiments demonstrated that SFXN1 promoted TNBC growth and metastasis in vitro and in vivo. Mechanistic studies revealed that SFXN1 promoted TNBC progression by inhibiting the autophagy receptor TOLLIP (toll interacting protein)-mediated autophagic degradation of CIP2A. The pro-tumorigenic effect of SFXN1 overexpression was partially prevented by lapatinib-mediated inhibition of the CIP2A/PP2A/p-AKT pathway. These findings may provide a new targeted therapy for patients with TNBC. [Display omitted] • SFXN1 is upregulated in TNBC and correlated with poor outcome. • SFXN1 regulated CIP2A at the protein levels and inhibits its TOLLIP-mediated autophagic degradation. • SFXN1 promotes tumor progression through the CIP2A/PP2A/p-AKT pathway and sensitivity to lapatinib in vitro and in vivo. [ABSTRACT FROM AUTHOR]

• The immunomodulatory subtype of triple negative breast cancer（TNBC） exhibits promising effectiveness in immunotherapy. • CRTAM induces STAT1 phosphorylation and upregulation of interferon-stimulated genes. • CRTAM enhances the infiltration of immune cells, particularly CD8+ T cells. • CRTAM may serve as a potential biomarker for predicting the efficacy of immunotherapy in TNBC. The immunomodulatory (IM) subtype of triple negative breast cancer (TNBC) exhibits high expression of immune cell signaling genes and is more responsive to immunotherapy. However, the specific mechanism underlying this phenomenon remains unclear. One of the potential key genes appears to be the cytotoxic and regulatory T cell molecule (CRTAM). A cohort of 360 previously untreated TNBC patients from Fudan University Shanghai Cancer Center (FUSCC) underwent RNA sequencing analysis of their primary tumor tissue. Combined with three RNA-seq datasets obtained from the GEO database, a LASSO regression analysis was conducted to identify genes specific to the IM type of TNBC. Our findings revealed elevated CRTAM expression in the IM-type TNBC, which correlated with a favorable overall survival and recurrence-free survival in TNBC patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated a strong association between CRTAM and immune responses as well as immune system processes. Notably, CRTAM overexpression induced STAT1 phosphorylation and upregulation of interferon-stimulated genes. We also found that CRTAM enhanced tumor-associated immune cell infiltration, especially CD8+ T cells, which may be related to the increased expression of MHC class I molecules caused by CRTAM overexpression. These results suggest that CRTAM may serve as a potential biomarker for predicting the efficacy of immunotherapy in TNBC. [ABSTRACT FROM AUTHOR]

Summary Triple-negative breast cancer (TNBC) patients have the worst prognosis and distant metastasis-free survival among all major subtypes of breast cancer. The poor clinical outlook is further exacerbated by a lack of effective targeted therapies for TNBC. Here we show that ectopic expression and therapeutic delivery of the secreted protein Tubulointerstitial nephritis antigen-like 1 (Tinagl1) suppresses TNBC progression and metastasis through direct binding to integrin α5β1, αvβ1, and epidermal growth factor receptor (EGFR), and subsequent simultaneous inhibition of focal adhesion kinase (FAK) and EGFR signaling pathways. Moreover, Tinagl1 protein level is associated with good prognosis and reversely correlates with FAK and EGFR activation status in TNBC. Our results suggest Tinagl1 as a candidate therapeutic agent for TNBC by dual inhibition of integrin/FAK and EGFR signaling pathways. Graphical Abstract Highlights • Endogenous and recombinant Tinagl1 suppress growth and metastasis of breast cancer • Tinagl1 inhibits EGFR and integrin/FAK activation through distinct mechanisms • Tinagl1 level negatively correlates with EGFR and FAK activation in TNBC • Tinagl1 is a good prognosis marker and candidate therapeutic agent for TNBC Shen et al. show that Tinagl1 suppresses triple-negative breast cancer (TNBC) by inhibiting FAK and EGFR signaling pathways simultaneously via binding to integrin α5β1, αvβ1, and EGFR. The Tinagl1 protein level is associated with good prognosis and inversely correlates with FAK and EGFR activation status in TNBC. [ABSTRACT FROM AUTHOR]